NOAEL Studies Cosmetic Ingredient

Cannabidiol (CBD) NOAEL Studies

INCI: CANNABIDIOL

CAS: 13956-29-1

Raw No Observed Adverse Effect Level endpoint records grouped by source. This page does not render calculated Margin of Safety values.

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FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z 40 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =550 mg/kg bw/day mouse (CD-1; female) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =400 mg/kg bw/day mouse (CD-1; male) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =80 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =550 mg/kg bw/day mouse (CD-1; female) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =400 mg/kg bw/day mouse (CD-1; male) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =80 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =550 mg/kg bw/day mouse (CD-1; female) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =400 mg/kg bw/day mouse (CD-1; male) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =80 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =550 mg/kg bw/day mouse (CD-1; female) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =400 mg/kg bw/day mouse (CD-1; male) oral: gavage 13 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 13 week oral (gavage) administration range-finding study in the mouse_GWTX1688 - bf4737f5-7bab-4c82-94f5-f69f2d9f7f64/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOAEL =80 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: other:
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=250 mg/kg bw/day rat (Wistar; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rat _GWTX1454 - c965856d-5747-418e-ad00-2423f3f9fed2/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=50 mg/kg bw/day rat (Wistar; male/female) oral: feed 104 weeks carcinogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - Carcinogenicity - 104 week oral (dietary) carcinogenicity study in the rat_JJG0003 - c1691e8d-6f9b-41b5-9f59-6dd5b91a97bf/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: histopathology: neoplastic
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=125 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: clinical signs: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=150 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_8302923 - f4ad860a-ebd3-4cba-a882-0d48600c9f11/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=100 mg/kg bw/day dog (Beagle; male/female) oral: gavage 39 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 39 week oral (gavage) administration toxicity study in the dog followed by a 4 week treatment-free period_8302924 - 253eeaba-db83-4169-b9fb-15f7e39437ac/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: ophthalmological examination: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=80 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_GWTX1429 - b9aa1847-fa1f-4712-95b5-15296d69f7d5/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: haematology: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=25 mg/kg bw/day rat (Sprague-Dawley; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) developmental toxicity study in the rat_JJG0015 - 72237633-ef52-4b6c-8447-f10dfc5b54e8/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=250 mg/kg bw/day rat (Wistar; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rat _GWTX1454 - c965856d-5747-418e-ad00-2423f3f9fed2/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=50 mg/kg bw/day rat (Wistar; male/female) oral: feed 104 weeks carcinogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - Carcinogenicity - 104 week oral (dietary) carcinogenicity study in the rat_JJG0003 - c1691e8d-6f9b-41b5-9f59-6dd5b91a97bf/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: histopathology: neoplastic
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=125 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: clinical signs: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=150 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_8302923 - f4ad860a-ebd3-4cba-a882-0d48600c9f11/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=100 mg/kg bw/day dog (Beagle; male/female) oral: gavage 39 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 39 week oral (gavage) administration toxicity study in the dog followed by a 4 week treatment-free period_8302924 - 253eeaba-db83-4169-b9fb-15f7e39437ac/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: ophthalmological examination: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=80 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_GWTX1429 - b9aa1847-fa1f-4712-95b5-15296d69f7d5/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: haematology: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=25 mg/kg bw/day rat (Sprague-Dawley; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) developmental toxicity study in the rat_JJG0015 - 72237633-ef52-4b6c-8447-f10dfc5b54e8/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=250 mg/kg bw/day rat (Wistar; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rat _GWTX1454 - c965856d-5747-418e-ad00-2423f3f9fed2/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=50 mg/kg bw/day rat (Wistar; male/female) oral: feed 104 weeks carcinogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - Carcinogenicity - 104 week oral (dietary) carcinogenicity study in the rat_JJG0003 - c1691e8d-6f9b-41b5-9f59-6dd5b91a97bf/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: histopathology: neoplastic
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=125 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: clinical signs: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=150 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_8302923 - f4ad860a-ebd3-4cba-a882-0d48600c9f11/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=100 mg/kg bw/day dog (Beagle; male/female) oral: gavage 39 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 39 week oral (gavage) administration toxicity study in the dog followed by a 4 week treatment-free period_8302924 - 253eeaba-db83-4169-b9fb-15f7e39437ac/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: ophthalmological examination: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=80 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_GWTX1429 - b9aa1847-fa1f-4712-95b5-15296d69f7d5/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: haematology: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=25 mg/kg bw/day rat (Sprague-Dawley; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) developmental toxicity study in the rat_JJG0015 - 72237633-ef52-4b6c-8447-f10dfc5b54e8/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=250 mg/kg bw/day rat (Wistar; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rat _GWTX1454 - c965856d-5747-418e-ad00-2423f3f9fed2/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=50 mg/kg bw/day rat (Wistar; male/female) oral: feed 104 weeks carcinogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - Carcinogenicity - 104 week oral (dietary) carcinogenicity study in the rat_JJG0003 - c1691e8d-6f9b-41b5-9f59-6dd5b91a97bf/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: histopathology: neoplastic
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=125 mg/kg bw/day rabbit (New Zealand White; male/female) oral: gavage GD7-19 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) study of embryo-foetal development in the rabbit _GWTX1452 - af8cb309-1b41-4ca4-ae99-a5077a564320/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: clinical signs: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=150 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_8302923 - f4ad860a-ebd3-4cba-a882-0d48600c9f11/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=100 mg/kg bw/day dog (Beagle; male/female) oral: gavage 39 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 39 week oral (gavage) administration toxicity study in the dog followed by a 4 week treatment-free period_8302924 - 253eeaba-db83-4169-b9fb-15f7e39437ac/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: ophthalmological examination: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=80 mg/kg bw/day rat (Wistar; male/female) oral: gavage 26 weeks repeated dose toxicity oral 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - RepeatedDoseToxicityOral - 26 week oral (gavage) administration toxicity study in the rat followed by a 4 week treatment-free period_GWTX1429 - b9aa1847-fa1f-4712-95b5-15296d69f7d5/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: haematology: no abnormal phenotype detected
FDA_Toxicity_33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z NOEL <=25 mg/kg bw/day rat (Sprague-Dawley; male/female) oral: gavage GD 6-17 developmental toxicity teratogenicity 33a0e61f-e087-4928-acb3-56a237369802_dossier.i6z - DevelopmentalToxicityTeratogenicity - Oral (gavage) developmental toxicity study in the rat_JJG0015 - 72237633-ef52-4b6c-8447-f10dfc5b54e8/3b986f49-e1e3-4118-8562-cb839a2e1dd2 - basis: mortality: no abnormal phenotype detected
SCCS_vision_codex 152 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
SCCS_vision_codex NOAEL =143 mg/kg/day rat oral 14 days NOAEL study {"dose":"Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control.","effect":"ed the vehicle only (corn oil) under the same conditions. Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control. There were no statistically significant differences in 22 haematology or serum chemistry parameters when compared to the control group. Therefore, 23 143 mg/kg/day was established as the NOAEL. 24 25 From Respondent 2 26 The aim of this study was to assess the possible health hazards which could arise from repeated 27 exposure of Full Spectrum Extract (REGULAR) via oral administration to rats over a period of 28 28 days. 29 The Full Spectrum Extract (REGULAR) is the test item with an intend use for novel food, this 30 Hemp Fullspectrum Extract (Regular) contained 8.84% of CBD. 31 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route in 32 graduated doses to 5 groups of tes","page":29,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_001"}
SCCS_vision_codex NOAEL =300 mg/kg/day mouse - 13-Week NOAEL study {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550,","dose":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively).","effect":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively). 23 Microscopic centrilobular hepatocyte hypertrophy in all animals given 300 mg/kg/day and in 24 some animals given 100 or 150 mg/kg/day was associated with increased liver weight in all 25 groups and macroscopic enlargement at ≥ 150 mg/kg/day. In conclusion, the no observed 26 adverse effect level (NOAEL) was 300 mg/kg/day CBD-OS, corresponding to the respective Week 27 13 maximum measured plasma concentration (Cmax) and area under the concentration-time 28 curve calculated to the last observable concentration at time t (AUC(0-t)) values of 9810 ng/mL 29 and 44300 ng h/mL in males and 5770 ng/mL and 46400 ng∙h/mL in females. 30 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550, or","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_002"}
SCCS_vision_codex NOAEL =400 mg/kg/day rat oral 90-Day NOAEL study {"dose":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion.","effect":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion. None of these adverse findings were observed at the 400 mg/kg/day dose level in 44 males or females. Based on the clinical observations, early deaths, and nephropathy noted at 45 500 mg/kg/day and 700/625 mg/kg/day males and 700/625 mg/kg/day females, the NOAEL 46 was 400 mg/kg/day for males (Cmax and AUC values of 6420 ng/mL and 37800 ng.h/mL) 47 and 550 mg/kg/day for females (Cmax and AUC values of 8440 ng/mL and 41200 ng.h/mL). 48 Respondent 1 provided a non-published study described below: 49 90-Day GLP Toxicity Study in Wistar Rats 50 The objective of this study was to determine the potential toxicity of CBD (dissolved in corn oil), 51 when orally administered via gavage for 90 days to Wistar rats. 52 Administration of CBD (dissolved in corn oil) to rats for at leas","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_003"}
SCCS_vision_codex NOAEL =25 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days.","effect":"9 phytocannabinoid content is 6.96% (of this, 6.27% is CBD); the remaining 4.34% consists of 20 fatty alkanes, sterols, terpenes and tocopherols. In the 90-day study, rats in Groups 5 to 8 had 21 a 28-day recovery period before being sacrificed. In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days. The recovery period was 30 and 31 days for the 24 female and male rats, respectively. The NOAEL in the 90-day study was concluded to be 800 25 mg/kg bw/day and 400 mg/kg bw/day for female and male Sprague Dawley rats, respectively 26 (Dziwenka et al., 2020). 27 On the basis of this 90-day repeated dose oral toxicity study with Natural CBD Isolate (purity = 28 99.94%), suspended in corn oil, in male and female Wistar rats with dose levels of 25, 50, 75 29 and 150 mg/kg body weight/ day the following conclusions can be made: no test item-related 30 mortalities and no toxicologically relevant findings concernin","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_004"}
SCCS_vision_codex NOAEL =50 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"37 No toxicologically relevant effects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturati","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_005"}
SCCS_vision_codex NOAEL =44 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"ects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturation and","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_006"}
SCCS_vision_codex NOAEL =1000 mg/kg bw/day rat oral 14-day NOAEL study {"dose":"The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw.","effect":"ed in the vehicle 3 (sunflower oil) just prior to administration. The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw. These doses were 5 based on the 14-day study lowest observed adverse effect level (LOAEL) of 1000 mg/kg bw/day 6 (the lowest dose group tested) with the aim of inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018).","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_008"}
SCCS_vision_codex NOAEL =360 mg/kg bw/day rat oral 90 days NOAEL study {"dose":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group.","effect":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018). 14 15 Respondent 2 provided a non-published study described below: 16 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route daily in 17 graduated doses to 4 groups of test animals, one dose level per group for a treatment period of 18 90 days. Animals of an additional control group were handled identically as the dose","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_009"}
SCCS_vision_codex NOAEL =9 mg/kg bw/day rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"/day. 4 The histopathological examination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory batte","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_010"}
SCCS_vision_codex NOAEL =250 mg/kg rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"ination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory battery 19 p","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_011"}
SCCS_vision_codex NOAEL =238 mg/kg rat oral 28- day NOAEL study {"dose":"However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment.","effect":"parameters, clinical pathology parameters and gross pathology in both sexes. However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment. Based on the 23 observed results under the experimental conditions employed in the study, it is concluded that 24 the No Observable Adverse Effect Level (NOAEL) is equal to or greater than 238 mg/kg 25 bw/day. 26 27 In the second one, rats were treated by gavage with 25, 50 and 200 mg/kg bw/day in corn oil 28 as vehicle. Treatment related findings were observed in clinical chemistry, liver weight and 29 histopathology of the adrenal and liver. In the main group animals, after 90 days of treatment, 30 a significant increase in liver weight was observed in G3 (50 mg/kg b.w./d dose group) and G4 31 (200 mg/kg b.w./d dose group) male and female animals accompanied by minima","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_012"}
SCCS_vision_codex NOAEL =99 % rat oral 28 days NOAEL study {"dose":"Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditi...","effect":"). Total cholesterol, total bilirubin and low-density lipoprotein levels of G6 females also 40 showed recovery and values were comparable to G5 female. There was no incidence of 41 cytoplasmic vacuolation in the liver and adrenal cells of G6 female animals. However, in G6 male 42 animals, decreased incidence and severity of cytoplasmic vacuolation of hepatocytes (4/5) and 43 cortical cells of adrenal (3/5) was observed without any inflammatory changes and biochemical 44 alterations. Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditions 48 tested. 49 50","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_013"}
SCCS_vision_codex NOAEL =150 mg/kg/day rat oral Chronic NOAEL study {"dose":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobul...","effect":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobular hypertrophy in the liver of animals given ≥ 50 mg/kg/day, the main 8 finding in this study, was associated with increased liver weight, macroscopic enlargement. A 9 NOAEL (150 mg/kg/day) was associated with an increase in ALP and ALT activities. Thyroid 10 follicular hypertrophy in both sexes, correlated with increased thyroid weights and macroscopic 11 enlargement in males, was considered an indirect effect of treatment due to its recognized 12 relationship with liver hypertrophy. Microscopically these were specified by liver centrilobular 13 hypertrophy and thyroid follicular cell hypertrophy in both sexes along with increased 14 adrenocortical vacuolation in males and minor ovar","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_015"}
SCCS_vision_codex NOAEL =100 mg/kg/day rat oral - NOAEL study {"dose":"There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances.","effect":"7 doses. There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances. Drug-related liver changes characterised by hepatocyte 29 hypertrophy associated with increased liver weight, macroscopic enlargement, and marked 30 increases in ALP (up to 8-fold compared to controls) were seen at all doses. These were 31 considered adaptive and demonstrated a tendency for reversal at the end of the recovery period. 32 No other toxicological effects were observed. The NOAEL (100 mg/kg/day) was associated 33 with CBD exposures (AUC) of 20500 ng.h/mL in males and 22,400 ng.h/mL in females 34 35 36 SCCS comment 37 Extensive toxicology data and literature were provided from studies in mice, rats, rabbits, dogs, 38 monkeys (including juvenile rats and juvenile dogs) with oral CBD (EMA, Respondents 1 to 3). 39 In this Opinion, only a factual description of study results with a brief discussion of toxicity 40 findings has been provided. Most of the studies found that the liver was one of","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_016"}
SCCS_vision_codex NOAEL =47 mg/kg bw/d rat oral 13-week NOAEL study {"dose":"46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat.","effect":"s been provided. Most of the studies found that the liver was one of the target organs: 41 -In mice, the target organs of toxicity in the 13-week study were the liver and the kidneys. 42 -In rats, the target organs for toxicities were liver, thyroid, and adrenals, presented by 43 change in organ weight. 44 -In dogs, the target organ for toxicity was liver, with hepatocyte hypertrophy, macroscopic 45 enlargement and increased liver weight. 46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat. 48 49","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_017"}
SCCS_vision_codex NOAEL =19 mg/kg/day rat - - reproductive toxicity {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","dose":"During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day.","effect":"eaths and no adverse clinical or post-dosing observations. During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day. There were no treatment-related necropsy observations in either sex 17 and no test article-related effects on male or female reproductive indices, male reproductive 18 organ weights, female estrus cycling, or any caesarean-section parameters at doses up to 250 19 mg/kg/day Purified CBD, which was determined to be the NOAEL. Evaluation of CBD effects on 20 male and female reproductive performance is considered adequate, and it is agreed that no 21 significant negative effects were observed in rat. A Safety margin of 60-fold was calculated for 22 inclusion in the SmPC section 5.3 based on exposure measurements from the rat embryofetal 23 study (GWTX1454) at 250 mg/kg/day dose level on Day GD17. Adjusted human AUC(0-24h) 24 2790 ng.h/ml was used for calculation. 25 26 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","page":35,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_018"}
SCCS_vision_codex NOAEL =250 mg/kg/day rat oral - NOAEL study {"dose":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose.","effect":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose. 7 In an oral (gavage) Wistar rat embryofoetal development (EFD) study of purified CBD 8 (Epidyolex® at 0, 75, 150, or 250 mg/kg/day), the dose of 250 mg/kg/day was associated with 9 decreased body weight gain and total litter loss in 2 of 20 dams. The NOAEL for maternal toxicity 10 was amended to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 11 250 mg/kg/day. The NOAEL of 150 mg/kg/day equates to an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with eviden","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_020"}
SCCS_vision_codex NOAEL =80 mg/kg/day rat oral developmental developmental toxicity {"dose":"an estimated human equivalent dose 12 of 24.2 mg/kg/day.","effect":"an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with evidence of maternal toxicity. The NOAEL for embryofoetal 18 developmental toxicity (80 mg/kg/day) was associated with a maternal exposure of 2,030 19 ng∙h/mL (i.e., much lower exposures than in rats). This exposure in rabbits is approximately 1.2 20 times the AUC expected for a human dose of 1500 mg/day using the exposure in humans 21 observed for a dose of 1500 mg/day (AUC0-inf of 1,618 ng.h/mL). Using allometric scaling the 22 NOAEL of 80 mg/kg/day equates to an estimated human equivalent dose of 25.8 mg/kg/day.66 23 This value is 1.3 times higher tha","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_021"}
SCCS_vision_codex NOAEL =13 mg/kg/day rat - Developmental developmental toxicity {"dose":"This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit.","effect":"sistent across studies, and do not provide 2 a basis for deriving a point of departure (POD) for human health risk assessment. 3 4 5 3.4.5.2 Developmental Toxicity 6 7 From EMA 8 9 Embryo-foetal development was evaluated in rat and rabbit. Rabbit seemed to be more sensitive 10 to effects of CBD compared to rat. This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit. Embryo-foetal development in rat was insensitive to 12 high CBD exposure (Cmax up to 12800 ng/ml). The NOAEL for maternal toxicity was amended 13 to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 250 mg/kg/day. 14 NOAEL for effects on embryo-foetal development in rabbit was 80 mg/kg/day. Foetal variations 15 observed at 125 mg/kg/day CBD (e.g., unossified metacarpal, bulging eyes, and nonerupted 16 incisors) were considered to be secondary to the reduced foetal weights. Maternal exposure at 17 80 mg/kg/day Purified CBD corresponded to GD 19 Cmax and AUC(0-t) values of 220 ng/mL 18 and 2030 ng∙h/","page":37,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_023"}
SCCS_vision_codex NOAEL >97 % - oral 2 months NOAEL study {"dose":"Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment.","effect":"to the risk 11 of hepatocellular damage associated with cannabidiol. Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment. 14 15 3.4.10 Special investigations 16 17 / 18 19 20 3.4 SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_026"}
SCCS_vision_codex NOAEL =6 % - oral 90- day NOAEL study {"dose":"ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses.","effect":"SCCS-rejected applicant NOAEL: ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED 32 33 MOS assessment for Hand oil 6% CBD in MCT oil -limited body areas (% SED) 34 35 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.196= 714.29 230 Tallon and Child 2023 230/0.196 = 1173.47 72 Applicant study 72/0.196 = 367.35 36 Applicant study 36/ 0.196 =183.67 120 Averaged out 120/0.196= 612.25 36 37","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_027"}
SCCS_vision_codex NOAEL =1.3 % rat - 90-day NOAEL study {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS c...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.108= 1296.30 230 Tallon and Child 2023 230/0.108= 2129.63 72 Applicant study 72/0.108= 666.67 36 Applicant study 36/ 0.108= 333.33 120 Averaged out 120/0.108= 1111.11 4 From Respondent 2 5 6 In a 90-day study commissioned by the sponsor in order to gain data for an EFSA submission, 7 male and female rats were dosed orally with Natural CBD Isolate, vehicled in corn oil. The 8 established NOAEL was 25 mg/kg bw/day for both sexes. 9 10 Therefore,","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_030"}
SCCS_vision_codex NOAEL =24.75 mg/kg rat oral 90-day dermal absorption {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated ora...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated oral 3 rat toxicity study conducted on raw material OPTIMA CBD XB, the maximum recommended 4 concentrations are as follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_032"}
SCCS_vision_codex NOAEL =197.54 mg/kg rat oral 90-day dermal absorption {"dose":"5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7...","effect":"follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7 0.76 0.76 Deodorant non-spray 22.08 1* 1* Lipstick 0.9 24.75 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 0.76 0.77 7 Taking into account the NOAEL of 197.54 mg/kg b.w./d for CBD from the 90-day repeated oral 8 rat toxicity study conducted on raw material OPTIMA BROAD EXTRACT XB, the maximum 9 concentrations are as follows: 10 11 Product Relative daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face crea","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_034"}
SCCS_vision_codex NOAEL =25 mg/kg rat oral 90-day dermal absorption {"dose":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodo...","effect":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodorant non-spray 22.08 1* 1* Lipstick 0.9 197.54 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 1* 1* 12 13 SCCS comment 14 The SCCS has considered an Oral NOAEL of 25 mg/kg b.w./day from the 90-day repeated oral 15 rat toxicity studies. This corresponds to a systemic PoD for CBD of 6.25 mg/kg b.w./day, 16 considering an oral bioavailability of 25%. 17 18 The maximum CBD concentrations for dermal and oral products were determined as follows: 19","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_036"}
SCCS_vision_codex NOAEL =1 % - oral - NOAEL study {"dose":"3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869...","effect":"_________________________________________________________________________________________ ___________________________________________________________________________________________ 45 If the MoS is greater than 100 for aggregate (dermal and oral) with a concentration of 0.19 1 % of CBD in the cosmetic product, then the maximum concentration for each product taken 2 individually is also considered safe. 3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869 21785 Hand wash soap Hand wash soap 10 3.33 0.0006327 9878 Leave on skin and hair products Body lotion 10 123.2 0.023408 267 Face cream 10 24.14 0.0045866 1363 Hand cream 10 32.7 0.006213 1006 Deodorant non-spray 10 22.08 0.0041952 1490 Hair styling 10 5.74 0.0010906 5731 Face make-u","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_037"}
SCCS_vision_codex NOAEL =0.19 % human oral - NOAEL study {"dose":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe.","effect":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe. 11 12 Delta 9THC evaluation 13 14 THC is not intended to be added intentionally in cosmetic products, but it could be present in 15 CBD derived from extract as impurity. 16 17 EFSA (CONTAM Panel2015) established an ARfD of 1 µg/kg bw/day via oral route, derived from 18 a human LOAEL of 2.5 mg/day, adjusted for a person with a weight of 70 kg and divided for an 19 UF of 30 (3 for extrapolation from the LOAEL to a NOAEL and 10 for interindividual differences). 20 21","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_040"}
SCCS_vision_codex NOAEL =41 - - - - NOAEL study {"effect":"Unlabeled table on page 41: NOAEL | Reference | MOS calculation","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_044"}
SCCS_vision_codex NOAEL =140 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 140 | Henderson et al 2023 | 140/0.196= 714.29","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_045"}
SCCS_vision_codex NOAEL =230 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 230 | Tallon and Child 2023 | 230/0.196 = 1173.47","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_046"}
SCCS_vision_codex NOAEL =72 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 72 | Applicant study | 72/0.196 = 367.35","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_047"}
SCCS_vision_codex NOAEL =36 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 36 | Applicant study | 36/ 0.196 =183.67","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_048"}
SCCS_vision_codex NOAEL =120 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 120 | Averaged out | 120/0.196= 612.25","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_049"}
SCCS_vision_codex NOAEL =42 - - - - NOAEL study {"effect":"Unlabeled table on page 42: NOAEL | Reference | MOS calculation","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_050"}
SCCS_vision_codex NOAEL =44 - - oral - dermal absorption {"dose":"Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","effect":"Unlabeled table on page 44: Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_056"}
SCCS_vision_codex NOAEL =24.75 - - - - NOAEL study {"effect":"Unlabeled table on page 44: Shower gel | 2.79 | 24.75 | 12.38 | 50 | 1* | 1*","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_057"}
SCCS_vision_codex NOAEL =45 - - oral - NOAEL study {"effect":"Unlabeled table on page 45: Product families | Product categories | Dermal or oral absorption | Eproduct normalize d | Dermal and oral SED | NOAEL syst | MOS | Max. conc","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_058"}
SCCS_vision_codex NOAEL =6.25 - - - - NOAEL study {"effect":"Unlabeled table on page 45: Rinse-off skin & hair cleansing products (except hand wash) | Shower gel | 10 | 2.79 | 0.0005301 | 6.25 | 11790 | 0.19","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_059"}
SCCS_vision_codex NOAEL =143 mg/kg/day rat oral 14 days NOAEL study {"dose":"Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control.","effect":"ed the vehicle only (corn oil) under the same conditions. Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control. There were no statistically significant differences in 22 haematology or serum chemistry parameters when compared to the control group. Therefore, 23 143 mg/kg/day was established as the NOAEL. 24 25 From Respondent 2 26 The aim of this study was to assess the possible health hazards which could arise from repeated 27 exposure of Full Spectrum Extract (REGULAR) via oral administration to rats over a period of 28 28 days. 29 The Full Spectrum Extract (REGULAR) is the test item with an intend use for novel food, this 30 Hemp Fullspectrum Extract (Regular) contained 8.84% of CBD. 31 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route in 32 graduated doses to 5 groups of tes","page":29,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_001"}
SCCS_vision_codex NOAEL =300 mg/kg/day mouse - 13-Week NOAEL study {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550,","dose":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively).","effect":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively). 23 Microscopic centrilobular hepatocyte hypertrophy in all animals given 300 mg/kg/day and in 24 some animals given 100 or 150 mg/kg/day was associated with increased liver weight in all 25 groups and macroscopic enlargement at ≥ 150 mg/kg/day. In conclusion, the no observed 26 adverse effect level (NOAEL) was 300 mg/kg/day CBD-OS, corresponding to the respective Week 27 13 maximum measured plasma concentration (Cmax) and area under the concentration-time 28 curve calculated to the last observable concentration at time t (AUC(0-t)) values of 9810 ng/mL 29 and 44300 ng h/mL in males and 5770 ng/mL and 46400 ng∙h/mL in females. 30 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550, or","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_002"}
SCCS_vision_codex NOAEL =400 mg/kg/day rat oral 90-Day NOAEL study {"dose":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion.","effect":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion. None of these adverse findings were observed at the 400 mg/kg/day dose level in 44 males or females. Based on the clinical observations, early deaths, and nephropathy noted at 45 500 mg/kg/day and 700/625 mg/kg/day males and 700/625 mg/kg/day females, the NOAEL 46 was 400 mg/kg/day for males (Cmax and AUC values of 6420 ng/mL and 37800 ng.h/mL) 47 and 550 mg/kg/day for females (Cmax and AUC values of 8440 ng/mL and 41200 ng.h/mL). 48 Respondent 1 provided a non-published study described below: 49 90-Day GLP Toxicity Study in Wistar Rats 50 The objective of this study was to determine the potential toxicity of CBD (dissolved in corn oil), 51 when orally administered via gavage for 90 days to Wistar rats. 52 Administration of CBD (dissolved in corn oil) to rats for at leas","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_003"}
SCCS_vision_codex NOAEL =25 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days.","effect":"9 phytocannabinoid content is 6.96% (of this, 6.27% is CBD); the remaining 4.34% consists of 20 fatty alkanes, sterols, terpenes and tocopherols. In the 90-day study, rats in Groups 5 to 8 had 21 a 28-day recovery period before being sacrificed. In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days. The recovery period was 30 and 31 days for the 24 female and male rats, respectively. The NOAEL in the 90-day study was concluded to be 800 25 mg/kg bw/day and 400 mg/kg bw/day for female and male Sprague Dawley rats, respectively 26 (Dziwenka et al., 2020). 27 On the basis of this 90-day repeated dose oral toxicity study with Natural CBD Isolate (purity = 28 99.94%), suspended in corn oil, in male and female Wistar rats with dose levels of 25, 50, 75 29 and 150 mg/kg body weight/ day the following conclusions can be made: no test item-related 30 mortalities and no toxicologically relevant findings concernin","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_004"}
SCCS_vision_codex NOAEL =50 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"37 No toxicologically relevant effects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturati","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_005"}
SCCS_vision_codex NOAEL =44 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"ects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturation and","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_006"}
SCCS_vision_codex NOAEL =1000 mg/kg bw/day rat oral 14-day NOAEL study {"dose":"The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw.","effect":"ed in the vehicle 3 (sunflower oil) just prior to administration. The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw. These doses were 5 based on the 14-day study lowest observed adverse effect level (LOAEL) of 1000 mg/kg bw/day 6 (the lowest dose group tested) with the aim of inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018).","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_008"}
SCCS_vision_codex NOAEL =360 mg/kg bw/day rat oral 90 days NOAEL study {"dose":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group.","effect":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018). 14 15 Respondent 2 provided a non-published study described below: 16 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route daily in 17 graduated doses to 4 groups of test animals, one dose level per group for a treatment period of 18 90 days. Animals of an additional control group were handled identically as the dose","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_009"}
SCCS_vision_codex NOAEL =9 mg/kg bw/day rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"/day. 4 The histopathological examination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory batte","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_010"}
SCCS_vision_codex NOAEL =250 mg/kg rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"ination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory battery 19 p","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_011"}
SCCS_vision_codex NOAEL =238 mg/kg rat oral 28- day NOAEL study {"dose":"However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment.","effect":"parameters, clinical pathology parameters and gross pathology in both sexes. However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment. Based on the 23 observed results under the experimental conditions employed in the study, it is concluded that 24 the No Observable Adverse Effect Level (NOAEL) is equal to or greater than 238 mg/kg 25 bw/day. 26 27 In the second one, rats were treated by gavage with 25, 50 and 200 mg/kg bw/day in corn oil 28 as vehicle. Treatment related findings were observed in clinical chemistry, liver weight and 29 histopathology of the adrenal and liver. In the main group animals, after 90 days of treatment, 30 a significant increase in liver weight was observed in G3 (50 mg/kg b.w./d dose group) and G4 31 (200 mg/kg b.w./d dose group) male and female animals accompanied by minima","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_012"}
SCCS_vision_codex NOAEL =99 % rat oral 28 days NOAEL study {"dose":"Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditi...","effect":"). Total cholesterol, total bilirubin and low-density lipoprotein levels of G6 females also 40 showed recovery and values were comparable to G5 female. There was no incidence of 41 cytoplasmic vacuolation in the liver and adrenal cells of G6 female animals. However, in G6 male 42 animals, decreased incidence and severity of cytoplasmic vacuolation of hepatocytes (4/5) and 43 cortical cells of adrenal (3/5) was observed without any inflammatory changes and biochemical 44 alterations. Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditions 48 tested. 49 50","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_013"}
SCCS_vision_codex NOAEL =150 mg/kg/day rat oral Chronic NOAEL study {"dose":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobul...","effect":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobular hypertrophy in the liver of animals given ≥ 50 mg/kg/day, the main 8 finding in this study, was associated with increased liver weight, macroscopic enlargement. A 9 NOAEL (150 mg/kg/day) was associated with an increase in ALP and ALT activities. Thyroid 10 follicular hypertrophy in both sexes, correlated with increased thyroid weights and macroscopic 11 enlargement in males, was considered an indirect effect of treatment due to its recognized 12 relationship with liver hypertrophy. Microscopically these were specified by liver centrilobular 13 hypertrophy and thyroid follicular cell hypertrophy in both sexes along with increased 14 adrenocortical vacuolation in males and minor ovar","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_015"}
SCCS_vision_codex NOAEL =100 mg/kg/day rat oral - NOAEL study {"dose":"There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances.","effect":"7 doses. There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances. Drug-related liver changes characterised by hepatocyte 29 hypertrophy associated with increased liver weight, macroscopic enlargement, and marked 30 increases in ALP (up to 8-fold compared to controls) were seen at all doses. These were 31 considered adaptive and demonstrated a tendency for reversal at the end of the recovery period. 32 No other toxicological effects were observed. The NOAEL (100 mg/kg/day) was associated 33 with CBD exposures (AUC) of 20500 ng.h/mL in males and 22,400 ng.h/mL in females 34 35 36 SCCS comment 37 Extensive toxicology data and literature were provided from studies in mice, rats, rabbits, dogs, 38 monkeys (including juvenile rats and juvenile dogs) with oral CBD (EMA, Respondents 1 to 3). 39 In this Opinion, only a factual description of study results with a brief discussion of toxicity 40 findings has been provided. Most of the studies found that the liver was one of","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_016"}
SCCS_vision_codex NOAEL =47 mg/kg bw/d rat oral 13-week NOAEL study {"dose":"46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat.","effect":"s been provided. Most of the studies found that the liver was one of the target organs: 41 -In mice, the target organs of toxicity in the 13-week study were the liver and the kidneys. 42 -In rats, the target organs for toxicities were liver, thyroid, and adrenals, presented by 43 change in organ weight. 44 -In dogs, the target organ for toxicity was liver, with hepatocyte hypertrophy, macroscopic 45 enlargement and increased liver weight. 46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat. 48 49","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_017"}
SCCS_vision_codex NOAEL =19 mg/kg/day rat - - reproductive toxicity {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","dose":"During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day.","effect":"eaths and no adverse clinical or post-dosing observations. During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day. There were no treatment-related necropsy observations in either sex 17 and no test article-related effects on male or female reproductive indices, male reproductive 18 organ weights, female estrus cycling, or any caesarean-section parameters at doses up to 250 19 mg/kg/day Purified CBD, which was determined to be the NOAEL. Evaluation of CBD effects on 20 male and female reproductive performance is considered adequate, and it is agreed that no 21 significant negative effects were observed in rat. A Safety margin of 60-fold was calculated for 22 inclusion in the SmPC section 5.3 based on exposure measurements from the rat embryofetal 23 study (GWTX1454) at 250 mg/kg/day dose level on Day GD17. Adjusted human AUC(0-24h) 24 2790 ng.h/ml was used for calculation. 25 26 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","page":35,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_018"}
SCCS_vision_codex NOAEL =250 mg/kg/day rat oral - NOAEL study {"dose":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose.","effect":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose. 7 In an oral (gavage) Wistar rat embryofoetal development (EFD) study of purified CBD 8 (Epidyolex® at 0, 75, 150, or 250 mg/kg/day), the dose of 250 mg/kg/day was associated with 9 decreased body weight gain and total litter loss in 2 of 20 dams. The NOAEL for maternal toxicity 10 was amended to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 11 250 mg/kg/day. The NOAEL of 150 mg/kg/day equates to an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with eviden","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_020"}
SCCS_vision_codex NOAEL =80 mg/kg/day rat oral developmental developmental toxicity {"dose":"an estimated human equivalent dose 12 of 24.2 mg/kg/day.","effect":"an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with evidence of maternal toxicity. The NOAEL for embryofoetal 18 developmental toxicity (80 mg/kg/day) was associated with a maternal exposure of 2,030 19 ng∙h/mL (i.e., much lower exposures than in rats). This exposure in rabbits is approximately 1.2 20 times the AUC expected for a human dose of 1500 mg/day using the exposure in humans 21 observed for a dose of 1500 mg/day (AUC0-inf of 1,618 ng.h/mL). Using allometric scaling the 22 NOAEL of 80 mg/kg/day equates to an estimated human equivalent dose of 25.8 mg/kg/day.66 23 This value is 1.3 times higher tha","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_021"}
SCCS_vision_codex NOAEL =13 mg/kg/day rat - Developmental developmental toxicity {"dose":"This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit.","effect":"sistent across studies, and do not provide 2 a basis for deriving a point of departure (POD) for human health risk assessment. 3 4 5 3.4.5.2 Developmental Toxicity 6 7 From EMA 8 9 Embryo-foetal development was evaluated in rat and rabbit. Rabbit seemed to be more sensitive 10 to effects of CBD compared to rat. This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit. Embryo-foetal development in rat was insensitive to 12 high CBD exposure (Cmax up to 12800 ng/ml). The NOAEL for maternal toxicity was amended 13 to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 250 mg/kg/day. 14 NOAEL for effects on embryo-foetal development in rabbit was 80 mg/kg/day. Foetal variations 15 observed at 125 mg/kg/day CBD (e.g., unossified metacarpal, bulging eyes, and nonerupted 16 incisors) were considered to be secondary to the reduced foetal weights. Maternal exposure at 17 80 mg/kg/day Purified CBD corresponded to GD 19 Cmax and AUC(0-t) values of 220 ng/mL 18 and 2030 ng∙h/","page":37,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_023"}
SCCS_vision_codex NOAEL >97 % - oral 2 months NOAEL study {"dose":"Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment.","effect":"to the risk 11 of hepatocellular damage associated with cannabidiol. Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment. 14 15 3.4.10 Special investigations 16 17 / 18 19 20 3.4 SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_026"}
SCCS_vision_codex NOAEL =6 % - oral 90- day NOAEL study {"dose":"ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses.","effect":"SCCS-rejected applicant NOAEL: ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED 32 33 MOS assessment for Hand oil 6% CBD in MCT oil -limited body areas (% SED) 34 35 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.196= 714.29 230 Tallon and Child 2023 230/0.196 = 1173.47 72 Applicant study 72/0.196 = 367.35 36 Applicant study 36/ 0.196 =183.67 120 Averaged out 120/0.196= 612.25 36 37","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_027"}
SCCS_vision_codex NOAEL =1.3 % rat - 90-day NOAEL study {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS c...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.108= 1296.30 230 Tallon and Child 2023 230/0.108= 2129.63 72 Applicant study 72/0.108= 666.67 36 Applicant study 36/ 0.108= 333.33 120 Averaged out 120/0.108= 1111.11 4 From Respondent 2 5 6 In a 90-day study commissioned by the sponsor in order to gain data for an EFSA submission, 7 male and female rats were dosed orally with Natural CBD Isolate, vehicled in corn oil. The 8 established NOAEL was 25 mg/kg bw/day for both sexes. 9 10 Therefore,","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_030"}
SCCS_vision_codex NOAEL =24.75 mg/kg rat oral 90-day dermal absorption {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated ora...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated oral 3 rat toxicity study conducted on raw material OPTIMA CBD XB, the maximum recommended 4 concentrations are as follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_032"}
SCCS_vision_codex NOAEL =197.54 mg/kg rat oral 90-day dermal absorption {"dose":"5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7...","effect":"follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7 0.76 0.76 Deodorant non-spray 22.08 1* 1* Lipstick 0.9 24.75 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 0.76 0.77 7 Taking into account the NOAEL of 197.54 mg/kg b.w./d for CBD from the 90-day repeated oral 8 rat toxicity study conducted on raw material OPTIMA BROAD EXTRACT XB, the maximum 9 concentrations are as follows: 10 11 Product Relative daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face crea","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_034"}
SCCS_vision_codex NOAEL =25 mg/kg rat oral 90-day dermal absorption {"dose":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodo...","effect":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodorant non-spray 22.08 1* 1* Lipstick 0.9 197.54 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 1* 1* 12 13 SCCS comment 14 The SCCS has considered an Oral NOAEL of 25 mg/kg b.w./day from the 90-day repeated oral 15 rat toxicity studies. This corresponds to a systemic PoD for CBD of 6.25 mg/kg b.w./day, 16 considering an oral bioavailability of 25%. 17 18 The maximum CBD concentrations for dermal and oral products were determined as follows: 19","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_036"}
SCCS_vision_codex NOAEL =1 % - oral - NOAEL study {"dose":"3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869...","effect":"_________________________________________________________________________________________ ___________________________________________________________________________________________ 45 If the MoS is greater than 100 for aggregate (dermal and oral) with a concentration of 0.19 1 % of CBD in the cosmetic product, then the maximum concentration for each product taken 2 individually is also considered safe. 3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869 21785 Hand wash soap Hand wash soap 10 3.33 0.0006327 9878 Leave on skin and hair products Body lotion 10 123.2 0.023408 267 Face cream 10 24.14 0.0045866 1363 Hand cream 10 32.7 0.006213 1006 Deodorant non-spray 10 22.08 0.0041952 1490 Hair styling 10 5.74 0.0010906 5731 Face make-u","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_037"}
SCCS_vision_codex NOAEL =0.19 % human oral - NOAEL study {"dose":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe.","effect":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe. 11 12 Delta 9THC evaluation 13 14 THC is not intended to be added intentionally in cosmetic products, but it could be present in 15 CBD derived from extract as impurity. 16 17 EFSA (CONTAM Panel2015) established an ARfD of 1 µg/kg bw/day via oral route, derived from 18 a human LOAEL of 2.5 mg/day, adjusted for a person with a weight of 70 kg and divided for an 19 UF of 30 (3 for extrapolation from the LOAEL to a NOAEL and 10 for interindividual differences). 20 21","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_040"}
SCCS_vision_codex NOAEL =41 - - - - NOAEL study {"effect":"Unlabeled table on page 41: NOAEL | Reference | MOS calculation","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_044"}
SCCS_vision_codex NOAEL =140 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 140 | Henderson et al 2023 | 140/0.196= 714.29","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_045"}
SCCS_vision_codex NOAEL =230 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 230 | Tallon and Child 2023 | 230/0.196 = 1173.47","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_046"}
SCCS_vision_codex NOAEL =72 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 72 | Applicant study | 72/0.196 = 367.35","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_047"}
SCCS_vision_codex NOAEL =36 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 36 | Applicant study | 36/ 0.196 =183.67","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_048"}
SCCS_vision_codex NOAEL =120 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 120 | Averaged out | 120/0.196= 612.25","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_049"}
SCCS_vision_codex NOAEL =42 - - - - NOAEL study {"effect":"Unlabeled table on page 42: NOAEL | Reference | MOS calculation","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_050"}
SCCS_vision_codex NOAEL =44 - - oral - dermal absorption {"dose":"Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","effect":"Unlabeled table on page 44: Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_056"}
SCCS_vision_codex NOAEL =24.75 - - - - NOAEL study {"effect":"Unlabeled table on page 44: Shower gel | 2.79 | 24.75 | 12.38 | 50 | 1* | 1*","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_057"}
SCCS_vision_codex NOAEL =45 - - oral - NOAEL study {"effect":"Unlabeled table on page 45: Product families | Product categories | Dermal or oral absorption | Eproduct normalize d | Dermal and oral SED | NOAEL syst | MOS | Max. conc","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_058"}
SCCS_vision_codex NOAEL =6.25 - - - - NOAEL study {"effect":"Unlabeled table on page 45: Rinse-off skin & hair cleansing products (except hand wash) | Shower gel | 10 | 2.79 | 0.0005301 | 6.25 | 11790 | 0.19","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_059"}
SCCS_vision_codex NOAEL =143 mg/kg/day rat oral 14 days NOAEL study {"dose":"Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control.","effect":"ed the vehicle only (corn oil) under the same conditions. Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control. There were no statistically significant differences in 22 haematology or serum chemistry parameters when compared to the control group. Therefore, 23 143 mg/kg/day was established as the NOAEL. 24 25 From Respondent 2 26 The aim of this study was to assess the possible health hazards which could arise from repeated 27 exposure of Full Spectrum Extract (REGULAR) via oral administration to rats over a period of 28 28 days. 29 The Full Spectrum Extract (REGULAR) is the test item with an intend use for novel food, this 30 Hemp Fullspectrum Extract (Regular) contained 8.84% of CBD. 31 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route in 32 graduated doses to 5 groups of tes","page":29,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_001"}
SCCS_vision_codex NOAEL =300 mg/kg/day mouse - 13-Week NOAEL study {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550,","dose":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively).","effect":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively). 23 Microscopic centrilobular hepatocyte hypertrophy in all animals given 300 mg/kg/day and in 24 some animals given 100 or 150 mg/kg/day was associated with increased liver weight in all 25 groups and macroscopic enlargement at ≥ 150 mg/kg/day. In conclusion, the no observed 26 adverse effect level (NOAEL) was 300 mg/kg/day CBD-OS, corresponding to the respective Week 27 13 maximum measured plasma concentration (Cmax) and area under the concentration-time 28 curve calculated to the last observable concentration at time t (AUC(0-t)) values of 9810 ng/mL 29 and 44300 ng h/mL in males and 5770 ng/mL and 46400 ng∙h/mL in females. 30 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550, or","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_002"}
SCCS_vision_codex NOAEL =400 mg/kg/day rat oral 90-Day NOAEL study {"dose":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion.","effect":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion. None of these adverse findings were observed at the 400 mg/kg/day dose level in 44 males or females. Based on the clinical observations, early deaths, and nephropathy noted at 45 500 mg/kg/day and 700/625 mg/kg/day males and 700/625 mg/kg/day females, the NOAEL 46 was 400 mg/kg/day for males (Cmax and AUC values of 6420 ng/mL and 37800 ng.h/mL) 47 and 550 mg/kg/day for females (Cmax and AUC values of 8440 ng/mL and 41200 ng.h/mL). 48 Respondent 1 provided a non-published study described below: 49 90-Day GLP Toxicity Study in Wistar Rats 50 The objective of this study was to determine the potential toxicity of CBD (dissolved in corn oil), 51 when orally administered via gavage for 90 days to Wistar rats. 52 Administration of CBD (dissolved in corn oil) to rats for at leas","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_003"}
SCCS_vision_codex NOAEL =25 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days.","effect":"9 phytocannabinoid content is 6.96% (of this, 6.27% is CBD); the remaining 4.34% consists of 20 fatty alkanes, sterols, terpenes and tocopherols. In the 90-day study, rats in Groups 5 to 8 had 21 a 28-day recovery period before being sacrificed. In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days. The recovery period was 30 and 31 days for the 24 female and male rats, respectively. The NOAEL in the 90-day study was concluded to be 800 25 mg/kg bw/day and 400 mg/kg bw/day for female and male Sprague Dawley rats, respectively 26 (Dziwenka et al., 2020). 27 On the basis of this 90-day repeated dose oral toxicity study with Natural CBD Isolate (purity = 28 99.94%), suspended in corn oil, in male and female Wistar rats with dose levels of 25, 50, 75 29 and 150 mg/kg body weight/ day the following conclusions can be made: no test item-related 30 mortalities and no toxicologically relevant findings concernin","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_004"}
SCCS_vision_codex NOAEL =50 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"37 No toxicologically relevant effects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturati","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_005"}
SCCS_vision_codex NOAEL =44 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"ects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturation and","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_006"}
SCCS_vision_codex NOAEL =1000 mg/kg bw/day rat oral 14-day NOAEL study {"dose":"The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw.","effect":"ed in the vehicle 3 (sunflower oil) just prior to administration. The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw. These doses were 5 based on the 14-day study lowest observed adverse effect level (LOAEL) of 1000 mg/kg bw/day 6 (the lowest dose group tested) with the aim of inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018).","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_008"}
SCCS_vision_codex NOAEL =360 mg/kg bw/day rat oral 90 days NOAEL study {"dose":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group.","effect":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018). 14 15 Respondent 2 provided a non-published study described below: 16 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route daily in 17 graduated doses to 4 groups of test animals, one dose level per group for a treatment period of 18 90 days. Animals of an additional control group were handled identically as the dose","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_009"}
SCCS_vision_codex NOAEL =9 mg/kg bw/day rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"/day. 4 The histopathological examination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory batte","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_010"}
SCCS_vision_codex NOAEL =250 mg/kg rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"ination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory battery 19 p","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_011"}
SCCS_vision_codex NOAEL =238 mg/kg rat oral 28- day NOAEL study {"dose":"However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment.","effect":"parameters, clinical pathology parameters and gross pathology in both sexes. However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment. Based on the 23 observed results under the experimental conditions employed in the study, it is concluded that 24 the No Observable Adverse Effect Level (NOAEL) is equal to or greater than 238 mg/kg 25 bw/day. 26 27 In the second one, rats were treated by gavage with 25, 50 and 200 mg/kg bw/day in corn oil 28 as vehicle. Treatment related findings were observed in clinical chemistry, liver weight and 29 histopathology of the adrenal and liver. In the main group animals, after 90 days of treatment, 30 a significant increase in liver weight was observed in G3 (50 mg/kg b.w./d dose group) and G4 31 (200 mg/kg b.w./d dose group) male and female animals accompanied by minima","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_012"}
SCCS_vision_codex NOAEL =99 % rat oral 28 days NOAEL study {"dose":"Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditi...","effect":"). Total cholesterol, total bilirubin and low-density lipoprotein levels of G6 females also 40 showed recovery and values were comparable to G5 female. There was no incidence of 41 cytoplasmic vacuolation in the liver and adrenal cells of G6 female animals. However, in G6 male 42 animals, decreased incidence and severity of cytoplasmic vacuolation of hepatocytes (4/5) and 43 cortical cells of adrenal (3/5) was observed without any inflammatory changes and biochemical 44 alterations. Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditions 48 tested. 49 50","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_013"}
SCCS_vision_codex NOAEL =150 mg/kg/day rat oral Chronic NOAEL study {"dose":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobul...","effect":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobular hypertrophy in the liver of animals given ≥ 50 mg/kg/day, the main 8 finding in this study, was associated with increased liver weight, macroscopic enlargement. A 9 NOAEL (150 mg/kg/day) was associated with an increase in ALP and ALT activities. Thyroid 10 follicular hypertrophy in both sexes, correlated with increased thyroid weights and macroscopic 11 enlargement in males, was considered an indirect effect of treatment due to its recognized 12 relationship with liver hypertrophy. Microscopically these were specified by liver centrilobular 13 hypertrophy and thyroid follicular cell hypertrophy in both sexes along with increased 14 adrenocortical vacuolation in males and minor ovar","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_015"}
SCCS_vision_codex NOAEL =100 mg/kg/day rat oral - NOAEL study {"dose":"There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances.","effect":"7 doses. There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances. Drug-related liver changes characterised by hepatocyte 29 hypertrophy associated with increased liver weight, macroscopic enlargement, and marked 30 increases in ALP (up to 8-fold compared to controls) were seen at all doses. These were 31 considered adaptive and demonstrated a tendency for reversal at the end of the recovery period. 32 No other toxicological effects were observed. The NOAEL (100 mg/kg/day) was associated 33 with CBD exposures (AUC) of 20500 ng.h/mL in males and 22,400 ng.h/mL in females 34 35 36 SCCS comment 37 Extensive toxicology data and literature were provided from studies in mice, rats, rabbits, dogs, 38 monkeys (including juvenile rats and juvenile dogs) with oral CBD (EMA, Respondents 1 to 3). 39 In this Opinion, only a factual description of study results with a brief discussion of toxicity 40 findings has been provided. Most of the studies found that the liver was one of","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_016"}
SCCS_vision_codex NOAEL =47 mg/kg bw/d rat oral 13-week NOAEL study {"dose":"46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat.","effect":"s been provided. Most of the studies found that the liver was one of the target organs: 41 -In mice, the target organs of toxicity in the 13-week study were the liver and the kidneys. 42 -In rats, the target organs for toxicities were liver, thyroid, and adrenals, presented by 43 change in organ weight. 44 -In dogs, the target organ for toxicity was liver, with hepatocyte hypertrophy, macroscopic 45 enlargement and increased liver weight. 46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat. 48 49","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_017"}
SCCS_vision_codex NOAEL =19 mg/kg/day rat - - reproductive toxicity {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","dose":"During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day.","effect":"eaths and no adverse clinical or post-dosing observations. During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day. There were no treatment-related necropsy observations in either sex 17 and no test article-related effects on male or female reproductive indices, male reproductive 18 organ weights, female estrus cycling, or any caesarean-section parameters at doses up to 250 19 mg/kg/day Purified CBD, which was determined to be the NOAEL. Evaluation of CBD effects on 20 male and female reproductive performance is considered adequate, and it is agreed that no 21 significant negative effects were observed in rat. A Safety margin of 60-fold was calculated for 22 inclusion in the SmPC section 5.3 based on exposure measurements from the rat embryofetal 23 study (GWTX1454) at 250 mg/kg/day dose level on Day GD17. Adjusted human AUC(0-24h) 24 2790 ng.h/ml was used for calculation. 25 26 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","page":35,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_018"}
SCCS_vision_codex NOAEL =250 mg/kg/day rat oral - NOAEL study {"dose":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose.","effect":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose. 7 In an oral (gavage) Wistar rat embryofoetal development (EFD) study of purified CBD 8 (Epidyolex® at 0, 75, 150, or 250 mg/kg/day), the dose of 250 mg/kg/day was associated with 9 decreased body weight gain and total litter loss in 2 of 20 dams. The NOAEL for maternal toxicity 10 was amended to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 11 250 mg/kg/day. The NOAEL of 150 mg/kg/day equates to an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with eviden","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_020"}
SCCS_vision_codex NOAEL =80 mg/kg/day rat oral developmental developmental toxicity {"dose":"an estimated human equivalent dose 12 of 24.2 mg/kg/day.","effect":"an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with evidence of maternal toxicity. The NOAEL for embryofoetal 18 developmental toxicity (80 mg/kg/day) was associated with a maternal exposure of 2,030 19 ng∙h/mL (i.e., much lower exposures than in rats). This exposure in rabbits is approximately 1.2 20 times the AUC expected for a human dose of 1500 mg/day using the exposure in humans 21 observed for a dose of 1500 mg/day (AUC0-inf of 1,618 ng.h/mL). Using allometric scaling the 22 NOAEL of 80 mg/kg/day equates to an estimated human equivalent dose of 25.8 mg/kg/day.66 23 This value is 1.3 times higher tha","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_021"}
SCCS_vision_codex NOAEL =13 mg/kg/day rat - Developmental developmental toxicity {"dose":"This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit.","effect":"sistent across studies, and do not provide 2 a basis for deriving a point of departure (POD) for human health risk assessment. 3 4 5 3.4.5.2 Developmental Toxicity 6 7 From EMA 8 9 Embryo-foetal development was evaluated in rat and rabbit. Rabbit seemed to be more sensitive 10 to effects of CBD compared to rat. This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit. Embryo-foetal development in rat was insensitive to 12 high CBD exposure (Cmax up to 12800 ng/ml). The NOAEL for maternal toxicity was amended 13 to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 250 mg/kg/day. 14 NOAEL for effects on embryo-foetal development in rabbit was 80 mg/kg/day. Foetal variations 15 observed at 125 mg/kg/day CBD (e.g., unossified metacarpal, bulging eyes, and nonerupted 16 incisors) were considered to be secondary to the reduced foetal weights. Maternal exposure at 17 80 mg/kg/day Purified CBD corresponded to GD 19 Cmax and AUC(0-t) values of 220 ng/mL 18 and 2030 ng∙h/","page":37,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_023"}
SCCS_vision_codex NOAEL >97 % - oral 2 months NOAEL study {"dose":"Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment.","effect":"to the risk 11 of hepatocellular damage associated with cannabidiol. Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment. 14 15 3.4.10 Special investigations 16 17 / 18 19 20 3.4 SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_026"}
SCCS_vision_codex NOAEL =6 % - oral 90- day NOAEL study {"dose":"ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses.","effect":"SCCS-rejected applicant NOAEL: ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED 32 33 MOS assessment for Hand oil 6% CBD in MCT oil -limited body areas (% SED) 34 35 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.196= 714.29 230 Tallon and Child 2023 230/0.196 = 1173.47 72 Applicant study 72/0.196 = 367.35 36 Applicant study 36/ 0.196 =183.67 120 Averaged out 120/0.196= 612.25 36 37","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_027"}
SCCS_vision_codex NOAEL =1.3 % rat - 90-day NOAEL study {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS c...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.108= 1296.30 230 Tallon and Child 2023 230/0.108= 2129.63 72 Applicant study 72/0.108= 666.67 36 Applicant study 36/ 0.108= 333.33 120 Averaged out 120/0.108= 1111.11 4 From Respondent 2 5 6 In a 90-day study commissioned by the sponsor in order to gain data for an EFSA submission, 7 male and female rats were dosed orally with Natural CBD Isolate, vehicled in corn oil. The 8 established NOAEL was 25 mg/kg bw/day for both sexes. 9 10 Therefore,","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_030"}
SCCS_vision_codex NOAEL =24.75 mg/kg rat oral 90-day dermal absorption {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated ora...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated oral 3 rat toxicity study conducted on raw material OPTIMA CBD XB, the maximum recommended 4 concentrations are as follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_032"}
SCCS_vision_codex NOAEL =197.54 mg/kg rat oral 90-day dermal absorption {"dose":"5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7...","effect":"follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7 0.76 0.76 Deodorant non-spray 22.08 1* 1* Lipstick 0.9 24.75 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 0.76 0.77 7 Taking into account the NOAEL of 197.54 mg/kg b.w./d for CBD from the 90-day repeated oral 8 rat toxicity study conducted on raw material OPTIMA BROAD EXTRACT XB, the maximum 9 concentrations are as follows: 10 11 Product Relative daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face crea","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_034"}
SCCS_vision_codex NOAEL =25 mg/kg rat oral 90-day dermal absorption {"dose":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodo...","effect":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodorant non-spray 22.08 1* 1* Lipstick 0.9 197.54 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 1* 1* 12 13 SCCS comment 14 The SCCS has considered an Oral NOAEL of 25 mg/kg b.w./day from the 90-day repeated oral 15 rat toxicity studies. This corresponds to a systemic PoD for CBD of 6.25 mg/kg b.w./day, 16 considering an oral bioavailability of 25%. 17 18 The maximum CBD concentrations for dermal and oral products were determined as follows: 19","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_036"}
SCCS_vision_codex NOAEL =1 % - oral - NOAEL study {"dose":"3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869...","effect":"_________________________________________________________________________________________ ___________________________________________________________________________________________ 45 If the MoS is greater than 100 for aggregate (dermal and oral) with a concentration of 0.19 1 % of CBD in the cosmetic product, then the maximum concentration for each product taken 2 individually is also considered safe. 3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869 21785 Hand wash soap Hand wash soap 10 3.33 0.0006327 9878 Leave on skin and hair products Body lotion 10 123.2 0.023408 267 Face cream 10 24.14 0.0045866 1363 Hand cream 10 32.7 0.006213 1006 Deodorant non-spray 10 22.08 0.0041952 1490 Hair styling 10 5.74 0.0010906 5731 Face make-u","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_037"}
SCCS_vision_codex NOAEL =0.19 % human oral - NOAEL study {"dose":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe.","effect":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe. 11 12 Delta 9THC evaluation 13 14 THC is not intended to be added intentionally in cosmetic products, but it could be present in 15 CBD derived from extract as impurity. 16 17 EFSA (CONTAM Panel2015) established an ARfD of 1 µg/kg bw/day via oral route, derived from 18 a human LOAEL of 2.5 mg/day, adjusted for a person with a weight of 70 kg and divided for an 19 UF of 30 (3 for extrapolation from the LOAEL to a NOAEL and 10 for interindividual differences). 20 21","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_040"}
SCCS_vision_codex NOAEL =41 - - - - NOAEL study {"effect":"Unlabeled table on page 41: NOAEL | Reference | MOS calculation","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_044"}
SCCS_vision_codex NOAEL =140 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 140 | Henderson et al 2023 | 140/0.196= 714.29","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_045"}
SCCS_vision_codex NOAEL =230 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 230 | Tallon and Child 2023 | 230/0.196 = 1173.47","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_046"}
SCCS_vision_codex NOAEL =72 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 72 | Applicant study | 72/0.196 = 367.35","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_047"}
SCCS_vision_codex NOAEL =36 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 36 | Applicant study | 36/ 0.196 =183.67","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_048"}
SCCS_vision_codex NOAEL =120 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 120 | Averaged out | 120/0.196= 612.25","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_049"}
SCCS_vision_codex NOAEL =42 - - - - NOAEL study {"effect":"Unlabeled table on page 42: NOAEL | Reference | MOS calculation","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_050"}
SCCS_vision_codex NOAEL =44 - - oral - dermal absorption {"dose":"Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","effect":"Unlabeled table on page 44: Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_056"}
SCCS_vision_codex NOAEL =24.75 - - - - NOAEL study {"effect":"Unlabeled table on page 44: Shower gel | 2.79 | 24.75 | 12.38 | 50 | 1* | 1*","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_057"}
SCCS_vision_codex NOAEL =45 - - oral - NOAEL study {"effect":"Unlabeled table on page 45: Product families | Product categories | Dermal or oral absorption | Eproduct normalize d | Dermal and oral SED | NOAEL syst | MOS | Max. conc","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_058"}
SCCS_vision_codex NOAEL =6.25 - - - - NOAEL study {"effect":"Unlabeled table on page 45: Rinse-off skin & hair cleansing products (except hand wash) | Shower gel | 10 | 2.79 | 0.0005301 | 6.25 | 11790 | 0.19","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_059"}
SCCS_vision_codex NOAEL =143 mg/kg/day rat oral 14 days NOAEL study {"dose":"Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control.","effect":"ed the vehicle only (corn oil) under the same conditions. Administration of CBD once 19 daily by oral gavage for 14 days was well tolerated in rats at dose levels of up to 143 mg/kg/day, 20 with no biologically or statistically significant increase in the frequency or severity of any adverse 21 events comparted to vehicle control. There were no statistically significant differences in 22 haematology or serum chemistry parameters when compared to the control group. Therefore, 23 143 mg/kg/day was established as the NOAEL. 24 25 From Respondent 2 26 The aim of this study was to assess the possible health hazards which could arise from repeated 27 exposure of Full Spectrum Extract (REGULAR) via oral administration to rats over a period of 28 28 days. 29 The Full Spectrum Extract (REGULAR) is the test item with an intend use for novel food, this 30 Hemp Fullspectrum Extract (Regular) contained 8.84% of CBD. 31 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route in 32 graduated doses to 5 groups of tes","page":29,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_001"}
SCCS_vision_codex NOAEL =300 mg/kg/day mouse - 13-Week NOAEL study {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550,","dose":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively).","effect":"were higher than controls during Week 7 21 and 13 in males given ≥ 150 mg/kg/day (by approximately 65% and 40%, respectively) and 22 during Week 7 for females given 150 or 300 mg/kg/day (by 259% or 83%, respectively). 23 Microscopic centrilobular hepatocyte hypertrophy in all animals given 300 mg/kg/day and in 24 some animals given 100 or 150 mg/kg/day was associated with increased liver weight in all 25 groups and macroscopic enlargement at ≥ 150 mg/kg/day. In conclusion, the no observed 26 adverse effect level (NOAEL) was 300 mg/kg/day CBD-OS, corresponding to the respective Week 27 13 maximum measured plasma concentration (Cmax) and area under the concentration-time 28 curve calculated to the last observable concentration at time t (AUC(0-t)) values of 9810 ng/mL 29 and 44300 ng h/mL in males and 5770 ng/mL and 46400 ng∙h/mL in females. 30 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use (CHMP) 31 32 From Respondent 1 33 13-Week Dose Range Finding Study in Mouse 34 In a 13-week mouse study (0, 400, 550, or","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_002"}
SCCS_vision_codex NOAEL =400 mg/kg/day rat oral 90-Day NOAEL study {"dose":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion.","effect":"ed increase in the incidence and/or severity of nephropathy 41 was observed microscopically in drug groups and was considered adverse at 550 mg/kg/day and 42 700/625 mg/kg/day males and in 700/625 mg/kg/day females due to the severity and extent of 43 the lesion. None of these adverse findings were observed at the 400 mg/kg/day dose level in 44 males or females. Based on the clinical observations, early deaths, and nephropathy noted at 45 500 mg/kg/day and 700/625 mg/kg/day males and 700/625 mg/kg/day females, the NOAEL 46 was 400 mg/kg/day for males (Cmax and AUC values of 6420 ng/mL and 37800 ng.h/mL) 47 and 550 mg/kg/day for females (Cmax and AUC values of 8440 ng/mL and 41200 ng.h/mL). 48 Respondent 1 provided a non-published study described below: 49 90-Day GLP Toxicity Study in Wistar Rats 50 The objective of this study was to determine the potential toxicity of CBD (dissolved in corn oil), 51 when orally administered via gavage for 90 days to Wistar rats. 52 Administration of CBD (dissolved in corn oil) to rats for at leas","page":30,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_003"}
SCCS_vision_codex NOAEL =25 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days.","effect":"9 phytocannabinoid content is 6.96% (of this, 6.27% is CBD); the remaining 4.34% consists of 20 fatty alkanes, sterols, terpenes and tocopherols. In the 90-day study, rats in Groups 5 to 8 had 21 a 28-day recovery period before being sacrificed. In the 90-day study, male rats in Groups 1-8 22 were administered the test article daily for 93 days and female rats in Groups 1-8 were 23 administered test article daily for 94 days. The recovery period was 30 and 31 days for the 24 female and male rats, respectively. The NOAEL in the 90-day study was concluded to be 800 25 mg/kg bw/day and 400 mg/kg bw/day for female and male Sprague Dawley rats, respectively 26 (Dziwenka et al., 2020). 27 On the basis of this 90-day repeated dose oral toxicity study with Natural CBD Isolate (purity = 28 99.94%), suspended in corn oil, in male and female Wistar rats with dose levels of 25, 50, 75 29 and 150 mg/kg body weight/ day the following conclusions can be made: no test item-related 30 mortalities and no toxicologically relevant findings concernin","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_004"}
SCCS_vision_codex NOAEL =50 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"37 No toxicologically relevant effects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturati","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_005"}
SCCS_vision_codex NOAEL =44 mg/kg bw/day rat oral 90-day repeated dose toxicity {"dose":"41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes.","effect":"ects on fertility parameters were detected in this study. 38 The histopathological examination revealed treatment-related histomorphological changes in the 39 liver, thyroid glands, adrenal glands and ovaries were reversible under the conditions of this 40 study. 41 Based on microscopic findings recorded and considering presence of enhanced vacuolation (fatty 42 change) indicating inhibition of steroid synthesis in the adrenal glands and ovaries at or above 43 50 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) could be established at 25 44 mg/kg bw/day for both sexes. A histopathological no-observed-effect-level (NOEL) was not 45 determined due to presence of centrilobular hepatocellular hypertrophy, which is of adaptive 46 character, at 25 mg/kg bw/day in both sexes 47 48 A 90-day repeated dose oral toxicity study was conducted in Hsd.Han Wistar male and female 49 rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure 50 to the test article during postweaning maturation and","page":31,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_006"}
SCCS_vision_codex NOAEL =1000 mg/kg bw/day rat oral 14-day NOAEL study {"dose":"The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw.","effect":"ed in the vehicle 3 (sunflower oil) just prior to administration. The test article was administered via gavage at doses 4 of 0, 100, 360, and 720 mg/kg bw/day at a dosing volume of 5 mL/kg bw. These doses were 5 based on the 14-day study lowest observed adverse effect level (LOAEL) of 1000 mg/kg bw/day 6 (the lowest dose group tested) with the aim of inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018).","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_008"}
SCCS_vision_codex NOAEL =360 mg/kg bw/day rat oral 90 days NOAEL study {"dose":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group.","effect":"f inducing moderately toxic effects in the middle- 7 and high-dose groups (without causing mortality or suffering) and determining a no observed 8 adverse effect level (NOAEL) in the low-dose group. Animals assigned to the satellite groups 9 were treated identically up to day 90 and then observed without treatment for four weeks. No 10 toxicologically relevant, test article related changes were observed in male or female animals 11 given 100 mg/kg bw/day or in female animals given 360 mg/kg bw/day for 90 days. The NOAEL 12 for the test article in this 90-day study was considered to be 100 mg/kg bw/day for 13 male and 360 mg/kg bw/day for female Hsd.Han Wistar rats (Marx et al., 2018). 14 15 Respondent 2 provided a non-published study described below: 16 The test item Full Spectrum Extract (REGULAR) was administered daily via oral route daily in 17 graduated doses to 4 groups of test animals, one dose level per group for a treatment period of 18 90 days. Animals of an additional control group were handled identically as the dose","page":32,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_009"}
SCCS_vision_codex NOAEL =9 mg/kg bw/day rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"/day. 4 The histopathological examination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory batte","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_010"}
SCCS_vision_codex NOAEL =250 mg/kg rat oral 90-Day repeated dose toxicity {"dose":"7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females.","effect":"ination also revealed that, except for above-mentioned stress-related 5 findings in males, treatment-related microscopic findings in the liver, thyroid glands, kidneys, 6 urinary bladder, ovaries and adrenal glands were reversible under the conditions of this study. 7 Based on histopathology evaluation, due to presence of interstitial cell vacuolation of the ovary 8 and micro-vesicular vacuolation in the zona fasciculata of the adrenal glands in females at >750 9 mg/kg bw/day, the no-observed-adverse-effect-level (NOAEL) was established at 250 mg/kg 10 bw/day for females. 11 12 13 From Respondent 3 14 The respondent provided two 90-Day Repeated Dose Oral (Gavage) Toxicity Study in Sprague 15 Dawley Rats with 28-Day Recovery Period (OECD 408). 16 In the first one, rats were treated by gavage with 30, 60 and 238 mg/kg bw/day in corn oil as 17 vehicle. Repeated administration to Sprague Dawley Rats for 90 consecutive days had no test- 18 item related effects on the general health of the animals, functional observatory battery 19 p","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_011"}
SCCS_vision_codex NOAEL =238 mg/kg rat oral 28- day NOAEL study {"dose":"However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment.","effect":"parameters, clinical pathology parameters and gross pathology in both sexes. However, the 20 observed changes in body weight, net body weight gain, feed consumption, organ weight and 21 histopathology of the liver in the mid and high-dose group were reversible during the 28- day 22 recovery period and were not considered an adverse effect of test item treatment. Based on the 23 observed results under the experimental conditions employed in the study, it is concluded that 24 the No Observable Adverse Effect Level (NOAEL) is equal to or greater than 238 mg/kg 25 bw/day. 26 27 In the second one, rats were treated by gavage with 25, 50 and 200 mg/kg bw/day in corn oil 28 as vehicle. Treatment related findings were observed in clinical chemistry, liver weight and 29 histopathology of the adrenal and liver. In the main group animals, after 90 days of treatment, 30 a significant increase in liver weight was observed in G3 (50 mg/kg b.w./d dose group) and G4 31 (200 mg/kg b.w./d dose group) male and female animals accompanied by minima","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_012"}
SCCS_vision_codex NOAEL =99 % rat oral 28 days NOAEL study {"dose":"Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditi...","effect":"). Total cholesterol, total bilirubin and low-density lipoprotein levels of G6 females also 40 showed recovery and values were comparable to G5 female. There was no incidence of 41 cytoplasmic vacuolation in the liver and adrenal cells of G6 female animals. However, in G6 male 42 animals, decreased incidence and severity of cytoplasmic vacuolation of hepatocytes (4/5) and 43 cortical cells of adrenal (3/5) was observed without any inflammatory changes and biochemical 44 alterations. Based on the above findings the No Observed Adverse Effect Level (NOAEL) of CBD 45 Isolate powder 99% +/ THC Free was found to be 25 mg/kg b.w./day for Males and 200 46 mg/kg b.w./day for Females when administered to Sprague Dawley rats once daily for 90 47 consecutive days through oral route followed by 28 days recovery period under the conditions 48 tested. 49 50","page":33,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_013"}
SCCS_vision_codex NOAEL =150 mg/kg/day rat oral Chronic NOAEL study {"dose":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobul...","effect":"____________ ___________________________________________________________________________________________ 34 1 3.4.4.3 Chronic (> 12 months) toxicity 2 3 From EMA 4 5 Rat GWTX1412, 26-week oral toxicity study with 4-week recovery 6 In a 26-week Wistar male and female (N=10) rat study (0, 15, 50, or 150 mg/kg/day) with 7 Epidyolex, the centrilobular hypertrophy in the liver of animals given ≥ 50 mg/kg/day, the main 8 finding in this study, was associated with increased liver weight, macroscopic enlargement. A 9 NOAEL (150 mg/kg/day) was associated with an increase in ALP and ALT activities. Thyroid 10 follicular hypertrophy in both sexes, correlated with increased thyroid weights and macroscopic 11 enlargement in males, was considered an indirect effect of treatment due to its recognized 12 relationship with liver hypertrophy. Microscopically these were specified by liver centrilobular 13 hypertrophy and thyroid follicular cell hypertrophy in both sexes along with increased 14 adrenocortical vacuolation in males and minor ovar","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_015"}
SCCS_vision_codex NOAEL =100 mg/kg/day rat oral - NOAEL study {"dose":"There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances.","effect":"7 doses. There were consistent decreases in heart rate in 100 mg/kg/day males but no drug- 28 related cardiac rhythm disturbances. Drug-related liver changes characterised by hepatocyte 29 hypertrophy associated with increased liver weight, macroscopic enlargement, and marked 30 increases in ALP (up to 8-fold compared to controls) were seen at all doses. These were 31 considered adaptive and demonstrated a tendency for reversal at the end of the recovery period. 32 No other toxicological effects were observed. The NOAEL (100 mg/kg/day) was associated 33 with CBD exposures (AUC) of 20500 ng.h/mL in males and 22,400 ng.h/mL in females 34 35 36 SCCS comment 37 Extensive toxicology data and literature were provided from studies in mice, rats, rabbits, dogs, 38 monkeys (including juvenile rats and juvenile dogs) with oral CBD (EMA, Respondents 1 to 3). 39 In this Opinion, only a factual description of study results with a brief discussion of toxicity 40 findings has been provided. Most of the studies found that the liver was one of","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_016"}
SCCS_vision_codex NOAEL =47 mg/kg bw/d rat oral 13-week NOAEL study {"dose":"46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat.","effect":"s been provided. Most of the studies found that the liver was one of the target organs: 41 -In mice, the target organs of toxicity in the 13-week study were the liver and the kidneys. 42 -In rats, the target organs for toxicities were liver, thyroid, and adrenals, presented by 43 change in organ weight. 44 -In dogs, the target organ for toxicity was liver, with hepatocyte hypertrophy, macroscopic 45 enlargement and increased liver weight. 46 From the 90-day repeated oral rat toxicity studies, the SCCS considered a NOAEL of 25 47 mg/kg bw/d for CBD based on liver toxicity (cytoplasmic vacuolation of hepatocytes) in rat. 48 49","page":34,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_017"}
SCCS_vision_codex NOAEL =19 mg/kg/day rat - - reproductive toxicity {"citation":"Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","dose":"During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day.","effect":"eaths and no adverse clinical or post-dosing observations. During the post- 15 pairing phase, there was a treatment-related reduction in the overall body weight gain of males 16 given ≥ 150 mg/kg/day. There were no treatment-related necropsy observations in either sex 17 and no test article-related effects on male or female reproductive indices, male reproductive 18 organ weights, female estrus cycling, or any caesarean-section parameters at doses up to 250 19 mg/kg/day Purified CBD, which was determined to be the NOAEL. Evaluation of CBD effects on 20 male and female reproductive performance is considered adequate, and it is agreed that no 21 significant negative effects were observed in rat. A Safety margin of 60-fold was calculated for 22 inclusion in the SmPC section 5.3 based on exposure measurements from the rat embryofetal 23 study (GWTX1454) at 250 mg/kg/day dose level on Day GD17. Adjusted human AUC(0-24h) 24 2790 ng.h/ml was used for calculation. 25 26 Ref: EMA/458106/2019 Committee for Medicinal Products for Human Use","page":35,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_018"}
SCCS_vision_codex NOAEL =250 mg/kg/day rat oral - NOAEL study {"dose":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose.","effect":"as associated with maternal plasma cannabidiol exposures 6 approximately 9 times than in humans at the recommended human dose. 7 In an oral (gavage) Wistar rat embryofoetal development (EFD) study of purified CBD 8 (Epidyolex® at 0, 75, 150, or 250 mg/kg/day), the dose of 250 mg/kg/day was associated with 9 decreased body weight gain and total litter loss in 2 of 20 dams. The NOAEL for maternal toxicity 10 was amended to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 11 250 mg/kg/day. The NOAEL of 150 mg/kg/day equates to an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with eviden","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_020"}
SCCS_vision_codex NOAEL =80 mg/kg/day rat oral developmental developmental toxicity {"dose":"an estimated human equivalent dose 12 of 24.2 mg/kg/day.","effect":"an estimated human equivalent dose 12 of 24.2 mg/kg/day. This value is 1.2 times higher than the maximum approved dose for 13 Epidyolex® (20 mg/kg/day) in humans. 14 In an oral (gavage) New Zealand white rabbit EFD study of purified CBD (Epidyolex® at 0, 50, 15 80, or 125 mg/kg/day), foetal body weights were decreased (10%) and foetal variations 16 (unossified metacarpal, bulging eyes, and nonerupted incisors) increased at the 125 mg/kg/day 17 dose, which was also associated with evidence of maternal toxicity. The NOAEL for embryofoetal 18 developmental toxicity (80 mg/kg/day) was associated with a maternal exposure of 2,030 19 ng∙h/mL (i.e., much lower exposures than in rats). This exposure in rabbits is approximately 1.2 20 times the AUC expected for a human dose of 1500 mg/day using the exposure in humans 21 observed for a dose of 1500 mg/day (AUC0-inf of 1,618 ng.h/mL). Using allometric scaling the 22 NOAEL of 80 mg/kg/day equates to an estimated human equivalent dose of 25.8 mg/kg/day.66 23 This value is 1.3 times higher tha","page":36,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_021"}
SCCS_vision_codex NOAEL =13 mg/kg/day rat - Developmental developmental toxicity {"dose":"This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit.","effect":"sistent across studies, and do not provide 2 a basis for deriving a point of departure (POD) for human health risk assessment. 3 4 5 3.4.5.2 Developmental Toxicity 6 7 From EMA 8 9 Embryo-foetal development was evaluated in rat and rabbit. Rabbit seemed to be more sensitive 10 to effects of CBD compared to rat. This was evident by the observed dose-dependent body 11 weight loss compared to controls in rabbit. Embryo-foetal development in rat was insensitive to 12 high CBD exposure (Cmax up to 12800 ng/ml). The NOAEL for maternal toxicity was amended 13 to 150mg/kg/day due to 100% loss of pregnancy in 2 dams at the high dose of 250 mg/kg/day. 14 NOAEL for effects on embryo-foetal development in rabbit was 80 mg/kg/day. Foetal variations 15 observed at 125 mg/kg/day CBD (e.g., unossified metacarpal, bulging eyes, and nonerupted 16 incisors) were considered to be secondary to the reduced foetal weights. Maternal exposure at 17 80 mg/kg/day Purified CBD corresponded to GD 19 Cmax and AUC(0-t) values of 220 ng/mL 18 and 2030 ng∙h/","page":37,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_023"}
SCCS_vision_codex NOAEL >97 % - oral 2 months NOAEL study {"dose":"Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment.","effect":"to the risk 11 of hepatocellular damage associated with cannabidiol. Indeed, cannabidiol is associated with 12 dose-dependent elevations of hepatic transaminases (alanine aminotransferase [ALAT] and/or 13 aspartate aminotransferase [ASAT]), generally occurring within 2 months of initiating treatment. 14 15 3.4.10 Special investigations 16 17 / 18 19 20 3.4 SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_026"}
SCCS_vision_codex NOAEL =6 % - oral 90- day NOAEL study {"dose":"ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses.","effect":"SCCS-rejected applicant NOAEL: ING CALCULATION OF THE MOS) 21 22 From Respondent 1 23 24 In order to give a holistic assessment of CBD >97% purity we have used NOAEL’s across both 25 Henderson et al (2023) and Tallon and Child et al (2023) OECD compliant 90- day repeated- 26 dose oral toxicity studies referenced above along with both 36 mg/kg-bw/day and 72 27 mg/kg-bw/day doses. Studies pertaining to crude hemp extracts containing lower levels of 28 CBD were not considered representative and therefore discounted, it is our opinion that the 29 NOAEL’s obtained from the aforementioned studies represent new data pertaining to highly 30 purified CBD ingredients. 31 MOS= NOAEL/SED 32 33 MOS assessment for Hand oil 6% CBD in MCT oil -limited body areas (% SED) 34 35 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.196= 714.29 230 Tallon and Child 2023 230/0.196 = 1173.47 72 Applicant study 72/0.196 = 367.35 36 Applicant study 36/ 0.196 =183.67 120 Averaged out 120/0.196= 612.25 36 37","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_027"}
SCCS_vision_codex NOAEL =1.3 % rat - 90-day NOAEL study {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS c...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 42 1 MOS assessment for 1.3% CBD in a balm- 5.0 g per day application (%SED) 2 3 NOAEL (mg/kg bw) Reference MOS calculation 140 Henderson et al 2023 140/0.108= 1296.30 230 Tallon and Child 2023 230/0.108= 2129.63 72 Applicant study 72/0.108= 666.67 36 Applicant study 36/ 0.108= 333.33 120 Averaged out 120/0.108= 1111.11 4 From Respondent 2 5 6 In a 90-day study commissioned by the sponsor in order to gain data for an EFSA submission, 7 male and female rats were dosed orally with Natural CBD Isolate, vehicled in corn oil. The 8 established NOAEL was 25 mg/kg bw/day for both sexes. 9 10 Therefore,","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_030"}
SCCS_vision_codex NOAEL =24.75 mg/kg rat oral 90-day dermal absorption {"dose":"13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated ora...","effect":"SCCS/1685/25 Preliminary version Scientific Opinion on Cannabidiol (CBD) (CAS/EC No. 13956-29- 1/ 689-176-3) used in cosmetic products ___________________________________________________________________________________________ ___________________________________________________________________________________________ 44 1 From Respondent 3 2 Taking into account the NOAEL of 24.75 mg/kg b.w./d for CBD from the 90-day repeated oral 3 rat toxicity study conducted on raw material OPTIMA CBD XB, the maximum recommended 4 concentrations are as follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_032"}
SCCS_vision_codex NOAEL =197.54 mg/kg rat oral 90-day dermal absorption {"dose":"5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7...","effect":"follows: 5 6 Product Relative daily exposure (mg/kg b.w. /d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA CBD XB concentration (%) Shower gel 2.79 24.75 12.38 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 0.20 0.20 Face cream 24.14 1* 1* Hand cream 32.7 0.76 0.76 Deodorant non-spray 22.08 1* 1* Lipstick 0.9 24.75 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 0.76 0.77 7 Taking into account the NOAEL of 197.54 mg/kg b.w./d for CBD from the 90-day repeated oral 8 rat toxicity study conducted on raw material OPTIMA BROAD EXTRACT XB, the maximum 9 concentrations are as follows: 10 11 Product Relative daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face crea","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_034"}
SCCS_vision_codex NOAEL =25 mg/kg rat oral 90-day dermal absorption {"dose":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodo...","effect":"ive daily exposure (mg/kg b.w./d) Oral NOAEL Value (mg/kg b.w./d) Systemic PoD Value (mg/kg b.w./d) Dermal absorption (%) Maximum CBD concentration (%) Corresponding maximum OPTIMA BROAD EXTRACT XB concentration (%) Shower gel 2.79 197.54 98.77 50 1* 1* Shampoo 1.51 1* 1* Body lotion 123.2 1* 1* Face cream 24.14 1* 1* Hand cream 32.7 1* 1* Deodorant non-spray 22.08 1* 1* Lipstick 0.9 197.54 100 1* 1* Toothpaste 2.16 1* 1* Mouthwash 32.54 1* 1* 12 13 SCCS comment 14 The SCCS has considered an Oral NOAEL of 25 mg/kg b.w./day from the 90-day repeated oral 15 rat toxicity studies. This corresponds to a systemic PoD for CBD of 6.25 mg/kg b.w./day, 16 considering an oral bioavailability of 25%. 17 18 The maximum CBD concentrations for dermal and oral products were determined as follows: 19","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_036"}
SCCS_vision_codex NOAEL =1 % - oral - NOAEL study {"dose":"3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869...","effect":"_________________________________________________________________________________________ ___________________________________________________________________________________________ 45 If the MoS is greater than 100 for aggregate (dermal and oral) with a concentration of 0.19 1 % of CBD in the cosmetic product, then the maximum concentration for each product taken 2 individually is also considered safe. 3 4 5 Product families Product categories Dermal or oral absorption Eproduct normalize d Dermal and oral SED NOAEL syst MOS Max. conc (%) mg/kg bw /d mg/kg bw /d mg/kg bw /d % Rinse-off skin & hair cleansing products (except hand wash) Shower gel 10 2.79 0.0005301 6.25 11790 0.19 Hair conditioner 10 0.67 0.0001273 49097 Shampoo 10 1.51 0.0002869 21785 Hand wash soap Hand wash soap 10 3.33 0.0006327 9878 Leave on skin and hair products Body lotion 10 123.2 0.023408 267 Face cream 10 24.14 0.0045866 1363 Hand cream 10 32.7 0.006213 1006 Deodorant non-spray 10 22.08 0.0041952 1490 Hair styling 10 5.74 0.0010906 5731 Face make-u","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_037"}
SCCS_vision_codex NOAEL =0.19 % human oral - NOAEL study {"dose":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe.","effect":"CCS considers the use of a CBD dose 10 of up to 0.19% in both dermal and oral cosmetic product safe. 11 12 Delta 9THC evaluation 13 14 THC is not intended to be added intentionally in cosmetic products, but it could be present in 15 CBD derived from extract as impurity. 16 17 EFSA (CONTAM Panel2015) established an ARfD of 1 µg/kg bw/day via oral route, derived from 18 a human LOAEL of 2.5 mg/day, adjusted for a person with a weight of 70 kg and divided for an 19 UF of 30 (3 for extrapolation from the LOAEL to a NOAEL and 10 for interindividual differences). 20 21","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_040"}
SCCS_vision_codex NOAEL =41 - - - - NOAEL study {"effect":"Unlabeled table on page 41: NOAEL | Reference | MOS calculation","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_044"}
SCCS_vision_codex NOAEL =140 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 140 | Henderson et al 2023 | 140/0.196= 714.29","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_045"}
SCCS_vision_codex NOAEL =230 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 230 | Tallon and Child 2023 | 230/0.196 = 1173.47","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_046"}
SCCS_vision_codex NOAEL =72 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 72 | Applicant study | 72/0.196 = 367.35","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_047"}
SCCS_vision_codex NOAEL =36 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 36 | Applicant study | 36/ 0.196 =183.67","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_048"}
SCCS_vision_codex NOAEL =120 - - - - NOAEL study {"effect":"Unlabeled table on page 41: 120 | Averaged out | 120/0.196= 612.25","page":41,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_049"}
SCCS_vision_codex NOAEL =42 - - - - NOAEL study {"effect":"Unlabeled table on page 42: NOAEL | Reference | MOS calculation","page":42,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_050"}
SCCS_vision_codex NOAEL =44 - - oral - dermal absorption {"dose":"Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","effect":"Unlabeled table on page 44: Product | Relative daily exposure (mg/kg b.w. /d) | Oral NOAEL Value (mg/kg b.w./d) | Systemic PoD Value (mg/kg b.w./d) | Dermal absorption (%) | Maximum CBD concentration (%) | Corresponding maximum OPTIMA CBD XB concentration (%)","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_056"}
SCCS_vision_codex NOAEL =24.75 - - - - NOAEL study {"effect":"Unlabeled table on page 44: Shower gel | 2.79 | 24.75 | 12.38 | 50 | 1* | 1*","page":44,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_057"}
SCCS_vision_codex NOAEL =45 - - oral - NOAEL study {"effect":"Unlabeled table on page 45: Product families | Product categories | Dermal or oral absorption | Eproduct normalize d | Dermal and oral SED | NOAEL syst | MOS | Max. conc","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_058"}
SCCS_vision_codex NOAEL =6.25 - - - - NOAEL study {"effect":"Unlabeled table on page 45: Rinse-off skin & hair cleansing products (except hand wash) | Shower gel | 10 | 2.79 | 0.0005301 | 6.25 | 11790 | 0.19","page":45,"pdf":"sccs_o_307.pdf","row_type":"noael_study","study_id":"sccs_o_307_noael_059"}
ToxValDB_ECHA_IUCLID 13 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
ToxValDB_ECHA_IUCLID LEL >=50 mg/kg bw/day Dog oral chronic; 39 weeks chronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7ca82e4b0a7c65d22227a; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: decreased body weight|clinical biochemistry: increased circulating alanine transaminase level; TOXICOLOGICAL_EFFECT_CATEGORY=body weight|clinical chemistry; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15832240_15832244:M:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_60c3969658b1ea06a76be870074870ae
ToxValDB_ECHA_IUCLID LEL >=10 mg/kg bw/day Dog oral chronic; 39 weeks chronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7ca82e4b0a7c65d22227a; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: decreased susceptibility to weight gain|clinical biochemistry: increased circulating alkaline phosphatase level|clinical signs: abnormal feces composition|histopathology: non-neoplastic: liver; hypertrophy|organ weights and organ / body weight ratios: increased liver weight; TOXICOLOGICAL_EFFECT_CATEGORY=body weight|clinical chemistry|clinical signs|nonneoplastic histopathology|organ weight; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15832241_15832242:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_79acaac5b6a8a535ae5979b8d4f91fa5
ToxValDB_ECHA_IUCLID LEL >=15 mg/kg bw/day Rat oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7ca40e4b0a7c65d220ea5; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: decreased susceptibility to weight gain|clinical signs: convulsive seizures|mortality: abnormal survival; TOXICOLOGICAL_EFFECT_CATEGORY=body weight|clinical signs|mortality/survival; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15831311_15831312_15835199_15835200_15835204_15838235_15838237:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_b65234068268d4cd0b2db85df242fdaf
ToxValDB_ECHA_IUCLID LEL =150 mg/kg bw/day Rat oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7ca40e4b0a7c65d220ea5; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=clinical biochemistry: increased circulating aspartate transaminase level|clinical biochemistry: increased circulating cholesterol level; TOXICOLOGICAL_EFFECT_CATEGORY=clinical chemistry; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15835201_15835203:M:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_a58447d6d8bc57e6b33efe7459c906d9
ToxValDB_ECHA_IUCLID LEL >=1 mg/kg bw/day Rat oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7ca8fe4b0a7c65d222621; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=histopathology: non-neoplastic: abnormal diestrus|histopathology: non-neoplastic: abnormal metestrus; TOXICOLOGICAL_EFFECT_CATEGORY=reproduction; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15835202_15835205_15838236:F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_4d440ce77770ca2f52a81c0a6b21d9bd
ToxValDB_ECHA_IUCLID LEL >=40 mg/kg bw/day Rat oral chronic; 26 weeks chronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cb55e4b0a7c65d225c93; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=histopathology: non-neoplastic: increased alveolar macrophage number|histopathology: non-neoplastic: liver; hypertrophy|histopathology: non-neoplastic: thyroid gland hyperplasia|organ weights and organ / body weight ratios: increased liver weight; TOXICOLOGICAL_EFFECT_CATEGORY=nonneoplastic histopathology|organ weight; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842008_15842009_15845905_15845906_15845907:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_8496384915130ea7ee43dc92188cc4d4
ToxValDB_ECHA_IUCLID LEL >=400 mg/kg bw/day Mouse oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cc28e4b0a7c65d22944d; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=clinical biochemistry: increased circulating alanine transaminase level|clinical biochemistry: increased circulating cholesterol level|clinical biochemistry: increased circulating globulin level|gross pathology: enlarged liver|histopathology: non-neoplastic: liver; hypertrophy|organ weights and organ / body weight ratios: increased liver weight; TOXICOLOGICAL_EFFECT_CATEGORY=clinical chemistry|gross pathology|nonneoplastic histopathology|organ weight; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842328_15842329:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_f365da2c9611a5161252e298fa776019
ToxValDB_ECHA_IUCLID LEL =700 mg/kg bw/day Mouse oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cc28e4b0a7c65d22944d; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=mortality: abnormal survival; TOXICOLOGICAL_EFFECT_CATEGORY=mortality/survival; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842328_15842329:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_0629c8f47e45a5a1afa30fb601f85d32
ToxValDB_ECHA_IUCLID LEL =625 mg/kg bw/day Mouse oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cc28e4b0a7c65d22944d; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=gross pathology: distended stomach; TOXICOLOGICAL_EFFECT_CATEGORY=gross pathology; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842330_15842332_15842333_15842335_15842337:M:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_1f846257ab723ed5843b0c74fd081ba4
ToxValDB_ECHA_IUCLID LEL >=550 mg/kg bw/day Mouse oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cc28e4b0a7c65d22944d; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=clinical biochemistry: increased circulating total protein level|gross pathology: granular kidney; TOXICOLOGICAL_EFFECT_CATEGORY=clinical chemistry|gross pathology; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842330_15842332_15842333_15842335_15842337:M:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_60b8359541a6a2ccee4918ae7e9f25f0
ToxValDB_ECHA_IUCLID NOEL <=100 mg/kg bw/day Rat oral subchronic; 13 weeks subchronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cc0ce4b0a7c65d228b43; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: no abnormal phenotype detected|clinical biochemistry: no abnormal phenotype detected|clinical signs: no abnormal phenotype detected|haematology: no abnormal phenotype detected|mortality: no abnormal phenotype detected|ophthalmological examination: no abnormal phenotype detected|urinalysis: no abnormal phenotype detected; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15831311_15831312_15835199_15835200_15835204_15838235_15838237:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_1216957bf1ad5a6b29989775a1fb0d91
ToxValDB_ECHA_IUCLID NOEL <=80 mg/kg bw/day Rat oral chronic; 26 weeks chronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cb55e4b0a7c65d225c93; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: no abnormal phenotype detected|clinical biochemistry: no abnormal phenotype detected|clinical signs: no abnormal phenotype detected|haematology: no abnormal phenotype detected|mortality: no abnormal phenotype detected|ophthalmological examination: no abnormal phenotype detected|urinalysis: no abnormal phenotype detected; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842008_15842009_15845905_15845906_15845907:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_a299351d508e85f264b3cc50850b7c24
ToxValDB_ECHA_IUCLID NOEL <=150 mg/kg bw/day Rat oral chronic; 26 weeks chronic STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/66a7cad7e4b0a7c65d223bec; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://echa.europa.eu/; SUBSOURCE_URL=https://iuclid6.echa.europa.eu/us-fda-toxicity-data?documentUUID=3b986f49-e1e3-4118-8562-cb839a2e1dd2; TOXICOLOGICAL_EFFECT=body weight and weight gain: no abnormal phenotype detected|clinical signs: no abnormal phenotype detected|food consumption and compound intake: no abnormal phenotype detected|haematology: no abnormal phenotype detected|histopathology: non-neoplastic: no abnormal phenotype detected|mortality: no abnormal phenotype detected|ophthalmological examination: no abnormal phenotype detected|urinalysis: no abnormal phenotype detected; STUDY_GROUP=ECHA IUCLID_dup_Repeated Dose Toxicity Oral_15842008_15842009_15845905_15845906_15845907:M/F:--; QC_CATEGORY=Programmatically extracted from structured data source; Source overall passed QC, but this record was not manually checked; QC_STATUS=not determined; SOURCE_HASH=ToxValhc_0a3edbb466144164a30ca16fbb58bf81
openFDA substances 4 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
openFDA substances FDA UNII substance identifier 19GBJ60SN5 UNII - - - chemical {"approval_status":null,"molecular_formula":"C21H30O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"19GBJ60SN5"}
openFDA substances FDA UNII substance identifier 19GBJ60SN5 UNII - - - chemical {"approval_status":null,"molecular_formula":"C21H30O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"19GBJ60SN5"}
openFDA substances FDA UNII substance identifier 19GBJ60SN5 UNII - - - chemical {"approval_status":null,"molecular_formula":"C21H30O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"19GBJ60SN5"}
openFDA substances FDA UNII substance identifier 19GBJ60SN5 UNII - - - chemical {"approval_status":null,"molecular_formula":"C21H30O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"19GBJ60SN5"}