Methylamido-Dihydro-Noralfaprostal (MDN), Methylamido Dihydro Noralfaprostal; Isopropyl Cloprostenate; Dechloro Dihydroxy Difluoro Ethylcloprostenolamide, PROSTAGLANDIN ANALOGUES:

{"dose":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats foll...","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats following 6 months' s.c. exposure to Travoprost at up to 0.1 mg/kg/day. The critical effect in the 6-month study was altered bone histopathology (NOAEL = 0.01 mg/kg/day, LOAEL = 0.1 mg/kg/day) (U.S. FDA 2000). In a 3-generation study, Sprague-Dawley rats were dosed by s.c. injection at 0, 0.12, 0.36, and 0.72 μg/kg/day on GD 7 to postnatal day (PND) 21. Reported effects included a decrease in gestation length and an increase in litters with stillborn pups at all dose levels in the F0 generation and an increase in litter loss and a decrease in litters with viable pups and numbers of pups per litter were reported at 0.72 μg/kg/day. Effects reported in the F1 gener","page":72,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_009"}

sccs_o_302.pdf

{"dose":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats foll...","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats following 6 months' s.c. exposure to Travoprost at up to 0.1 mg/kg/day. The critical effect in the 6-month study was altered bone histopathology (NOAEL = 0.01 mg/kg/day, LOAEL = 0.1 mg/kg/day) (U.S. FDA 2000). In a 3-generation study, Sprague-Dawley rats were dosed by s.c. injection at 0, 0.12, 0.36, and 0.72 μg/kg/day on GD 7 to postnatal day (PND) 21. Reported effects included a decrease in gestation length and an increase in litters with stillborn pups at all dose levels in the F0 generation and an increase in litter loss and a decrease in litters with viable pups and numbers of pups per litter were reported at 0.72 μg/kg/day. Effects reported in the F1 gener","page":72,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_009"}

sccs_o_302.pdf

{"dose":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats foll...","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats following 6 months' s.c. exposure to Travoprost at up to 0.1 mg/kg/day. The critical effect in the 6-month study was altered bone histopathology (NOAEL = 0.01 mg/kg/day, LOAEL = 0.1 mg/kg/day) (U.S. FDA 2000). In a 3-generation study, Sprague-Dawley rats were dosed by s.c. injection at 0, 0.12, 0.36, and 0.72 μg/kg/day on GD 7 to postnatal day (PND) 21. Reported effects included a decrease in gestation length and an increase in litters with stillborn pups at all dose levels in the F0 generation and an increase in litter loss and a decrease in litters with viable pups and numbers of pups per litter were reported at 0.72 μg/kg/day. Effects reported in the F1 gener","page":72,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_009"}

sccs_o_302.pdf

{"dose":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats foll...","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 72 There were no microscopic findings in male and female reproductive tissues in CD rats following 6 months' s.c. exposure to Travoprost at up to 0.1 mg/kg/day. The critical effect in the 6-month study was altered bone histopathology (NOAEL = 0.01 mg/kg/day, LOAEL = 0.1 mg/kg/day) (U.S. FDA 2000). In a 3-generation study, Sprague-Dawley rats were dosed by s.c. injection at 0, 0.12, 0.36, and 0.72 μg/kg/day on GD 7 to postnatal day (PND) 21. Reported effects included a decrease in gestation length and an increase in litters with stillborn pups at all dose levels in the F0 generation and an increase in litter loss and a decrease in litters with viable pups and numbers of pups per litter were reported at 0.72 μg/kg/day. Effects reported in the F1 gener","page":72,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_009"}

sccs_o_302.pdf

{"dose":"3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references:","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 94 4.4 SAFETY EVALUATION (including calculation of the MoS) Applicant 1: The obtained NOAEL of 15 µg/kw bw/d achieved in the three-generation reproductive toxicity study in rats of the structural analogue Cloprostenol will used as PoD for the calculation of the Margin of Safety (MoS) compliant to the guidance of the SCCS. This will be related to the value of 5.61% (mean: 3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references: EMA, 2004; SCCS, 2022, 2023). This standard SCCS procedure resulted in very comfortable Margins of Safety as dem","page":94,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_015"}

sccs_o_302.pdf

{"dose":"3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references:","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 94 4.4 SAFETY EVALUATION (including calculation of the MoS) Applicant 1: The obtained NOAEL of 15 µg/kw bw/d achieved in the three-generation reproductive toxicity study in rats of the structural analogue Cloprostenol will used as PoD for the calculation of the Margin of Safety (MoS) compliant to the guidance of the SCCS. This will be related to the value of 5.61% (mean: 3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references: EMA, 2004; SCCS, 2022, 2023). This standard SCCS procedure resulted in very comfortable Margins of Safety as dem","page":94,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_015"}

sccs_o_302.pdf

{"dose":"3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references:","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 94 4.4 SAFETY EVALUATION (including calculation of the MoS) Applicant 1: The obtained NOAEL of 15 µg/kw bw/d achieved in the three-generation reproductive toxicity study in rats of the structural analogue Cloprostenol will used as PoD for the calculation of the Margin of Safety (MoS) compliant to the guidance of the SCCS. This will be related to the value of 5.61% (mean: 3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references: EMA, 2004; SCCS, 2022, 2023). This standard SCCS procedure resulted in very comfortable Margins of Safety as dem","page":94,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_015"}

sccs_o_302.pdf

{"dose":"3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references:","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 94 4.4 SAFETY EVALUATION (including calculation of the MoS) Applicant 1: The obtained NOAEL of 15 µg/kw bw/d achieved in the three-generation reproductive toxicity study in rats of the structural analogue Cloprostenol will used as PoD for the calculation of the Margin of Safety (MoS) compliant to the guidance of the SCCS. This will be related to the value of 5.61% (mean: 3.87% plus 1.74% SD) for dermal absorption for the calculation of the Systemic Exposure Dose (SED, mg/kg bw/day, references: EMA, 2004; SCCS, 2022, 2023). This standard SCCS procedure resulted in very comfortable Margins of Safety as dem","page":94,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_015"}

sccs_o_302.pdf

{"dose":"5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD):","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 150 response that is insufficiently explored. 5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD): Not specified Pale extremities were observed immediately. after dosing in animals at 30 and 100 µg/kg bw/day A dose-dependent increase in the incidence of post- implantation loss in the intermediate (12.1%) and high- dose (49.6%) groups compared to controls (6.0%) with two high-dose animals having litters with no live f","page":150,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_052"}

sccs_o_302.pdf

{"dose":"5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD):","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 150 response that is insufficiently explored. 5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD): Not specified Pale extremities were observed immediately. after dosing in animals at 30 and 100 µg/kg bw/day A dose-dependent increase in the incidence of post- implantation loss in the intermediate (12.1%) and high- dose (49.6%) groups compared to controls (6.0%) with two high-dose animals having litters with no live f","page":150,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_052"}

sccs_o_302.pdf

{"dose":"5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD):","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 150 response that is insufficiently explored. 5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD): Not specified Pale extremities were observed immediately. after dosing in animals at 30 and 100 µg/kg bw/day A dose-dependent increase in the incidence of post- implantation loss in the intermediate (12.1%) and high- dose (49.6%) groups compared to controls (6.0%) with two high-dose animals having litters with no live f","page":150,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_052"}

sccs_o_302.pdf

{"dose":"5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD):","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 150 response that is insufficiently explored. 5.3.6.2 Developmental Toxicity Applicant 1 Study type, Doses Key findings NOAEL Reference Dose range finding studies Prenatal developmental toxicity, intravenous study, rats (strain not specified) (7 females/dose) 0, 10, 30 and 100 µg/kg bw/day Tafluprost Gestation day (GD): Not specified Pale extremities were observed immediately. after dosing in animals at 30 and 100 µg/kg bw/day A dose-dependent increase in the incidence of post- implantation loss in the intermediate (12.1%) and high- dose (49.6%) groups compared to controls (6.0%) with two high-dose animals having litters with no live f","page":150,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_052"}

sccs_o_302.pdf

{"citation":"Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 140 Conclusion: Under the conditions of the study, the local (ocular) or systemic NOAEL for the test substance Tafluprost was established at 2.7 μg/eye/day (0.67–0.9 µg/kg bw/day). Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost. As expressed in the Preamble, the SCCS is of the opinion that the proposed read-across between DDDE and Tafluprost does not fulfil the critical requirements for an unbiased and transparent read-across and is not supported by other line(s) of evidence. Therefore, these results h","page":140,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_030"}

sccs_o_302.pdf

{"citation":"Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 140 Conclusion: Under the conditions of the study, the local (ocular) or systemic NOAEL for the test substance Tafluprost was established at 2.7 μg/eye/day (0.67–0.9 µg/kg bw/day). Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost. As expressed in the Preamble, the SCCS is of the opinion that the proposed read-across between DDDE and Tafluprost does not fulfil the critical requirements for an unbiased and transparent read-across and is not supported by other line(s) of evidence. Therefore, these results h","page":140,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_030"}

sccs_o_302.pdf

{"citation":"Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 140 Conclusion: Under the conditions of the study, the local (ocular) or systemic NOAEL for the test substance Tafluprost was established at 2.7 μg/eye/day (0.67–0.9 µg/kg bw/day). Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost. As expressed in the Preamble, the SCCS is of the opinion that the proposed read-across between DDDE and Tafluprost does not fulfil the critical requirements for an unbiased and transparent read-across and is not supported by other line(s) of evidence. Therefore, these results h","page":140,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_030"}

sccs_o_302.pdf

{"citation":"Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost","effect":"SCCS/1680/25 Final version Opinion on Prostaglandin analogues used in cosmetic products ___________________________________________________________________________________________ _________________________________________________________________________ 140 Conclusion: Under the conditions of the study, the local (ocular) or systemic NOAEL for the test substance Tafluprost was established at 2.7 μg/eye/day (0.67–0.9 µg/kg bw/day). Ref.: (CDER, 2011) SCCS comments for Applicant 1 submission Applicant 1 provided in vivo sub-chronic toxicity studies for the compound Tafluprost. As expressed in the Preamble, the SCCS is of the opinion that the proposed read-across between DDDE and Tafluprost does not fulfil the critical requirements for an unbiased and transparent read-across and is not supported by other line(s) of evidence. Therefore, these results h","page":140,"pdf":"sccs_o_302.pdf","row_type":"noael_study","study_id":"sccs_o_302_noael_030"}

sccs_o_302.pdf