and its salts is currently regulated in entry 9a of Annex III to the Cosmetics, s................................................................... 98, SODIUM PICRAMATE

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=2.5; DOSE=No dose-response relationship was seen.; EFFECT=____________________________________________________________________ 32 bw/d. During histopathology retinal degeneration was diagnosed only for the males. The results were re-evaluated in a pathology peer review and it was concluded that this linear focal retinopathy was similar to the spontaneous incidence of focal linear degeneration of around 3% in this rat strain. No dose-response relationship was seen. At 20 mg/kg bw/d an increased incidence of abnormally shaped pituitary glands was observed. Conclusion The NOAEL is considered to be 2.5 mg/kg bw/d (free base: 1.4 mg/kg bw/d), based on an increase in AST levels. Ref.: 33 Comment of the SCCP The myocyte degeneration observed in the dose range finding study was not reported in the main study. Both evaluations were made by the same evaluator in the same time period. No comment on these conflicting results was given in discussion of the study results as well as in the dossier. A further 12-week oral toxicity study in rats was cited in Ref. 52 and also referenced in the dossier; CITATION=Ref.: 33 Comment of the SCCP The myocyte degeneration observed in the dose range finding study was not reported in the main study; CITATION_NUMBERS=[33]; REFERENCE=Ref.: 33 Comment of the SCCP The myocyte degeneration observed in the dose range finding study was not reported in the main study; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 33 Comment of the SCCP The myocyte degeneration observed in the dose range finding study was not reported in the main study","dose":"No dose-response relationship was seen.","duration":"12-week","effect":"____________________________________________________________________ 32 bw/d. During histopathology retinal degeneration was diagnosed only for the males. The results were re-evaluated in a pathology peer review and it was concluded that this linear focal retinopathy was similar to the spontaneous incidence of focal linear degeneration of around 3% in this rat strain. No dose-response relationship was seen. At 20 mg/kg bw/d an increased incidence of abnormally shaped pituitary glands was observed. Conclusion The NOAEL is considered to be 2.5 mg/kg bw/d (free base: 1.4 mg/kg bw/d), based on an increase in AST levels. Ref.: 33 Comment of the SCCP The myocyte degeneration observed in the dose range finding study was not reported in the main study. Both evaluations were made by the same evaluator in the same time period. No comment on these conflicting results was given in discussion of the study results as well as in the dossier. A further 12-week oral toxicity study in rats was cited in Ref. 52 and also referenced in the dossier","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"2.5","page":32,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_002"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=2.5; DOSE=ized water, pH 5.0 + 0.3) were administered once daily to groups of 15 male and 15 female Sprague Dawley rats by oral gavage in a total volume of 10 ml/kg bw for a periods of 91 consecutive days followed by a 28-day recovery period (control and 20 mg/kg bw/d groups only).; EFFECT=ized water, pH 5.0 + 0.3) were administered once daily to groups of 15 male and 15 female Sprague Dawley rats by oral gavage in a total volume of 10 ml/kg bw for a periods of 91 consecutive days followed by a 28-day recovery period (control and 20 mg/kg bw/d groups only). The control group received vehicle only. Dose formulations were prepared daily. Animals were housed individually. Dose levels were selected on the basis of a previously conducted 13 week oral toxicity study included in Submission II (Ref. 33). A NOAEL was considered by the SCCP to be 2.5 mg/kg bw/d (free base: 1.4 mg/kg bw/d), based on an increase in AST levels and conflicting results on myocyte degeneration observed in the dose range finding and the main study (SCCP/1084/07). In-life evaluations included twice daily mortality/morbidity checks, daily recording of clinical signs, weekly recording of clinical observations, body weight and food consumption, abbreviated functional observational battery (FOB) (days 26 and 54) and full FOB (days 89- 90), and ophthal; CITATION=(Ref. 33); CITATION_NUMBERS=[33]; REFERENCE=(Ref. 33); DETAILS_JSON={"cas_number":"95-70-5","citation":"(Ref. 33)","dose":"ized water, pH 5.0 + 0.3) were administered once daily to groups of 15 male and 15 female Sprague Dawley rats by oral gavage in a total volume of 10 ml/kg bw for a periods of 91 consecutive days followed by a 28-day recovery period (control and 20 mg/kg bw/d groups only).","duration":"28-day","effect":"ized water, pH 5.0 + 0.3) were administered once daily to groups of 15 male and 15 female Sprague Dawley rats by oral gavage in a total volume of 10 ml/kg bw for a periods of 91 consecutive days followed by a 28-day recovery period (control and 20 mg/kg bw/d groups only). The control group received vehicle only. Dose formulations were prepared daily. Animals were housed individually. Dose levels were selected on the basis of a previously conducted 13 week oral toxicity study included in Submission II (Ref. 33). A NOAEL was considered by the SCCP to be 2.5 mg/kg bw/d (free base: 1.4 mg/kg bw/d), based on an increase in AST levels and conflicting results on myocyte degeneration observed in the dose range finding and the main study (SCCP/1084/07). In-life evaluations included twice daily mortality/morbidity checks, daily recording of clinical signs, weekly recording of clinical observations, body weight and food consumption, abbreviated functional observational battery (FOB) (days 26 and 54) and full FOB (days 89- 90), and ophthal","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"2.5","page":33,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_004"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=2.5; DOSE=In similar toxicokinetic studies with Sprague-Dawley rats the comparison of AUCs showed differences between oral (25 mg/kg bw:; EFFECT=e which was also found in faeces. The metabolite pattern was similar to that after oral administration. The bioavailability (derived from comparison to iv administration) after oral dosing was > 90% while 2% bioavailability was found after dermal application. In similar toxicokinetic studies with Sprague-Dawley rats the comparison of AUCs showed differences between oral (25 mg/kg bw: 112 mgeq x h/l) and dermal application (33 mg/kg bw in formulation: 2.27 mgeq x h/l). Following oral administration of 2.5 mg/kg bw (NOAEL dose) the AUC was 8.53 mgeq x h/l. The bioavailability (derived from comparison to iv administration) after oral dosing was 69% while 2% bioavailability was found after dermal administration in a formulation. Absorption, disposition and elimination in humans was studied following application of a hair dye formulation at a concentration of 0.825% toluene-2,5-diamine sulfate to the scalp. The exposed area was 250 cm2. Following application of formulation I (non-oxidative conditions), the sum of excreted radioactivi; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"In similar toxicokinetic studies with Sprague-Dawley rats the comparison of AUCs showed differences between oral (25 mg/kg bw:","duration":"","effect":"e which was also found in faeces. The metabolite pattern was similar to that after oral administration. The bioavailability (derived from comparison to iv administration) after oral dosing was > 90% while 2% bioavailability was found after dermal application. In similar toxicokinetic studies with Sprague-Dawley rats the comparison of AUCs showed differences between oral (25 mg/kg bw: 112 mgeq x h/l) and dermal application (33 mg/kg bw in formulation: 2.27 mgeq x h/l). Following oral administration of 2.5 mg/kg bw (NOAEL dose) the AUC was 8.53 mgeq x h/l. The bioavailability (derived from comparison to iv administration) after oral dosing was 69% while 2% bioavailability was found after dermal administration in a formulation. Absorption, disposition and elimination in humans was studied following application of a hair dye formulation at a concentration of 0.825% toluene-2,5-diamine sulfate to the scalp. The exposed area was 250 cm2. Following application of formulation I (non-oxidative conditions), the sum of excreted radioactivi","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"2.5","page":60,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_010"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=entration was observed at the end of the study in males or females at doses of up to 10 mg/kg bw/d.; EFFECT=entration was observed at the end of the study in males or females at doses of up to 10 mg/kg bw/d. At 20 mg/kg bw/d, mean AST concentrations were elevated in males and females at the end of the study as some animals clearly exceeded historical control ranges. One of the reviewers noted, in contrast to the original evaluation and the second reviewer, muscle degeneration in multiple organs at 20 mg/kg bw/d. Considering the AST results as well as other clinical pathology results, both pathologists concluded that the NOAEL for clinical pathology was 10 mg/kg bw/d. Comment of the SCCS AST (aspartate aminotransferase, also known as glutamate oxalacetate transaminase, GOT) release is closely related to myotoxicity and, therefore, changes in the plasma level have to be considered with a substance known to induce myodegenerative changes. It is well known that p-phenylenediamine and several derivatives including toluene-2,5-diamine induce such effects on skeletal muscles. Toluene-2,5-diamine was effective already after a s.c. 3-day treat; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"entration was observed at the end of the study in males or females at doses of up to 10 mg/kg bw/d.","duration":"3-day","effect":"entration was observed at the end of the study in males or females at doses of up to 10 mg/kg bw/d. At 20 mg/kg bw/d, mean AST concentrations were elevated in males and females at the end of the study as some animals clearly exceeded historical control ranges. One of the reviewers noted, in contrast to the original evaluation and the second reviewer, muscle degeneration in multiple organs at 20 mg/kg bw/d. Considering the AST results as well as other clinical pathology results, both pathologists concluded that the NOAEL for clinical pathology was 10 mg/kg bw/d. Comment of the SCCS AST (aspartate aminotransferase, also known as glutamate oxalacetate transaminase, GOT) release is closely related to myotoxicity and, therefore, changes in the plasma level have to be considered with a substance known to induce myodegenerative changes. It is well known that p-phenylenediamine and several derivatives including toluene-2,5-diamine induce such effects on skeletal muscles. Toluene-2,5-diamine was effective already after a s.c. 3-day treat","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"10","page":32,"route":"","species":"","study_id":"sccs_o_093_noael_003"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.; EFFECT=cutaneous absorption of toluene-2,5-diamine under in vivo conditions. The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were c; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.","duration":"91-day","effect":"cutaneous absorption of toluene-2,5-diamine under in vivo conditions. The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were c","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"10","page":61,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_011"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.; EFFECT=0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were calculated from the plasma concentration versus time profiles. Toluene-2,5-diamine sulfate was rapidly absorbed following an oral dose, with a Tmax of approximately 0.5 hr. Cmax values correspondin; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.","duration":"91-day","effect":"0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were calculated from the plasma concentration versus time profiles. Toluene-2,5-diamine sulfate was rapidly absorbed following an oral dose, with a Tmax of approximately 0.5 hr. Cmax values correspondin","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"10","page":61,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_012"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study.; EFFECT=lculate the Margin of Safety using the area under curve. This approach is accepted as being scientifically valid. In this new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. The mean plasma AUC(0-∞) values were 1241 ngeq-hr/mL and 3553 ngeq-hr/mL for the low and high concentration mixtures, respectively. These values were compared to the rat mean AUC(0-∞) of 46.3 µgeq-hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study. The toxicokinetics-based Margin of Safety was 37.3 and 13.0, respectively. By interpolation assuming direct proportionality the human plasma AUC(0-∞) value corresponding to a MoS of 25 was calculated to be 1852 ng eq-hr/mL which corresponds to a concentration of 2.24% derived from the 1.5% AUC and assuming again proportionality. Therefore, the applied concentration of 2% is considered to be safe with regard to systemic toxicity (toxicokinetics; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study.","duration":"91 day","effect":"lculate the Margin of Safety using the area under curve. This approach is accepted as being scientifically valid. In this new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. The mean plasma AUC(0-∞) values were 1241 ngeq-hr/mL and 3553 ngeq-hr/mL for the low and high concentration mixtures, respectively. These values were compared to the rat mean AUC(0-∞) of 46.3 µgeq-hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study. The toxicokinetics-based Margin of Safety was 37.3 and 13.0, respectively. By interpolation assuming direct proportionality the human plasma AUC(0-∞) value corresponding to a MoS of 25 was calculated to be 1852 ng eq-hr/mL which corresponds to a concentration of 2.24% derived from the 1.5% AUC and assuming again proportionality. Therefore, the applied concentration of 2% is considered to be safe with regard to systemic toxicity (toxicokinetics","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"10","page":62,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_017"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.; EFFECT=rcutaneous absorption of toluene-2,5-diamine under in vivo conditions. The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were c; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.","duration":"91-day","effect":"rcutaneous absorption of toluene-2,5-diamine under in vivo conditions. The analysis of the results obtained in the four dose groups involving a 20 cm2 dosing surface indicates that mean plasma AUC(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were c","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"10","page":65,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_023"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.; EFFECT=(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were calculated from the plasma concentration versus time profiles. Toluene-2,5-diamine sulfate was rapidly absorbed following an oral dose, with a Tmax of approximately 0.5 hr. Cmax values correspondin; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used.","duration":"91-day","effect":"(0-∞) was directly proportional to applied dose (expressed as µg/cm2), and thus proportional to concentration used. An additional rat oral toxicokinetic study was conducted in order to determine systemic exposure after a single dose of either 5 or 10 mg/kg bw toluene-2,5-diamine sulfate. The latter dose corresponds to the NOAEL determined in the new 91-day oral toxicity study. The AUC(0-∞) value obtained in the 10 mg/kg bw dose group is considered to represent the systemic exposure at the dose corresponding to the NOAEL from the 91-day oral toxicity study. Male and female animals (6 per sex per dose) were administered an oral gavage dose of [14C]-toluene-2-5-diamine sulfate. Blood samples were collected at regular intervals over a 72-hour period, and radioactivity was measured in plasma. Toxicokinetic parameters including AUC(0-∞) were calculated from the plasma concentration versus time profiles. Toluene-2,5-diamine sulfate was rapidly absorbed following an oral dose, with a Tmax of approximately 0.5 hr. Cmax values correspondin","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"10","page":65,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_024"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study.; EFFECT=This approach is accepted as being scientifically valid. The SCCS favours a toxicokinetics-based Margin of Safety. In a new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. The mean plasma AUC(0-∞) values were 1241 ng eq-hr/mL and 3553 ng eq-hr/mL for the low and high concentration mixtures, respectively. These values were compared to the rat mean AUC(0-∞) of 46.3 µg eq-hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study. The toxicokinetics-based Margin of Safety was 37.3 and 13.0, respectively. By interpolation assuming direct proportionality the human plasma AUC(0-∞) value corresponding to a MoS of 25 was calculated to be 1852 ng eq-hr/mL which corresponds to a concentration of 2.24% derived from the 1.5% AUC and assuming again proportionality. Therefore, the applied concentration of 2% is considered to be safe with regard to systemic toxicity (toxicokinetics; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study.","duration":"91 day","effect":"This approach is accepted as being scientifically valid. The SCCS favours a toxicokinetics-based Margin of Safety. In a new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. The mean plasma AUC(0-∞) values were 1241 ng eq-hr/mL and 3553 ng eq-hr/mL for the low and high concentration mixtures, respectively. These values were compared to the rat mean AUC(0-∞) of 46.3 µg eq-hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day established in the 91 day oral toxicity study. The toxicokinetics-based Margin of Safety was 37.3 and 13.0, respectively. By interpolation assuming direct proportionality the human plasma AUC(0-∞) value corresponding to a MoS of 25 was calculated to be 1852 ng eq-hr/mL which corresponds to a concentration of 2.24% derived from the 1.5% AUC and assuming again proportionality. Therefore, the applied concentration of 2% is considered to be safe with regard to systemic toxicity (toxicokinetics","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"10","page":66,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_026"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=14) at the NOAEL dose of 10 mg/kg bw/day (0-∞) eq; EFFECT=Unlabeled table on page 62: rat mean AUC of 46.3 µg -hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day (0-∞) eq; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"14) at the NOAEL dose of 10 mg/kg bw/day (0-∞) eq","duration":"","effect":"Unlabeled table on page 62: rat mean AUC of 46.3 µg -hr/mL (see Ref. 14) at the NOAEL dose of 10 mg/kg bw/day (0-∞) eq","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"10","page":62,"route":"","species":"rat","study_id":"sccs_o_093_noael_027"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=50; DOSE=of the females in the dose groups were similar to the controls.; EFFECT=of the females in the dose groups were similar to the controls. The changes in the incidences of intrauterine death observed were not dose-related. The number and sex of the foetuses as well as the foetal body weights were not influenced by substance treatment. The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes. The positive control (Vitamin A) did not show teratogenicity and only slight embryotoxicity. Conclusion The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. Ref.: 53 Study in rats Guideline: / Species/strain: Sprague Dawley rats Group size: 23 mated females Test substance: toluene-2,5-diamine sulfate in distilled water, Vitamin A in rape seed oil Batch: 23005 Purity: / Dose: 0, 10, 50 and 80 mg/kg bw/d, positive control Vitamin A 15 mg/kg bw/d Route: oral, gavage Exposure: once daily from day 6 to 15 of gestation GLP: / The test and control solutions were administered; CITATION=Ref.: 53 Study in rats Guideline: / Species/strain: Sprague Dawley rats Group size: 23 mated females Test substance: toluene-2,5-diamine sulfate in distilled water, Vitamin A in rape see; CITATION_NUMBERS=[53,23,2,5]; REFERENCE=Ref.: 53 Study in rats Guideline: / Species/strain: Sprague Dawley rats Group size: 23 mated females Test substance: toluene-2,5-diamine sulfate in distilled water, Vitamin A in rape see; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 53 Study in rats Guideline: / Species/strain: Sprague Dawley rats Group size: 23 mated females Test substance: toluene-2,5-diamine sulfate in distilled water, Vitamin A in rape see","dose":"of the females in the dose groups were similar to the controls.","duration":"","effect":"of the females in the dose groups were similar to the controls. The changes in the incidences of intrauterine death observed were not dose-related. The number and sex of the foetuses as well as the foetal body weights were not influenced by substance treatment. The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes. The positive control (Vitamin A) did not show teratogenicity and only slight embryotoxicity. Conclusion The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. Ref.: 53 Study in rats Guideline: / Species/strain: Sprague Dawley rats Group size: 23 mated females Test substance: toluene-2,5-diamine sulfate in distilled water, Vitamin A in rape seed oil Batch: 23005 Purity: / Dose: 0, 10, 50 and 80 mg/kg bw/d, positive control Vitamin A 15 mg/kg bw/d Route: oral, gavage Exposure: once daily from day 6 to 15 of gestation GLP: / The test and control solutions were administered","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"50","page":48,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_007"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=50; DOSE=_________________________________________________________________________________________ 49 reduced at 50 mg/kg bw/d during the dosing period.; EFFECT=_________________________________________________________________________________________ 49 reduced at 50 mg/kg bw/d during the dosing period. For the period d 15-19 these changes were not observed. Post implantation loss was increased at 80 mg/kg bw/d. Number of foetuses, sex distribution and foetal weights were comparable to controls. Visceral and skeletal variations were in the normal range, no malformations were observed. The positive control showed a high incidence of skeletal malformations. Conclusion The NOAEL of toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies. 3.3.9. Toxicokinetics 3.3.9.1. Toxicokinetics in vitro Study 1, metabolism in primary hepatocytes of human, rat and mouse Guideline: / Cells: hepatocytes from humans (pooled from 3 male donors), male Sprague- Dawley rats and male ICR/CD-1 mice Test substance: toluene-2,5-diamine sulfate; CITATION=Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies; CITATION_NUMBERS=[54]; REFERENCE=Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies","dose":"_________________________________________________________________________________________ 49 reduced at 50 mg/kg bw/d during the dosing period.","duration":"","effect":"_________________________________________________________________________________________ 49 reduced at 50 mg/kg bw/d during the dosing period. For the period d 15-19 these changes were not observed. Post implantation loss was increased at 80 mg/kg bw/d. Number of foetuses, sex distribution and foetal weights were comparable to controls. Visceral and skeletal variations were in the normal range, no malformations were observed. The positive control showed a high incidence of skeletal malformations. Conclusion The NOAEL of toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies. 3.3.9. Toxicokinetics 3.3.9.1. Toxicokinetics in vitro Study 1, metabolism in primary hepatocytes of human, rat and mouse Guideline: / Cells: hepatocytes from humans (pooled from 3 male donors), male Sprague- Dawley rats and male ICR/CD-1 mice Test substance: toluene-2,5-diamine sulfate","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"50","page":49,"route":"","species":"rat","study_id":"sccs_o_093_noael_008"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=50; DOSE=49 reduced at 50 mg/kg bw/d during the dosing period.; EFFECT=49 reduced at 50 mg/kg bw/d during the dosing period. For the period d 15-19 these changes were not observed. Post implantation loss was increased at 80 mg/kg bw/d. Number of foetuses, sex distribution and foetal weights were comparable to controls. Visceral and skeletal variations were in the normal range, no malformations were observed. The positive control showed a high incidence of skeletal malformations. Conclusion The NOAEL of toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies. 3.3.9. Toxicokinetics 3.3.9.1. Toxicokinetics in vitro Study 1, metabolism in primary hepatocytes of human, rat and mouse Guideline: / Cells: hepatocytes from humans (pooled from 3 male donors), male Sprague- Dawley rats and male ICR/CD-1 mice Test substance: toluene-2,5-diamine sulfate Batch: 2346 Purity: 98.3% (NMR) Test concentration: 10 µM Incubation time: 4 h Study per; CITATION=Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies; CITATION_NUMBERS=[54]; REFERENCE=Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies","dose":"49 reduced at 50 mg/kg bw/d during the dosing period.","duration":"","effect":"49 reduced at 50 mg/kg bw/d during the dosing period. For the period d 15-19 these changes were not observed. Post implantation loss was increased at 80 mg/kg bw/d. Number of foetuses, sex distribution and foetal weights were comparable to controls. Visceral and skeletal variations were in the normal range, no malformations were observed. The positive control showed a high incidence of skeletal malformations. Conclusion The NOAEL of toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Ref.: 54 Comment The use of a positive control is uncommon in teratogenicity studies. 3.3.9. Toxicokinetics 3.3.9.1. Toxicokinetics in vitro Study 1, metabolism in primary hepatocytes of human, rat and mouse Guideline: / Cells: hepatocytes from humans (pooled from 3 male donors), male Sprague- Dawley rats and male ICR/CD-1 mice Test substance: toluene-2,5-diamine sulfate Batch: 2346 Purity: 98.3% (NMR) Test concentration: 10 µM Incubation time: 4 h Study per","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"50","page":49,"route":"","species":"rat","study_id":"sccs_o_093_noael_009"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=50; DOSE=SCCS/1479/12 Opinion on toluene-2,5-diamine ___________________________________________________________________________________________ 64 toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d.; EFFECT=SCCS/1479/12 Opinion on toluene-2,5-diamine ___________________________________________________________________________________________ 64 toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Toxicokinetics In an in vitro metabolism study with primary hepatocytes of human, rat and mouse toluene- 2,5-diamine sulfate was extensively metabolized by the hepatocytes of all species investigated (order: rat ≈ mouse > human). With human hepatocytes the substance was completely metabolized after 4 h. For all three species N-acetylation was the major metabolic reaction and the results indicate that toluene-2,5-diamine sulfate is substrate for both types on N-; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"SCCS/1479/12 Opinion on toluene-2,5-diamine ___________________________________________________________________________________________ 64 toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d.","duration":"","effect":"SCCS/1479/12 Opinion on toluene-2,5-diamine ___________________________________________________________________________________________ 64 toluene-2,5-diamine sulfate in rats for maternal toxicity is 50 mg/kg bw/d, the NOAEL of embryotoxicity and teratogenicity 80 mg/kg bw/d. Toxicokinetics In an in vitro metabolism study with primary hepatocytes of human, rat and mouse toluene- 2,5-diamine sulfate was extensively metabolized by the hepatocytes of all species investigated (order: rat ≈ mouse > human). With human hepatocytes the substance was completely metabolized after 4 h. For all three species N-acetylation was the major metabolic reaction and the results indicate that toluene-2,5-diamine sulfate is substrate for both types on N-","endpoint":"","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"50","page":64,"route":"","species":"rat","study_id":"sccs_o_093_noael_022"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=69; DOSE=Margin of Safety Toxicokinetic data for Sprague-Dawley rats indicate that oral availability of toluene-2,5- diamine at 10 mg/kg bw is 69%.; EFFECT=f toluene-2,5-diamine together with hydrogen peroxide have been tested in three experimental studies after topical application to mice or rats. The sensitivity of these studies may have been low as no response to hair dye formulations containing known carcinogens was observed. Thus, no conclusions with regard to carcinogenicity can be drawn from the skin painting studies. Margin of Safety Toxicokinetic data for Sprague-Dawley rats indicate that oral availability of toluene-2,5- diamine at 10 mg/kg bw is 69%. The NOAEL from a 90-day study (10 mg/kg bw/d) was corrected accordingly to 6.9 resulting in a MOS of 18. The applicant proposed to use the new human exposure study in vivo to calculate the Margin of Safety using the area under curve. This approach is accepted as being scientifically valid. The SCCS favours a toxicokinetics-based Margin of Safety. In a new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. T; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"Margin of Safety Toxicokinetic data for Sprague-Dawley rats indicate that oral availability of toluene-2,5- diamine at 10 mg/kg bw is 69%.","duration":"90-day","effect":"f toluene-2,5-diamine together with hydrogen peroxide have been tested in three experimental studies after topical application to mice or rats. The sensitivity of these studies may have been low as no response to hair dye formulations containing known carcinogens was observed. Thus, no conclusions with regard to carcinogenicity can be drawn from the skin painting studies. Margin of Safety Toxicokinetic data for Sprague-Dawley rats indicate that oral availability of toluene-2,5- diamine at 10 mg/kg bw is 69%. The NOAEL from a 90-day study (10 mg/kg bw/d) was corrected accordingly to 6.9 resulting in a MOS of 18. The applicant proposed to use the new human exposure study in vivo to calculate the Margin of Safety using the area under curve. This approach is accepted as being scientifically valid. The SCCS favours a toxicokinetics-based Margin of Safety. In a new study human systemic exposure was determined following application of an oxidative hair colouring formulation containing 1.5 and 4.0% toluene-2,5-diamine, respectively. T","endpoint":"carcinogenicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"%","noael_value":"69","page":66,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_025"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT== 0.39; DOSE=Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...; EFFECT=_____________________________________ 62 3.3.12. Special investigations No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxi; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...","duration":"90-day","effect":"_____________________________________ 62 3.3.12. Special investigations No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxi","endpoint":"dermal absorption","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw","noael_value":"= 0.39","page":62,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_013"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT== 6.9; DOSE=Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...; EFFECT=) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodynamics (3.2) and toxicokinetics (3.2). Given the AUC figures obtained from rats and humans the 4- fold factor for interspe; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...","duration":"90-day","effect":") CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodynamics (3.2) and toxicokinetics (3.2). Given the AUC figures obtained from rats and humans the 4- fold factor for interspe","endpoint":"dermal absorption","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6.9","page":62,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_016"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT== 10; DOSE=Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...; EFFECT=____ 62 3.3.12. Special investigations No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodyna; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...","duration":"90-day","effect":"____ 62 3.3.12. Special investigations No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodyna","endpoint":"dermal absorption","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 10","page":62,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_014"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=69; DOSE=Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...; EFFECT=No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodynamics (3.2) and toxicokinetics (3.2). Given; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NO...","duration":"90-day","effect":"No data submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Toluene-2,5-diamine sulfate (Oxidative conditions) A. Conventional method Absorption through the skin A (mean + 1SD) = 40.02 µg/cm² Skin Area surface SAS = 580 cm2 Dermal absorption per treatment SAS x A x 0.001 = 23.21 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.39 mg/kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/d (90-day, rat, oral) NOAEL corrected for bio-availability (69%) = 6.9 mg/kg bw/d Margin of Safety NOAEL / SED = 18 B. Based on toxicokinetics Following the SCCS Notes of Guidance, available oral absorption data and the toxicokinetic properties of the substance should be taken into account. According to WHO, the 100-fold uncertainty factor can be subdivided in interspecies differences (10-fold) in toxicodynamics (2.5) and toxicokinetics (4) and inter-individual differences (10-fold) in toxicodynamics (3.2) and toxicokinetics (3.2). Given","endpoint":"dermal absorption","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"%","noael_value":"69","page":62,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_015"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=Conclusion Administration of toluene-2,5-diamine sulfate once daily by oral gavage at a dose of 20 mg/kg bw/d was associated with microscopic changes in the skeletal muscle of the thigh, diaphragm, tongue, and periocular muscle that correlated with elevations in AST.; EFFECT=e were not present at the recovery group sacrifice. Conclusion Administration of toluene-2,5-diamine sulfate once daily by oral gavage at a dose of 20 mg/kg bw/d was associated with microscopic changes in the skeletal muscle of the thigh, diaphragm, tongue, and periocular muscle that correlated with elevations in AST. These target organ effects resolved following the 28-day recovery period. No treatment-related findings were reported at 10 mg/kg bw/d. Based on these results, the no-observed- adverse-effect level (NOAEL) was determined to be 10 mg/kg bw/d. Ref.: 13 (subm III) 3.3.5.3. Chronic (> 12 months) toxicity No data submitted 3.3.6. Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Taken from SCCP/1084/07 Bacterial Reverse Mutation Test Guideline: OECD 471 Species/strain: Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537 Replicates: triplicates in 2 individual experiments both in the presence and absence of S9-mix. Test substance: toluene-2,5-diamine sulfate Solvent: DMSO Batch: R99; CITATION=Ref.: 13 (subm III) 3; CITATION_NUMBERS=[13,3]; REFERENCE=Ref.: 13 (subm III) 3; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 13 (subm III) 3","dose":"Conclusion Administration of toluene-2,5-diamine sulfate once daily by oral gavage at a dose of 20 mg/kg bw/d was associated with microscopic changes in the skeletal muscle of the thigh, diaphragm, tongue, and periocular muscle that correlated with elevations in AST.","duration":"28-day","effect":"e were not present at the recovery group sacrifice. Conclusion Administration of toluene-2,5-diamine sulfate once daily by oral gavage at a dose of 20 mg/kg bw/d was associated with microscopic changes in the skeletal muscle of the thigh, diaphragm, tongue, and periocular muscle that correlated with elevations in AST. These target organ effects resolved following the 28-day recovery period. No treatment-related findings were reported at 10 mg/kg bw/d. Based on these results, the no-observed- adverse-effect level (NOAEL) was determined to be 10 mg/kg bw/d. Ref.: 13 (subm III) 3.3.5.3. Chronic (> 12 months) toxicity No data submitted 3.3.6. Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Taken from SCCP/1084/07 Bacterial Reverse Mutation Test Guideline: OECD 471 Species/strain: Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537 Replicates: triplicates in 2 individual experiments both in the presence and absence of S9-mix. Test substance: toluene-2,5-diamine sulfate Solvent: DMSO Batch: R99","endpoint":"genotoxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"10","page":34,"route":"oral","species":"","study_id":"sccs_o_093_noael_005"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=60; DOSE=rt, skeletal muscle, tongue and diaphragm in both sexes in all dose groups.; EFFECT=rt, skeletal muscle, tongue and diaphragm in both sexes in all dose groups. Ref.: 32 Peer review of two external experts The histological slides from relevant tissues (diaphragm, skeletal muscle, tongue and heart) from this study were reviewed by two independent pathologists. Both pathologists agreed that treatment-related myofiber necrosis, degeneration, and/or inflammatory change were present in skeletal muscle, tongue, and diaphragm of both males and females given 30 or 60 mg/kg bw/d in this study and that the NOAEL for muscle degenerative change in this study was 15 mg/kg bw/d. Ref.: 4, 5 (subm III) 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Study 1 Guideline: OECD 408 (1981) Species/strain: Sprague-Dawley rats, Crl:CD(SD)BR Group size: 15 animals per sex per dose Test substance: toluene-2,5-diamine sulfate in deionised water Batch: CH 1143 Purity: 99.7% Dose: 0, 2.5, 5, 10, 20 mg/kg bw/d Route: oral, gavage Exposure: once daily for 13 weeks GLP: in compliance Doses of 0, 2.5, 5, 10, 20 mg/kg bw/d; CITATION=Ref.: 32 Peer review of two external experts The histological slides from relevant tissues (diaphragm, skeletal muscle, tongue and heart) from this study were reviewed by two independent; CITATION_NUMBERS=[32]; REFERENCE=Ref.: 32 Peer review of two external experts The histological slides from relevant tissues (diaphragm, skeletal muscle, tongue and heart) from this study were reviewed by two independent; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 32 Peer review of two external experts The histological slides from relevant tissues (diaphragm, skeletal muscle, tongue and heart) from this study were reviewed by two independent","dose":"rt, skeletal muscle, tongue and diaphragm in both sexes in all dose groups.","duration":"Sub-chronic","effect":"rt, skeletal muscle, tongue and diaphragm in both sexes in all dose groups. Ref.: 32 Peer review of two external experts The histological slides from relevant tissues (diaphragm, skeletal muscle, tongue and heart) from this study were reviewed by two independent pathologists. Both pathologists agreed that treatment-related myofiber necrosis, degeneration, and/or inflammatory change were present in skeletal muscle, tongue, and diaphragm of both males and females given 30 or 60 mg/kg bw/d in this study and that the NOAEL for muscle degenerative change in this study was 15 mg/kg bw/d. Ref.: 4, 5 (subm III) 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Study 1 Guideline: OECD 408 (1981) Species/strain: Sprague-Dawley rats, Crl:CD(SD)BR Group size: 15 animals per sex per dose Test substance: toluene-2,5-diamine sulfate in deionised water Batch: CH 1143 Purity: 99.7% Dose: 0, 2.5, 5, 10, 20 mg/kg bw/d Route: oral, gavage Exposure: once daily for 13 weeks GLP: in compliance Doses of 0, 2.5, 5, 10, 20 mg/kg bw/d","endpoint":"repeated dose toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"60","page":31,"route":"oral","species":"rat","study_id":"sccs_o_093_noael_001"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=10; DOSE=General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.; EFFECT=oluene-2,5-diamine sulfate. For 2.4% toluene-2,5-diamine sulfate, the amount absorbed under non-oxidative conditions (mean + 1SD) is 9.25 ± 2.54 = 11.79 µg/cm². Under oxidative conditions, the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.","duration":"90-day","effect":"oluene-2,5-diamine sulfate. For 2.4% toluene-2,5-diamine sulfate, the amount absorbed under non-oxidative conditions (mean + 1SD) is 9.25 ± 2.54 = 11.79 µg/cm². Under oxidative conditions, the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of","endpoint":"reproductive toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"10","page":63,"route":"oral","species":"rabbit","study_id":"sccs_o_093_noael_018"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=20; DOSE=General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.; EFFECT=9.25 ± 2.54 = 11.79 µg/cm². Under oxidative conditions, the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.","duration":"90-day","effect":"9.25 ± 2.54 = 11.79 µg/cm². Under oxidative conditions, the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of","endpoint":"reproductive toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"20","page":63,"route":"oral","species":"rabbit","study_id":"sccs_o_093_noael_019"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=45; DOSE=Conclusion The NOAEL for reproductive toxicity was 45 mg/kg bw/d.; EFFECT=rentes, coagulation gland, prostate gland, vesicular gland) were examined microscopically. Results 4 animals (one of P- and 3 of F1-generation) died due to intubation-induced lesions. Body weight development, feed consumption and observation of the animals did not show substance treatment related differences. Observations and measurements in the pups of both generations until weaning did not show differences in the parameters evaluated. No detrimental effect on male and female fertility was found. Conclusion The NOAEL for reproductive toxicity was 45 mg/kg bw/d. Ref.: 52 3.3.8.2. Teratogenicity Study in rabbits Guideline: / Species/strain: New Zealand White Rabbit Group size: 16 (vehicle control and dose groups), 18 (positive control Vitamin A in rape seed oil) Test substance: toluene-2,5-diamine sulfate in distilled water; CITATION=Ref.: 52 3; CITATION_NUMBERS=[52,3]; REFERENCE=Ref.: 52 3; DETAILS_JSON={"cas_number":"95-70-5","citation":"Ref.: 52 3","dose":"Conclusion The NOAEL for reproductive toxicity was 45 mg/kg bw/d.","duration":"","effect":"rentes, coagulation gland, prostate gland, vesicular gland) were examined microscopically. Results 4 animals (one of P- and 3 of F1-generation) died due to intubation-induced lesions. Body weight development, feed consumption and observation of the animals did not show substance treatment related differences. Observations and measurements in the pups of both generations until weaning did not show differences in the parameters evaluated. No detrimental effect on male and female fertility was found. Conclusion The NOAEL for reproductive toxicity was 45 mg/kg bw/d. Ref.: 52 3.3.8.2. Teratogenicity Study in rabbits Guideline: / Species/strain: New Zealand White Rabbit Group size: 16 (vehicle control and dose groups), 18 (positive control Vitamin A in rape seed oil) Test substance: toluene-2,5-diamine sulfate in distilled water","endpoint":"reproductive toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"45","page":47,"route":"oral","species":"rabbit","study_id":"sccs_o_093_noael_006"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=45; DOSE=General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.; EFFECT=, the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.","duration":"90-day","effect":", the amount absorbed is 21.81 ± 4.87 = 26.68 µg/cm². The latter value may be used for the conventional MOS calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of","endpoint":"reproductive toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"45","page":63,"route":"oral","species":"rabbit","study_id":"sccs_o_093_noael_020"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_093; REPORT_TITLE=OPINION ON Toluene-2,5-diamine and its sulfate COLIPA n° A5; OPINION_NUMBER=SCCS/1479/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=18 September 2012; VALUE_TEXT=50; DOSE=General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.; EFFECT=calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"95-70-5","citation":"","dose":"General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw.","duration":"90-day","effect":"calculation after correction (26.68 x 3.6 / 2.4 = 40.02 µg/cm²) since the intended on head concentration is 3.6%. General toxicity The acute median lethal oral dose was calculated to be 102 mg/kg bw. In a 90-day study, the NOAEL is considered to be 10 mg/kg bw/d based on an increase in AST levels and myocyte degeneration observed at 20 mg/kg bw/d. The NOAEL for reproductive toxicity was 45 mg/kg bw/d. The NOAEL of embryotoxicity and teratogenicity of toluene-2,5-diamine sulfate in rabbits is 50 mg/kg bw/d. The NOAEL of","endpoint":"reproductive toxicity","ingredient":"and its salts is currently regulated in entry 9a of Annex III to the Cosmetics","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"50","page":63,"route":"oral","species":"rabbit","study_id":"sccs_o_093_noael_021"}

sccs_o_093.pdf

SOURCE_SUBDIR=sccs_o_273; REPORT_TITLE=Scientific Committee on Consumer Safety; OPINION_NUMBER=SCCS/1647/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted on 26 October 2023; VALUE_TEXT=unclear:rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with; EFFECT=SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"","citation":"","dose":"","duration":"","effect":"SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","endpoint":"","ingredient":"s................................................................... 98","loael_value":"","noael_unit":"","noael_value":"unclear:rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","page":94,"route":"","species":"rat","study_id":"sccs_o_273_noael_017"}

sccs_o_273.pdf

SOURCE_SUBDIR=sccs_o_273_final; REPORT_TITLE=Scientific Committee on Consumer Safety; OPINION_NUMBER=SCCS/1647/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted on 26 October 2023; VALUE_TEXT=unclear:rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with; EFFECT=SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"","citation":"","dose":"","duration":"","effect":"SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","endpoint":"","ingredient":"s................................................................... 98","loael_value":"","noael_unit":"","noael_value":"unclear:rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","page":94,"route":"","species":"rat","study_id":"sccs_o_273_final_noael_017"}

sccs_o_273_final.pdf

{"effect":"SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","page":94,"pdf":"sccs_o_273.pdf","row_type":"noael_study","study_id":"sccs_o_273_noael_017"}

sccs_o_273.pdf

{"effect":"SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","page":94,"pdf":"sccs_o_273.pdf","row_type":"noael_study","study_id":"sccs_o_273_noael_017"}

sccs_o_273.pdf

{"effect":"SCCS-rejected applicant NOAEL: rat and/or humans (SCCS/1443/11, SCCS/1479/12), the interspecies and/or intra-species toxicokinetic default factor can be increased/decreased (case-by-case evaluation). Regarding substance-specific information for variations in toxicodynamics, deviation from the default value is possible if sufficiently justified. For instance, in case of different susceptibility to HPT-axis disturbances in rats and humans, a change of the interspecies toxicodynamic default factor of 2.5 may be required. * including historical NOAEL values Figure 13. Further subdivision of the uncertainty/assessment factor, taking toxicokinetics and toxicodynamics into account (based on WHO, 1994). Additional considerations: - Some cosmetic substances are not used on a daily basis, although their NOAEL values have been obtained in studies after daily administration of the substances. Combining these NOAEL values with daily exposures therefore results in a clear overestimation of the risk. The comparison of a NOAEL resulting from a daily exposure study with","page":94,"pdf":"sccs_o_273.pdf","row_type":"noael_study","study_id":"sccs_o_273_noael_017"}

sccs_o_273.pdf