3(or 4)-methylbenzene-1,2-diamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

50 mg/kg bw/day

Additional information

In a guideline reproductiion/developmental toxicity screening test in rats by oral gavage, there were no effects on fertility and no developmental effects, except in the presence of maternal toxicity. The NOAEL for maternal toxicity and reproductive and developmental effects was 50 mg oTDA/kg/day, with the LOAEL being 250 mg oTDA/kg/day.

Study details: male and female rats received single daily oral administration of the test material at different dose levels over a period covering 2 week of premating and mating, approximately 1 week post-mating for the males, and the entire gestation period and 4 days of lactation for the females. The tested dose levels were 0 (control), 10(low dose), 50 (mid dose) and 250 mg/kg bw/d (high dose). The parent animals were examined for mortality, clinical symptoms of toxicity, body weight, food consumption, and sex-specific reproduction parameters.At necropsy (after 4 weeks for the males; at the end of the lactation period of 4 days for the females), the animals were subjected to gross pathology, organ weighing and histopathology; particular attention was given to the reproduction organs. Referring to the pups, all of them were examined, weighed and counted; check for dead or moribund pups was made until day 4 post parturition. Sex ratio was determined. All surviving pups were sacrificed on day 4 post parturition for necropsy. All sacrificed pups, all stillborn pups and those pups, which died ahead of schedule, were examined externally, eviscerated and their organs were assessed macroscopically. Under the conditions of the present reproduction/developmental toxicity screening test: - The NOAEL for general, systemic toxicity was 10 mg/kg bw/d for the parental males; 50 mg/kg bw/d was set as LOAEL because of eyelid halfclosure after treatment, reduced activity, piloerection and salivation. - The NOAEL for general, systemic toxicity was 50 mg/kg bw/d for the parental females since salivation was considered as related to the mode of application and since decreased mean food consumption was not seen as adverse effect as no changes in body weight could be evidenced at this dose level. 250 mg/kg bw/d was set as LOAEL because of eyelid halfclosure after treatment, reduced activity, salivation, piloerection, discolored feces, decreased food consumption, lowered body weight and body weight gain. - The NOAEL for reproductive performance and fertility in male and female Wistar rats was 50 mg/kg bw/d. The LOAEL was set at 250 mg/kg bw/d because of decreased number of spermatids/g testis, decreased number of implantation sites. - The NOAEL for developmental toxicity was 50 mg/kg bw/d for both sexes. The LOAEL was set at 250 mg/kg bw/d because of increased post implantation loss, decreased number of delivered pups and decreased viability index.

Short description of key information:

o-TDA did not affect fertility in a reproduction screening study.

Effects on developmental toxicity

Description of key information

o-TDA was not a developmental toxicant in two species.  

Foetotoxicity was seen only in the presence of maternal toxicity.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

30 mg/kg bw/day

Additional information

In a reproductiion/developmental toxicity screening test in rats by oral gavage, there were no effects on fertility and no developmental effects, except in the presence of maternal toxicity. The NOAEL for maternal toxicity and reproductive and developmental effects was 50 mg oTDA/kg/day, with the LOAEL being 250 mg oTDA/kg/day.

There are guideline studies assessing possible developmental effects of o-TDA, one in rats and one in rabbits. o-TDA was orally administered to pregnant rats at levels of 0, 10, 30, 100 or 300 mg/kg body weight/day on days 6 through 15 of gestation. To rabbits, doses of 0, 3, 10, 30 or 100 mg/kg body weight/day were given orally on days 6 through 18 of gestation.

Maternal toxicity was evidenced in rats at 300 mg/kg/day by significantly lowered dam body weights and weight gains during gestation. In rabbits maternal toxicity was seen at 100 mg/kg/day as swollen, red or pink eyelids, reduced body weights on day 18 and reduced weight gains during gestation.

In rats, ortho-TDA had no effect on pregnancy, implantation, numbers of live foetuses, numbers of dead foetuses or numbers of resorption sites per dam. Foetal weights of dams treated at 300 mg/kg were significantly lower than the vehicle control. The findings of skeletal examinations showed a significant increase in the number of litters with incompletely ossified vertebrae at 100 and 300 mg/kg as well as missing sternebrae and incomplete skull closure at 300 mg/kg. Soft tissue examinations showed an increase in the percentage of litters with foetuses showing hemorrhagic abdomen at 10, 100, and 300 mg/kg, but while these were statistically significant, the increase was considered to be not treatment related.

In rabbits, skeletal and soft tissue examinations of foetuses from o-TDA treated dams revealed no significant differences in type or frequency of findings between any test group and the negative control. Treatment at 100 mg/kg significantly increased the percentage of dams that resorbed their entire litters and significantly reduced foetal weights and lowered neonatal survival.

Overall in two species o-TDA was not teratogenic.

Foetotoxicity was seen in the presence of maternal toxicity. The NOAEL for maternal and foetotoxicity was 100mg/kg in rats and 30 mg/kg in rabbits.

Justification for classification or non-classification

Ortho-TDA is not a reproductive toxicant and not teratogenic, so no classification is triggered according to the criteria described in Regulation (EC) No. 1272/2008.