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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
250 mg/kg bw/day
Additional information

The effects 1, 2, 3, 6-tretrahydrophthalic anhydride (THPA) on fertility, pregnancy and early lactation of the offspring have been investigated in a reproduction/developmental toxicity screening study conducted according to OECD test methods. Groups of rats were dosed by oral gavage at levels of 100, 250 and 600 mg/kg/day. Males were treated for 2 weeks prior to pairing and during pairing of all females until the day before necropsy, for a total of 6 weeks. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods and for 4 days post partum. No significant changes and no treatment-related effects were detected in males and females during thein vivophase. No significant differences in oestrus cycles, pre-coital interval and copulation plugs were observed and reproductive parameters (copulatory index and fertility index) did not show relevant intergroup differences in both sexes. No differences in the number of implantations or pre-birth loss data were noted. A prolonged gestation period, statistically significantly different from controls was noted with a dose-related trend. No toxicologically significant differences were noted in litter weight, mean pup weight and sex ratio. Total litter size was slightly reduced in animals dosed at 600 mg/kg/day. It was concluded that an effect on pregnancy, demonstrated by a prolonged gestation period, and a smaller litter size, was treatment-related. These effects showed a dose related trend but were considered to have toxicological significance only at the highest dose level (600 mg/kg/day). A slight effect was also observed during gestation in the body weight of the high dose females. On the basis of the results obtained, the lower dose of 250 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL).This study is acceptable and satisfies the guideline requirement for a reproduction and developmental toxicity screening study in rats (OECD 421).

A "higher tier" study such as a 2 -generation study was waived for the following reasons:

The available data for structural homologues of THPA indicate neither potential for teratogenic effects nor for reproduction toxicity in different species. These data together with the available information of the OECD 421 study allow a scientific validated evaluation of the respective endpoints and further tests would not be in line with concerns for animal welfare and unnecessary animal experimentation.


Short description of key information:
In a screening study for reproduction/developmental toxicity study with rats, the NOAEL is considered to be 250 mg/kg/day for reproductive performance of parents and for development of offspring.

Effects on developmental toxicity

Description of key information
In a screening study for reproduction/developmental toxicity study with rats, the NOAEL is considered to be 250 mg/kg/day for reproductive performance of parents and for development of offspring.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
250 mg/kg bw/day
Additional information

The effects 1, 2, 3, 6-tretrahydrophthalic anhydride (THPA) on fertility, pregnancy and early lactation of the offspring have been investigated in a reproduction/developmental toxicity screening study conducted according to OECD test methods. Groups of rats were dosed by oral gavage at levels of 100, 250 and 600 mg/kg/day. Males were treated for 2 weeks prior to pairing and during pairing of all females until the day before necropsy, for a total of 6 weeks. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods and for 4 days post partum. No significant changes and no treatment-related effects were detected in males and females during thein vivophase. No significant differences in oestrus cycles, pre-coital interval and copulation plugs were observed and reproductive parameters (copulatory index and fertility index) did not show relevant intergroup differences in both sexes. No differences in the number of implantations or pre-birth loss data were noted. A prolonged gestation period, statistically significantly different from controls was noted with a dose-related trend. No toxicologically significant differences were noted in litter weight, mean pup weight and sex ratio. Total litter size was slightly reduced in animals dosed at 600 mg/kg/day. It was concluded that an effect on pregnancy, demonstrated by a prolonged gestation period, and a smaller litter size, was treatment-related. These effects showed a dose related trend but were considered to have toxicological significance only at the highest dose level (600 mg/kg/day). A slight effect was also observed during gestation in the body weight of the high dose females. On the basis of the results obtained, the lower dose of 250 mg/kg/day was considered to be the No Observed Adverse Effect Level (NOAEL).This study is acceptable and satisfies the guideline requirement for a reproduction and developmental toxicity screening study in rats (OECD 421)

A "higher tier" study such as a formal developmental toxicity study was waived for the following reasons:

The available data from the OECD 421 study are regarded as supporting evidence as only basic parameters for developmental toxicity were assessed. The available data for structural homologues of THPA indicate neither potential for teratogenic effects nor for reproduction toxicity in different species. These data together with the available information of the OECD 421 study allow a scientific validated evaluation of the respective endpoints and further tests would not be in line with concerns for animal welfare and unnecessary animal experimentation.

Justification for classification or non-classification

Classification is not justified based on the available information from a screening study for reproduction/developmental toxicity and from the lack of findings in structurally related substances