Reaction products of tetraethylenepentamine and maleic anhydride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A combined repeated dose toxicity study with reproduction/developmental toxicity screening test is performed in rats, in which male and female rats are exposed to 0 (vehicle), 100, 300 and 1000 mg/kg bw/day via gavage (OECD 422).There were no clinical observations or changes in behavioral parameters related to test item treatment at any dose level.Clinical signs detected in pups from all test item-treated groups included small size, pale, weak, cold, no milk in stomach, physical injury, scab formation found dead or missing and, were considered to be low incidence findings observed in offspring in studies of this type and as such unlikely to be related to the toxicity of the test item.

Throughout the dosing period, there was no adverse effect of treatment with the test item on body weight development and dietary intake or food conversion efficiency in animals of either sex. Visual inspection of water bottles did not indicate any differences for the animals given the test item in relation to controls. Offspring body weights and litter weights on days 1 and 4 post partum were generally comparable with controls.

No toxicologically significant effects in hematology and clinical chemistry were detected in animals of either sex receiving the test item at any dose level.

There were no intergroup differences related to treatment with the test item. Sensory reactivity scores across all test item-treated groups were similar to controls. Motor activity evaluation during the final week of the treatment period revealed slightly but statistically significantly lower activity (last 20%) for males given the test item at 300 or 1000 mg/kg bw/day (active ingredient) in relation to controls (p<0.05). The remaining motor activity parameters for these animals were similar to controls and in the absence of any other signs of neurotoxicity, this finding was considered to be incidental.

For organ weights, no toxicologically significant effects were detected in animals of either sex at any dose level.

No macroscopic findings were observed which could be related to treatment with the test item. Macroscopic necropsy findings for control offspring on the study were typical for the age observed and neither the incidence nor the distribution of these observations indicated any adverse effect of maternal treatment with the test item (active ingredient) on offspring development at 100, 300 or 1000 mg/kg bw/day.

Histopathological examination of the selected tissues from the high dose animals of either sex did not reveal any abnormalities, which could be unequivocally related to treatment with the test item.

There was no effect of treatment on mating performance with all animals mating within four days after pairing. In total, five females did not achieve pregnancy following evidence of positive mating. All non-pregnant females appeared to be cycling normally and there was no obvious reason for the lack of pregnancy with the exception of females 18 and 96; these females had successfully mated with male 6 (control group) and male 84 (high dose group), respectively, which showed marked or moderate tubular atrophy in the testes and this was considered likely to have caused impaired fertility or indeed infertility. There was no reason identified at histopathology examination for the lack of pregnancy in the remaining two high dose females and taken together with the high incidence of non-pregnancies in this dose group, this observation was considered to be equivocal. Female 62 was paired with male 50 and the latter showed reduced secretion in the seminal vesicles which may have affected fertility although this remains unclear. Female 63 from the intermediate dose group showed evidence of implantation but there was no litter. As there were no such findings in the high dose group, these observations were deemed unlikely to be treatment related. With the exception of one female from the high dose group, gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was similar to controls; female 92 from the high dose group had a gestation length of 24½ days which may be due to its small litter size that included two pups, only one of which was born viable.

There was no effect of treatment with the test item on the mean number of corpora lutea, implantation counts or pre- and post-implantation losses. Of the litters born, litter size at birth and subsequently on days 1 and 4 post partum from females treated with the test item at all dose levels were comparable with controls. There were no intergroup differences in sex ratio (percentage male offspring) for litters from test item-treated dose groups when compared with controls. Statistical analysis of these data did not identify any statistically significant differences and any minor intergroup differences were considered to be due to normal biological variation. Surface righting reflex data did not reveal any detrimental effect of treatment with the substance at any dose level in relation to controls. 

The oral (gavage) administration of the substance (active ingredient) to Wistar Han™:RccHan™:WIST strain rats, at dose levels of up to 1000 mg/kg bw/day was well tolerated. Microscopic examination of the selected tissues from the high dose animals did not identify any treatment-related abnormalities and based on the available data the NOAEL for systemic toxicity was considered to be 1000 mg/kg bw/day.

The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity, within the confines of this screening study, was considered to be 300 mg/kg bw/day. This was due to the unusually high number of non-pregnant females in the high dose group and, although there was no effect of treatment with the test item at any dose level on any other reproduction or offspring developmental parameters this observation remains equivocal because an effect of treatment cannot be completely discounted.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

A GLP-compliant, combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 was performed by Rashid (2015). A NOAEL of 1000 mg/kg/day was derived for parental systemic toxicity and toxicity to reproduction. The substance doesn't need to be classified.