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Key value for chemical safety assessment

Effects on fertility

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

One study by oral route is reported for this endpoint:

The objective of this study (Takawale, 2010a) was to evaluate the potential toxic effects of the test item following daily oral administration (gavage) to male and female rats from before mating, through mating and, for the females, through gestation until day 3post-partum.

This study provides initial information on possible toxicological effects likely to arise from repeated exposure over a relatively limited period of time and on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

The study was conducted according to OECD Guideline 422 and EPA guideline OPPTS 870.3650 andwas in compliance with the principles of Good Laboratory Practice regulations.

Three groups of 10 males and 10 females Wistar rats received the test substance daily, by gavage, before mating and through mating and, for the females, through gestation until day 3post-partum.The dose-levels were 12, 24 or 48 mg/kg bw/day. Another group of 10 males and 10 females received the vehicle, sterile water, alone, under the same experimental conditions and acted as a control group. The dosing volume was 5 mL/kg bw/day.

Animals were examined daily for clinical signs and mortality and detailed clinical observations were performed once before the beginning of the treatment period and then once a week until the end of the study. Body weight was measured weekly, food consumption also except during the mating period. A Functional Observation Battery includingsensory reactivity to different stimuli, grip strength, motor activity assessments and other behaviour observations was performed in the week before treatment and at the end of the study. Blood and urine samples were taken for analysis of hematology, blood biochemistry and urine parameters at the end of the study from randomly selected five males and five females (except urine) from each group.

The animals were paired for mating after 2 weeks of treatment and the females were allowed to litter and rear their progeny until day 4post-partum. The total litter sizes and numbers of pups of each sex were recorded after birth. Pups were observed daily for clinical signs and pup body weights were recorded on days 1 and 4post-partum.

Males were sacrificedafter completion of the mating periodon treatment days 29 and 30and the females along with their pups were sacrificed onpost natal day 4. Non delivered females were sacrificed on the respective day 26 after the sperm positive vaginal smear as an evidence of mating.Dams were subjected to a complete macroscopic examination with particular attention paid to the reproductive organs. Designated organs were weighed and examined microscopically.

Pups sacrificed on postnatalday 4 and those found dead, were carefully examined for gross external abnormalities.

There were no treatment related deaths but 5 premature deaths (1 female, 1 female and 2 males and 1 female from the low, mid and high-dose groups respectively) were observed.The macroscopic examinations of the five decedents together with the histopatological findings confirmed that the death was due to misgavaging orregurgitation/aspiration of the test item.

Salivation was observed in all males and females of the high-dose group and in 5 males and 3 females of the mid-dose group. In addition, most of the animals treated at the highest dose had piloerection and respiratory sounds. In the mid-dose group, only 1 male had piloerection while respiratory sounds were noted in 3 males and 1 female respectively. In the low-dose group, respiratory sounds were occasionally observed in few animals as well as in one animal of the control group. No other clinical signs were observed at 12 mg/kg/day.

No test item related effects on body weight and body weight change wereobserved. In males, statistical analysis of the food consumption data revealed no significant effect in treated groups when compared with controls. In females, no effect on food consumption was observed in treated groups during premating and gestation period as compared to controls. However, statistically significant decrease in food consumption in the high-dose group was observed during post natal days 0-4 when compared with controls. There were no effects in females food consumption at 24 or 12 mg/kg/day.

There were no effects on mating, fertility or delivery at any dose-level. There were no increases in pup mortality in the test item-treated groups and there were no relevant clinical signs or gross abnormalities in the pups.Pup mean body weight at birth was slightly lower in the high-dose group when compared with controls.

However, the gain in body weight was recouped during the post natal period as the mean body weight of these pups on post-natal day 4 was in the normal biological range.

In the female and male reproductive organs, no histopathological lesions were found in treated groups which were considered to be test item related. However, test item-related histopathological changes were observed in small intestine and the mesenteric lymph node in all treated groups. Both males and females had infiltration with histiocytes that probably contained test-item lipid complexes which are poorly degraded by lysosomal enzymes. As no degenerative changes were associated, this effect was therefore considered to be non-adverse.

Based on the data generated from this study:

A No Observed Effect Level (NOEL) could not be established for the parental toxicity due to histopathological findings in small intestine and mesenteric lymph nodes in all treated groups. As no degenerative changes were associated, these findings were therefore considered to be non-adverse and the No Observed Adverse Effect Level (NOAEL) was considered to be 24 mg/kg/day.

The No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 48 mg/kg/day.

The No Observed Adverse Effect Level (NOAEL) for toxic effects on progeny was 48 mg/kg/day since the lower body weight at birth at this dose-level was only slight and completely recouped on post-natal day 4.


Short description of key information:
The potential reproductive/developmental toxicity of the substance was assessed using:
-a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test performed in rats by oral route according to OECD guideline 422 and Goood Laboratory Practices (Takawale, 2010a).
There were no effects on mating, fertility or delivery at any dose-level and pups showed no effects other than at the highest dose-level of the study (48mg/kg bw/day)a slighltly lower mean body weight at birth completely recouped on post-natal day 4.

The NOAEL for parental toxicity with respect to systemic toxic effects was 24 mg/kg bw/day.
The NOEL for reproductive performance (mating and fertility) was 48 mg/kg bw/day.
The NOAEL for toxic effects on progeny was 48 mg/kg bw/day.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
48 mg/kg bw/day

Justification for classification or non-classification

According to regulation 67-548 EEC and CLP regulation(EC) N° 1272/2008 the substanceis not classified as a reproductive toxicant.