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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

One study by oral route is reported for this endpoint:

The objective of this study (Davies, 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 5post-partum. An additional satellite group was included in the control and high-dose groups for observation of reversibility, persistence or delayed occurrence of systemic/irritative effects for 4ā€‘weeks post-treatment.

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 Sprague-Dawley rats received the test substance daily, by gavage, before mating and through mating and, for the females, through gestation until day 5post-partum.The dose-levels were 5, 15 or 45 mg/kg bw/day. The low- and intermediate-dose groups were each composed of 10 males and 10 females and the high-dose group was composed of 15 males and 15 females. In the high-dose group, the first 10 animals/sex having been mated were sacrificed at the end of the treatment period ; the last 5 animals/sex not mated were dosed for 4 weeks and then retained for a 4-week treatment-free period.

Another group of 15 males and 15 females received the vehicle, sesame oil, alone, under the same experimental conditions and acted as a control group. As for the high-dose group, the first 10 animals/sex were mated and sacrificed at the end of the treatment period and the last 5 animals/sex were retained for a 4-week treatment-free period. The dosing volume was 5 mL/kg bw/day.

 In all animals from the principal and satellite groups, clinical signs and mortality were checked at least once daily during the treatment period and detailed clinical examinations were performed once before the beginning of the treatment period and then once a week until the end of the study. Body weight and food consumption were recorded weekly and at designated intervals throughout gestation and lactation. A Functional Observation Battery, including assessment of responses, reflexes, forelimb grip strength, landing foot splay and rectal temperature, was performed on the first five males and the first five females to deliver from each principal group at the end of the study. At the end of the Functional Observation Battery, motor activity was measured over a 1-hour period.

Blood and urine samples were taken from the first five males and the first five females to deliver from each principal group at the end of the treatment period for analysis of hematology, blood biochemistry and urine parameters. In addition, hematological and selected blood biochemical parameters were measured at the end of the treatment-free period in the animals of the satellite group.

The first ten animals/sex/group were paired for mating after 2 weeks of treatment and the females were allowed to litter and rear their progeny until day 5post-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 5post-partum.

 In the principal groups, males were sacrificed after completion of the mating period and females on day 6post-partum. Animals from the satellite group were sacrificed at the end of the treatment-free period. All animals were subjected to a complete macroscopicpost-mortemexamination with a careful examination of the stomach lining due to the strong irritant / corrosive properties of the test item. A microscopic examination was performed on selected organs of the first five males and the first five females to deliver from the control and high-dose groups sacrificed at the end of the treatment period, on the one non-pregnant female and on all macroscopic lesions. In addition, the forestomach, ileum and mesenteric lymph nodes from the low- and intermediate-dose groups sacrificed on completion of the treatment period and from the control and high-dose groups sacrificed at the end of the treatment-free period were examined.

  Pups were sacrificed on post-natal day 5 and were carefully examined for gross external abnormalities and macroscopic abnormalities. Found dead and prematurely sacrificed pups were also examined for gross external and macroscopic abnormalities.

There were no unscheduled mortalities. Hypersalivation was observed in all males and females treated at 15 or 45 mg/kg bw/day. In addition, some males and females treated at 45 mg/kg bw/day had loud breathing, round back, piloerection, hypoactivity and half-closed eyes on occassions during the study. No relevant clinical signs were observed at 5 mg/kg bw/day.

Males treated at 45 mg/kg bw/day had statistically significantly lower mean body weight gains and food consumption in the first week of treatment (seven males lost weight). The deficit was not recouped during the treatment period or during the treatment-free period. Females treated at 45 mg/kg bw/day also had statistically significantly lower mean food consumption in the first week of treatment.There were no effects at 5 or 15 mg/kg bw/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. Mean pup body weight gain between post-natal days 1 and 5 at 45 mg/kg bw/ day was lower for both sexes when compared with controls. There were no effects at 15 or 15 mg/kg bw/ day.

Laboratory investigations showed that males treated at 45 mg/kg bw/day had a significant leucocytosis and a slight anemia together with a decrease in protein and albumin concentrations but at the end of the treatment-free period, all parameters were comparable with controls. There were no treatment-related effects on hematological and biochemical parameters at 5 or 15 mg/kg/day in males or in females at any dose-level.

No treatment-related effects on organ weights and no particular macroscopic findings were observed.

Microscopic examination revealed enlarged foamy macrophages graded as minimal or slight in the ileum of males and females treated at 45 mg/kg bw/day. No particular findings were found in the ileum of animals treated at 5 or 15 mg/kg bw/day. Enlarged foamy macrophages, occasionally forming aggregates at high dose and associated with dilation of sinuses, were also observed in the mesenteric lymph nodes with a dose-related trend at all dose-levels in females and from 15 mg/kg bw/day in males. At the lower doses, the finding was marginal: 1 male treated at 15 mg/kg bw/day and 1 female treated at 5 mg/kg bw/day had a minimal infiltration in the mesenteric lymph nodes. As no degenerative changes were associated, this effect was therefore considered to be non-adverse. Partial recovery was observed by the end of the treatment-free period.

Symptoms related to the strong irritant / corrosive nature of the test substance were observed in the forestomach of males treated at 45 mg/kg bw/day at the end of the treatment period. Males rats showed acanthosis and edema of the forestomach mucosa and ulcerations and hyperplasia in the forestomach.This was considered to be treatment-related and adverse. At the end of the treatment-free period, only 1/5 males had minimal acanthosis indicating recovery.

In conclusion, clinical signs of poor condition were observed in some males and females at 45 mg/kg bw/day. Week 1 body weight gain was markedly lower in males (some males lost weight) and food consumption was reduced in males and females. Males did not

recoup the low body weight gain and mean body weight remained lower at the end of the treatment-free period. There were no effects on mating, fertility or delivery and pups showed no effects other than a slightly lower mean body weight gain from post-natal day 1 to 5. A significant leucocytosis and a slight anemia together with a decrease in protein and albumin concentrations were observed in males but all showed recovery by the end of the treatment-free period. There were no treatment-related macroscopic findings or treatment-related effects on organ weights. At microscopic examination, the strong irritating/corrosive properties of the test item were confirmed through the findings in the forestomach of all males. These findings were regarded as an irritant/corrosive effect and not as symptoms of a cumulative-systemic toxicity but were considered to be adverse. Both males and females had enlarged foamy macrophages in the ileum and mesenteric lymph nodes. They probably represent histiocytes containing 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. Recovery was observed at the end of the treatment-free period in all organs, particularly in the forestomach, where only minimal acanthosis was observed in one male.

 At 5 and 15 mg/kg/day, there were no adverse clinical signs and no effects on body weight or food consumption. There were no effects on mating or fertility and there were no effects on the pups after birth. None of the hematological or blood biochemical parameters were affected by treatment and no abnormal responses, reflexes or behavior were observed during the Functional Observation Battery. There were no treatment-related macroscopic findings and no treatment-related effects on organ weights.There were no particular findings in the forestomach and ileum at microscopic examination. Mesenteric lymph nodes revealed only minimal or slight enlarged foamy macrophages in three females and one male treated at 15 mg/kg/day and in one female treated at 5 mg/kg/day.

 Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity with respect to systemic toxic effects was considered to be 15 mg/kg/day because of the reduction of body weight and body weight gain, the significant changes in hematological and blood biochemical parameters observed in males treated at 45 mg/kg/day.

The No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 45 mg/kg/day and the

No Observed Adverse Effect Level (NOAEL) for toxic effects on progeny was 45 mg/kg bw/ day since the lower body weight gain at this dose-level was only slight.


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 (Davies, 2010a).
There were no effects on mating, fertility or delivery at any dose-level and pups showed no effects other than a slighltly lower mean body weight gain from post-natal days 1 to 5 ath the highest dose-level of the study (45 mg/kg bw/day).

The NOAEL for parental toxicity with respect to systemic toxic effects was 15 mg/kg bw/day.
The NOEL for reproductive performance (mating and fertility) was 45 mg/kg bw/day.
The NOAEL for toxic effects on progeny was 45 mg/kg bw/day.

Justification for classification or non-classification

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

Additional information