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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

SYN545192 was evaluated for potential to cause effects on reproductive and developmental toxicity in a multi-generation reproductive toxicity study in the rat and in pre-natal developmental toxicity studies in the rat and rabbit.

SYN545192 was evaluated in a two-generation reproduction study in the rat at dietary inclusion levels of 0, 25, 100, 250 ppm (females) or 600 ppm (males). 

Effects on parent animals: At 600 ppm, body weight gain in the P generation was lower than control during the pre-pairing period and body weight was lower during the pre-pairing and after pairing periods. In the F1 generation, mean body weight and body weight gain were lower than control during the pre-pairing and after pairing periods. At 250 ppm, body weight gain in the P and F1 generations was lower than control during the pre-pairing and gestation periods and body weight was lower than control during the pre-pairing period and remained lower throughout the gestation and lactation periods. At 600 ppm, mean food consumption in the P generation was periodically statistically significantly lower than control during the pre-pairing and after pairing periods. At 250 ppm, mean food consumption in the P and F1 generations was periodically statistically significantly lower than control during the pre-pairing period, and it was significantly lower during the whole of the gestation period and part of the lactation period.

In the 250 ppm group, the mean corpora lutea count at necropsy in the P generation was statistically significantly lower than control. The group mean corpora lutea count at necropsy in the F1 generation was similar in all dose groups. The follicle and corpora lutea count made during micropathological examination of ovarian tissues from females of the F1 generation, showed a lower number of growing follicles and corpora lutea in the high dose group compared to the control group. There was an increased incidence of lactational diestrous in parental females of both generations at 250 ppm. These observations are consistent with a reduction in ovarian growing follicle and corpora lutea counts occurring as a consequence of prolonged lactational diestrus in dams that had to nurse their pups for longer due to the significant effect on pup body weight. The prolonged nursing of the pups delayed the dams returning to normal estrous cycling hence the higher incidence of lactational diestrus. These observations are therefore considered to be an indirect consequence of the effects on pup weight and maternal body weight and are not indicative of an effect on reproduction.

At 600 ppm, the weight of the liver adjusted for body weight was statistically significantly increased in the P and F1 generations. The weight of the liver adjusted for body weight was statistically significantly higher than control in the F1 females at 250 ppm. In both in P and F1 generations, microscopic examination revealed centrilobular hepatocellular hypertrophy in males at 600 ppm. There was also an increased incidence of cell hypertrophy in the pars distalis of the pituitary in the F1 generation in males at 600 ppm.

 

Effects on the offspring:The body weight of the P and F1 generation pups in the 250 ppm dose group was lower than control. The time until preputial separation was statistically significantly longer in the males in the 600 ppm dose group. However, the body weight at the time of sexual maturation was similar to the control value and other treated group values indicating that this observation is a secondary consequence of the lower body weight of these animals. The time until vaginal patency in the F1 female pups was not affected by treatment with the test item and there were no effects on anogenital distance. In the 250 ppm F1 males, relative spleen weight was lower than controls, and relative liver weight was higher in both sexes at 250 ppm.  

Effects on reproductive performance: There were no effects on the length or pattern of estrus cycles prior to mating, pre-coital interval, gestation length or the proportion of successful matings in P or F1 parents. There were no adverse effects on reproduction up to the top dose level of 600/250 ppm.  

Overall conclusion: The parental NOAEL was considered to be 100 ppm (equivalent to 6.8 mg/kg/day for P generation males during pre-pairing). The NOEL for reproduction was 600 ppm (equivalent to 40.5 mg/kg/day for P generation males during pre-pairing) and the offspring NOEL for general toxic effects was 100 ppm (equivalent to 7.8 mg/kg/day for F1 generation males during pre-pairing).

Developmental toxicity:In a developmental study in the rat,SYN545192was administeredat dose levels of 0, 7.5, 15 and 30 mg/kg/day. All female animals survived until the scheduled necropsy. Marked clinical signs of toxicity (ataxia, hunched posture, prostrate, decreased activity and ruffled fur) were observed at 30 mg/kg/day. Mean food consumption, body weight and body weight gain were lower at 30 mg/kg/day. Mean foetal body weight was lower at 30 mg/kg/day and there was a slight delay in ossification which was considered to be related to the treatment with the test item and secondary to maternal toxicity. At visceral examination, the incidences of thymus long cranial attained statistical significance at 30 mg/kg/day and these values were outside the historical control range. In the absence of increased incidences of findings in other related structures, the higher incidence of an isolated minor variation which is commonly seen in this laboratory was considered to be of no biological significance in terms of foetal development.

The NOEL for maternal and developmental toxicity was 15 mg/kg/day. 

In a dose-range finding study in pregnant rabbit, a dose level of 100 mg/kg/day produced severe body weight loss and reduced food consumption that resulted in the early termination of all females at this dose level. Excessive body weight losses and reduced food consumption also led to abortion and moribundity in individual females at 50 mg/kg/day indicating that this dose level was unsuitably high for a full developmental toxicity study. On this basis, dose levels of 0, 10, 20, and 35 mg/kg/day were selected for the definitive prenatal development toxicity study the rabbit. There were no treatment-related effects on the dams at any dose level. Marginaleffects on maternal body weight gain were seen at 20 and 35 mg/kg/day during gestation days 13-20. There were no effects on development. The NOEL for maternal and developmental toxicity was 35 mg/kg/day.


Short description of key information:
SYN545192 has no effect on fertility, sexual function or other parameters of reproductive performance. SYN545192 does not cause any specific indications of developmental toxicity. SYN545192 is not classified for reproductive toxicity.

Justification for classification or non-classification

Based on the available information the substance does not meet the criteria for classification as "reproductive toxicant" under Regulation (EC) 1272/2008, Annex I, Part 3, 3.7.2; reason for non-classification: conclusive but not sufficient for classification.

Based on the available information the substance does not meet the criteria for classification as "effects on or via lactation" under Regulation (EC) 1272/2008, Annex I, Part 3, 3.7.2; reason for non-classification: conclusive but not sufficient for classification.

Additional information