3-methyl-2-butenyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Studies specifically designed to assess effects of prenyl acetate on fertility are not available. However, in a well conducted subchronic oral toxicity study in rats using the structurally and metabolically related prenol (3-methylbut-2-en-1-ol; CAS No. 556-82-1), the scope of examinations was extended to cover also effects on reproductive organs, providing supportive evidence for effects on fertility (see also IUCLID chapter 7.5.1; BASF AG, 2002; 52C0274/00099). The read across made is justified, based on the high likelyhood that prenyl acetate would rapidly be hydrolized to prenol and acetate in the GIT and liver, and/or show a similar GIT / liver metabolism profile as prenol.

 

In this study according to OECD TG 408 and GLP, 3-methylbut-2-en-1-ol was administered to groups of 10 male and 10 female Wistar rats in the drinking water at concentrations of 0, 200, 1000 and 5000 ppm for 3 months (14.4 and 21.0 mg/kg bw/day, 65.4 and 82.1 mg/kg bw/day, 243.8 and 307.2 mg/kg bw/day for males and females). At necropsy, the weights of primary and secondary reproductive organs of the males and females were assessed followed by gross pathology and histopathological examinations. Furthermore, immediately after necropsy, the right testis and cauda epididymis were taken from all male animals. Sperm motility, sperm morphology and sperm head count (cauda epididymis and testis) were examined.

No treatment related changes in sperm analysis were observed. The weights of the reproductive organs were not influenced by the exposure, except a significantly increased relative weight of the testes (+13.7 %) and epididymides (+12.7 %) in the high dose males (considered as a consequence of the decreased mean terminal body weights in these animals) and a slightly (-13.6 %), but significantly (p ≤ 0.05) decreased absolute organ weight of the ovaries of the high dose females. However, the relative ovary weights were not affected. No histological abnormalities were observed in all organs investigated. Accordingly, no histological correlates were obtained for the changes in relative weights of the testes and epididymides and absolute weights of the ovaries. Considering the lack of a histopathological correlate, a given biological variation of these organ weight parameters in connection with the reduced terminal body weight of the high dose animals, these observations were not regarded as adverse effects. Therefore, the NOAEL for fertility was determined as the highest tested concentration of 5000 ppm (243.8 and 307.2 mg/kg bw/d for males and females).

 

Conclusion:

Based on the results from the subchronic toxicity study in rats according to OECD TG 408 and GLP, no evidence for adverse effects on fertility by 3-methylbut-2-en-1-ol was found up to the dose levels of 243.8 mg/kg bw/day for males and 307.2 mg/kg bw/day for females. Overall, the structurally and metabolically related analog to prenyl acetate does not give indications for adverse effects on reproductive organs or tissues. Therefore no rationale for a reproductive toxicity study (e.g. a two-generation study) with prenyl acetate is given based on the current data available. 

Effects on developmental toxicity

Additional information

No data on developmental toxicity are available for prenyl acetate. However, developmental toxicity data on the structurally and metabolically related prenol (3-methylbut-2-en-1-ol ; CAS No. 556-82-1) are taken into account for assessment via read across. This read across is justified, based on the high likelyhood that prenyl acetate would rapidly be hydrolized to prenol and acetate in the GIT and liver, and/or show a similar GIT / liver metabolism profile as prenol.

 

3-Methylbut-2-en-1-ol was tested for its prenatal developmental toxicity in Wistar rats according to OECD TG 414 and GLP (BASF, 2002; 30R0274/00116). The test substance was administered as an aqueous suspension in carboxymethylcellulose to 25 time-mated female Wistar rats/group by stomach tube at doses of 50, 200 and 600 mg/kg bw/day on day 6 through day 19 post coitum (p.c.). A standard dose volume of 10 ml/kg bw was used for each group. The control group, consisting of 25 females, was dosed with the vehicle only.

The oral administration of 3-methylbut-2-en-1-ol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition elicited clear signs of maternal toxicity at 600 mg/kg bw/day. Maternal toxicity was substantiated by adverse clinical findings like salivation, lacrimation, abdominal position and piloerection, which could be at least partly observed throughout the treatment period. One dam died before schedule, and relation to test substance application cannot be excluded. After initiation of treatment, mean food consumption, mean body weight and mean body weight gain were statistically significantly lowered if compared to the controls. Moreover, the corrected body weight gain and the mean carcass weight were also impaired. No signs of substance-induced maternal toxicity were observed at the low and the mid dose levels (50 or 200 mg/kg bw/day). There were no substance-related influences on the gestational parameters up to and including the highest dose level (600 mg/kg bw/day). Conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio or the calculated pre- and postimplantation losses were unaffected by treatment. The test substance administration evoked no signs of developmental toxicity and in particular no indications for teratogenicity at any of the dose levels tested. Placental and fetal body weights were unaffected. The external, soft tissue and/or skeletal (including cartilage) examinations of the fetuses revealed no biologically relevant differences between the control and the substance-treated groups.

Based on the results of this developmental toxicity study, the no observed adverse effect level (NOAEL) for maternal toxicity is 200 mg/kg bw/day and ≥ 600 mg/kg bw/day (the highest dose tested) for developmental toxicity.

 

Conclusion:

Based on the results of this developmental toxicity study with 3-Methylbut-2-en-1-ol, the no observed adverse effect level (NOAEL) for maternal toxicity is 200 mg/kg bw/day. The no observed adverse effect level (NOAEL) for developmental toxicity is≥600 mg/kg bw/day (the highest dose tested) and no evidence of fetotoxicity or teratogenicity was found. Overall, the structurally and metabolically related analogue to prenyl acetate does not show any developmental toxicity potential, therefore no developmental toxicity is to be expected for prenyl acetate.

Toxicity to reproduction: other studies

Additional information

No data available.

Justification for classification or non-classification

The present data on reproductive toxicity do not fulfill the criteria laid down in 67/548/EEC and 272/2008/EEC, and therefore, a non-classification is warranted.