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Key value for chemical safety assessment

Effects on fertility

Additional information

Data on this endpoint are presented in Section 4.1.2.9 of the EU RAR (2001; page 64ff).

The key studies for this endpoint are identical to the ones selected in EU RAR (see robust study summary in IUCLID Section 7.6.2).

No studies specifically investigating effects on fertility are available. However, in a 90d subchronic inhalation study of cumene weights of testis and ovaries were examined as were testicular sperm heads and epididymal spermatozoa (Cushman et al., 1995). Fischer 344 rats were exposed to concentrations at 0, 100, 500 and 1200 ppm for 6 h per day, 5 days per week, for 13 weeks.

No changes in reproductive organs were observed. There was also no major effect on quantitative or morphologic evaluations of spermatogenesis and no effects on testicular weights. Testicular findings were limited to atrophy in one rat at 1200 ppm. Abnormalities of the head/tail/junction regions were observed in all groups including the controls, but were attributed to individual aberrations and not exposure related effects.

In relation to fertility, there is no information available in humans and there are no animal studies specifically investigating such effects.

However, no changes were seen in the reproductive organs in rats exposed for 13 weeks with 0, 100, 500 and 1200 ppm to cumene.

Effects on developmental toxicity

Additional information

Data on this endpoint are presented in Section 4.1.2.9 of the EU RAR (2001; page 64ff).

The key studies for this endpoint are identical to the ones selected in EU RAR (see robust study summary in IUCLID Section 7.6.2).

The two studies of developmental toxicity were performed according to GLP and were based on US EPA guidelines.

 

Studies in rats

Groups of 25 female Sprague-Dawley rats were exposed to cumene vapour for six hours/day on gestational days 6 through 15 at target concentrations of 0, 100, 500 and 1200 ppm (Darmer et al. 1997). At scheduled sacrifice were performed on day 21.

No dams died, aborted or delivered early. Three dams at 500 ppm and two dams each at 100 and 0 ppm were not pregnant. All pregnant dams had live litters (one or more live foetuses) at scheduled sacrifice on 21 day.

Maternal toxicity was observed at 500 and 1200 ppm. At 1200 ppm body weight gain was significantly reduced by about 20%. Gestational parameters were unaffected by exposure. There were no significant increases in the incidences of individual malformations or of pooled external, visceral or skeletal malformations at any exposure level. There were significantly reduced incidences of bilateral dilated ureters and distension of the urinary bladder at 1200 ppm. Skeletal variations showed no statistically increased incidences related to exposure.

In conclusion, exposure to cumene vapour by inhalation during organogenesis in Sprague Dawley rats resulted in consistent maternal toxicity at 500 and 1200 ppm. No exposure related developmental toxicity was observed at any exposure concentration.

 

For this study the NOEL for maternal toxicity was 100 ppm. The NOEL for developmental toxicity (including teratogenicity) was greater than the highest dose tested, 1200 ppm.

 

The authors concluded that cumene was not teratogenic in this study.

 

Studies in rabbits

Groups of 15 rabbits (New Zealand White) were exposed to cumene vapour for six hours/day on gestational days 6 through 18 at concentrations of 0, 500, 1200 and 2300 ppm (Darmer et al. 1997). At scheduled sacrifice on gestational day 29.

Maternal toxicity was observed in all exposed groups. At 2300 ppm deaths and a significant reduction in weight gain and food consumption during the exposure period occurred.

Colour changes in the lungs of four does were observed at 2300 ppm. Gestational parameters were unaffected by exposure. There were no significant increases in the incidences of individual malformations or of pooled external, visceral or skeletal malformations at any exposure level. The only external variation noted, ecchymosis on the head, was significantly increased at 500 (but not 1200 or 2300) ppm.

In conclusion, exposure to cumene vapour by inhalation during organogenesis in New Zealand White rabbits resulted in consistent maternal toxicity at 2300 ppm and less severe maternal effects at 500 and 1200 ppm. No exposure related developmental toxicity was observed at any exposure concentration.

There was no NOEL established for maternal toxicity, the NOEL for developmental toxicity was at least 2300 ppm. No developmental toxicity including teratogenicity was observed at any exposure concentration employed.

In two well-conducted studies in rats and rabbits no developmental effects were observed. There is no information available in humans.

Justification for classification or non-classification

The general lack of findings in male rats and female rats exposed for 13 weeks, combined with the lack of developmental toxicity reported in studies of rats and rabbits exposed to cumene by inhalation indicate that cumene is not a reproductive toxicant.