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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

There are no data for the intermediate mixture; however information is available on the specific components present.

 

In a 2-generation study on cyclohexane, no effect was seen on reproductive parameters at the maximum dose tested (Krechmann, 2000).

 

There is no evidence that toluene has any effect on fertility and does not warrant classification for reproductive toxicity. Roberts et al (2003) conducted a combined two-generation fertility and teratogenicity inhalation study in rats. Toluene exposure did not induce adverse effects on fertility and the NOAEC for effects on fertility was the highest dose tested. The EU RAR (2003) concluded “In humans, no studies of effects of toluene on sperm count were found. Limited data in humans have not shown indication of effects on fertility in men or menstrual function in women”.

 

F0 male and female CD-1 mice were administered 4-vinylcyclohexene by oral gavage at doses of 0, 100, 250 or 500mg/kg body weight/day for 16 weeks prior to conception of an F1 breeding generation. Direct dosing (0 or 500 mg/kg body weight/day, by gavage) of 21-day old weaning F1 adults commenced 7-8 weeks prior to conception of an F2 generation, therefore, adults were exposed to 4-vinylcyclohexene before and during mating, throughout pregnancy and lactation, with continuous exposure of the foetuses and pups occurring secondary to maternal treatment (i.e. occurring in utero or via milk, respectively). 4-vinylcyclohexene, at doses up to 500 mg/kg body weight/day, which resulted in generalised toxicity, was clearly toxic to ovarian follicles in female offspring (significant reduction in primordial oocytes, growing follicles and antral follicles) and produced a slight but statistically significant effect on sperm motility in F1 male offspring (concentration and morphology unaffected). However there were no effects on reproductive performance of the F0 or F1 generations, including mating and fertility indices, live litter size, sex ratio and pup survival to post-natal day 4. The NOAEL reproductive performance/foetotoxicity/teratogenicity was 500 mg/kg/day and the LOAEL gonadal toxicity (F1 males and females) was 500 mg/kg (Grizzle, 1994). The US HPV challenge program reports the structure-activity investigations indicate that metabolism to a diepoxide is central to the induction of ovarian toxicity by 4-vinylcyclohexene in the mouse.

 

Data are available on the specific component n-hexane, which is classified with regard effects on fertility:

 

n-Hexane (Classification: EU Harmful, Xn R62; GHS/CLP Category 2, H361f): Testicular atrophy in male rats is seen after repeated dose oral or inhalation exposure to generally high doses of n-hexane which also produce peripheral neuropathy and other systemic effects.

Materials require classification if they contain ≥ 3% n-hexane according to Reg (EC) 1272/2008 ≥ 5% according to Dir 1999/45/EC.


Short description of key information:
No data are available for the intermediate; however information is available for the major and minor components present. Of these, n-hexane is classified with regard to effects on fertility and triggers mandatory classification.

Effects on developmental toxicity

Description of key information
No data are available for the intermediate; however information is available for the major and minor components present. Of these, toluene is classified with regard to effects on foetal development and triggers mandatory classification.
Additional information

There are no data for the intermediate. However there are data available on the specific components one of which, toluene is classified for possible developmental toxicity.

 

Data available on the specific major component n-hexane indicate no hazard with respect to developmental toxicity and no classification is warranted (ASTDR, 1999).

 

The developmental toxicity of cyclohexane was assessed in rats and rabbits (Krechmann, 2000). No compound-related evidence of developmental toxicity was observed, even at the highest doses tested.

 

Two generations of mice were administered 4-vinylcyclohexene by oral gavage at doses up to 500mg/kg body weight/day in a continuous breeding program. Therefore, adults were exposed before and during mating, throughout pregnancy and lactation, with continuous exposure of the foetuses and pups occurring secondary to maternal treatment (i.e. occurring in utero or via milk, respectively). 4-vinylcyclohexene, at doses up to 500 mg/kg body weight/day, which resulted in maternal toxicity, had no adverse effects on pregnancy or pre-and post-natal foetal development following exposure for 2 generations. Whilst not a developmental toxicity study, the study provides sufficient evidence that 4-vinylcyclohexene is not fetotoxic or teratogenic in the mouse (Grizzle, 1994).

 

Toluene is classified for possible developmental toxicity:

Toluene (Classification: EU – Harmful Xn, R63; GHS/CLP – Category 2, H361d): There is no evidence that toluene produces malformation in animals or humans. There is some evidence of developmental toxicity (lower body weight at birth and delayed vaginal opening) at toluene exposure concentrations ≥ 1000 ppm, concentrations which are associated with slight maternal toxicity. The NOAEC for developmental and maternal effects is 600 ppm (2261 mg/m3) (Thiel and Chahoud, 1997).

Complex substances and intermediates require classification if they contain ≥ 3% toluene according to Reg (EC) 1272/2008 or ≥ 5% according to Dir 1999/45/EC.

 

Additional References

ATSDR (1999). Toxicological Profile for n-Hexane.U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.http://www.atsdr.cdc.gov/toxprofiles/tp113. html

EU RAR (2003). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. Pdf 

US EPA HPV Challenge Program, November 2006. 4-Vinylcyclohexene, CAS 100-40-3

Justification for classification or non-classification

The intermediate contains 2 components (n-hexane, toluene) which are classified for reproductive and developmental effects:

 

It contains ≥ 3% n-hexane which is known to cause testicular atrophy, therefore the following classification is mandated: “Suspected of damaging fertility” Category 2, H361f according to Reg (EC) 1272/2008 and “Possible risk of impaired fertility” Category 3 Xn, R62, according to Dir 1999/45/EC.

 

It also contains ≥ 3% toluene; therefore the following classification is mandated: Category 2, H361d “Suspected of damaging the unborn child” according to Reg (EC) 1272/2008 and Xn, Cat 3 R63 “Possible risk of harm to unborn child” according to Dir 1999/45/EC.