Cyclododecanone, reaction products with 3-chloro-2-methyl-1-propene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

No data available for the reaction product.

Effects on developmental toxicity

Additional information

No data are available for the reaction product. However, toluene is a component of the reaction product with a concentration relevant for classification.

The developmental toxicity of toluene was reviewed and reported in the EU RAR (2003). Developmental toxicity has been assessed in a number of studies in several species and there is no evidence that toluene produces malformations in rats or rabbits (Roberts et al, 2007; Klimisch et al, 1992). However, some evidence of developmental toxicity in the absence of maternal toxicity has been reported in rat inhalation studies (Thiel and Chahoud, 1997; Hass et al, 1999). Roberts and co-workers used whole body inhalation (6 h/day) in pregnant rats exposed to toluene at concentrations of 0, 250, 750, 1500 or 3000 ppm from GD6-15 (Roberts et al, 2007). Toluene induced evidence of maternal toxicity at 3000 and 1500 ppm. There were no adverse effects on implantation number, foetal viability or foetal sex distribution at caesarean section on GD20. Litter weight and mean foetal weight was reduced at 3000 ppm and mean foetal weight was lower at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. 

The developmental toxicity of toluene was evaluated in the Himalayan rabbit (Klimisch et al, 1992). Pregnant females were exposed to toluene by inhalation 6 h/day at concentrations of 0, 30, 100, 100, 300 or 500 ppm. Toluene was not embryotoxic, foetotoxic, or teratogenic to rabbits.

Thiel and Chahoud (1997) assessed pregnant female rats exposed to toluene via inhalation 6 h/day during gestation (days 9 -21) at concentrations of 0, 300, 600, 1000 or 1200 ppm. A detailed evaluation of physical development of offspring was conducted and included a number of reflex tests, measures of locomotor activity/co-ordination and a discrimination learning test. Maternal toluene exposures of 1200 ppm resulted in a reduced body weight gain of rat dams and offspring had lower body weight at birth and day 7 and a higher mortality until weaning. Some developmental landmarks (incisor eruption and vaginal opening) were delayed in this group and are likely to be secondary to the effect on body weight. At 1000 ppm maternal body weight gain was low and offspring had low body weight at birth and delayed vaginal opening. There were no differences in the development of reflexes, rota rod performance and locomotor activity that were attributable to treatment with toluene and no effects were found on learning ability in the operant conditioning task.

Rats were exposed to 1200 ppm or 0 ppm toluene for 6 h/day from day 7 of pregnancy until day 18 postnatally (Hass et al, 1999). Developmental and neurobehavioural effects in the offspring were investigated using a test battery including assessment of functions similar to those in the OECD 426, i.e., physical development, reflex ontogeny, motor function, motor activity, sensory function, and learning and memory. The exposure did not cause maternal toxicity or decreased viability of the offspring, however pup birth weight was lower and effects were reported on water maze performance and open field activity. Evaluation of the toxicological relevance of these findings during the EU risk assessment of toluene lead the UK CA to state that there were design limitations as only one exposure level was investigated and it considered that "it is not possible to assess the presence or absence of consistent dose-response relationships". They concluded that there was "weak evidence that toluene may elicit developmental neurotoxicity, manifested as differences in water maze performance and open field activity" and that "the conclusion that toluene is a developmental neurotoxicant to be a tentative one with uncertainties remaining to be addressed". Consequently no conclusion on developmental neurotoxicity can be made on the basis of these data.

It is concluded that toluene is not teratogenic but there is evidence of developmental toxicity (lower birth weight, delayed vaginal opening) at toluene exposure concentrations ≥ 1000 ppm. There are contradicting data as to whether these concentrations are also maternally toxic. In the study of Thiel and Chahoud, maternal body weight at 1000 ppm was statistically significantly lower than concurrent control group (9%) at the end of gestation whereas there were no effects on maternal body weight at 1200 ppm in the study of Hass et al (1999). The NOAEC for developmental effects is 600 ppm (2261 mg/m3) on the basis of lower birth weight and delayed vaginal opening.

Toxicity to reproduction: other studies

Additional information

No data available for the reaction product.

Justification for classification or non-classification

The present data on reproductive toxicity fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008 and a classification as Repr. Cat3; R63 (67/548/EEC) and reproductive toxicant; Cat2d (regulation (EU) 1272/2008) is warranted.