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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
960 mg/m³
Species:
rat
Quality of whole database:
Adequate information is available to characterise the effects of benzene on fertility following inhalation exposure.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a one-generation reproduction toxicity study, there were no significant effects at any dose tested (up to 300 ppm) on maternal body weight and body weight gain and on fertility/reproductive endpoints as measured by percentage of pregnant animals, mean gestational length, number of litters, litter size, and viability of the pups and the weanlings. The only statistically significant postnatal developmental effects for offspring were lower female pup body weight on day 21 and lower liver weight at the 300 ppm exposure level. These differences were small (10 and 14%, respectively) and considered not to be adverse. An exposure concentration of 300 ppm (960 mg/m3) is a NOAEC for fertility/reproductive toxicity in adults and postnatal developmental effects for offspring.


Short description of key information:
It is recognised that there is a data gap for a multi-generation study (REACH reference 8.7.3). The applicant submits that this study does not need to be conducted as benzene is known to be a mutagenic and carcinogenic substance and appropriate risk management measures are implemented. Benzene is produced and used under strictly controlled conditions. In addition a single generation study with a high dose of 300ppm (960 mg/m3) showed no effects on female fertility.

Justification for selection of Effect on fertility via inhalation route:
There were no significant effects on fertility/reproductive endpoints or postnatal development in a one generation study involving exposures up to 300 ppm (960 mg/m3).

Effects on developmental toxicity

Description of key information

Developmental toxicity of inhaled benzene has been investigated in 3 species (rat, mouse and rabbit). No evidence of teratogenicity was seen in any

species. Minor fetotoxic effects (reduced foetal weight, length and associated delays in skeletal ossification) were seen at concentration > 50 ppm and generally accompanied by maternal toxicity. The NOAEC for maternal and pre-natal developmental toxicity was 10 ppm (32 mg/m3).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
32 mg/m³
Species:
rat
Quality of whole database:
Adequate information is available to characterise the ffects of benzene on foetal development following inhalation exposure.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The pre-natal developmental toxicity (or teratogenic) potential of benzene inhaled at doses ranging from 1 to 500 ppm by pregnant Sprague-Dawley rats on gestation days 6-15 has been investigated in two studies (Coate et al, 1984; Kuna and Kapp, 1981). No maternal toxicity was observed at 100ppm (Coate et al, 1984) but maternal body weight and bodyweight gain were decreased at 50 and 500 ppm (Kuna and Kapp, 1981). Reduced foetal weight was seen at 100 ppm (Coate et al, 1984) and at 50 and 500 ppm (Kuna and Kapp). Reduced crown rump lengths and associated delay in ossification of extremities and sternebrae were seen in the same foetuses.

Overall, the NOAEC for teratogenicity in the rat was 500 ppm (1600 mg/m3), the NOAEC for maternal and developmental toxicity was 10 ppm (32 mg/m3).

The effect of inhaled benzene on pre-natal developmental toxicity/teratogenicity was also assessed in CF-1 mice and New Zealand white rabbits. There were no significant effects on maternal clinical condition, body weight or body weight gain. Benzene exposure did not significantly affect the incidence of pregnancies or the average number of live foetuses or resorptions per litter in either species. Mean foetal body weight, but not crown-rump length, was decreased significantly in benzene exposed mice but there were no effects in rabbits. No teratogenic malformations were observed in either species. However, increases in the occurrence of several minor skeletal variants (including delayed ossification of sternebrae, skull bones and of unfused occipital bones of the skull) were reported in offspring of benzene-exposed mice.

The NOAEC for maternal toxicity was 500 ppm (1600 mg/m3) in rabbits and mice. 500 ppm (1600 mg/m3) was the NOAEC for pre-natal developmental toxicity in rabbits and the LOAEC for pre-natal developmental toxicity in mice.


Justification for selection of Effect on developmental toxicity: via inhalation route:
The pre-natal developmental toxicity of benzene has been investigated in rats, mice and rabbits. Reductions in maternal and foetal body weights (together with reduced crown rump lengths and associated delays in ossification of extremities and sternebrae) were reported in rats, with a NOAEC of 10 ppm (32 mg/m3). The NOAEC for teratogenicity was 500 ppm (1600 mg/m3), the highest level tested.

Justification for classification or non-classification

Based on the results of a rat single generation toxicity/fertility study and developmental toxicity studies in 3 species and according to EU criteria benzene does not warrant classification for reproductive or developmental toxicity under Dir 67/548 or Regulation (EC) No 1272/2008 of the European Parliament.