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Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
LOAEC
140 mg/m³
Additional information

AGE was tested for its effects on fertility in two species in a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (rats and mice; NTP, 1990).

Osborne-Mendel rats (20/sex/dose) were exposed at concentrations of 0, 140, 467 and 934 mg/m3 AGE vapors during 8 weeks premating period (6 hours/day, 5 days/week). Mating (1:1) begun 2 days after the end of the 8 week exposure period: control animals with control animals, exposed males with control females and control males with exposed females. Two males died at 934 mg/m3. A decrease in body weight gain was observed in males (70% and 82 % compared to control) and females (86% and 92% compared to control) in high- and mid-dose animals at the end of exposure. A slight decrease of body weight gain was also seen in the low dose animals. At termination female body weight had recovered, while male body weights were still reduced at all dose levels (90, 89 and 84% of control at 140, 467 and 934 mg/m3, respectively). No significant effects were seen on motility or on the number of sperms. However, the percentage of abnormal sperms present at 934 mg/m3 was statistically significantly increased (1.11% compared to 0.64% in the control) in exposed males. When males were exposed previous to mating, the number of pregnant females, the number of implantation sites, the number of litters, the litter size and pups viability decreased in a dose-related manner at all dose levels. No effect on duration of gestation and sex ratio was observed. When females were exposed none of the above effects were observed. The NOAEC for parental toxicity was established to be 140 mg/m3 due to decreased body weight gain in males. The NOAEC for fertility was established to be lower than 140 mg/m3 based on the decreased number of pregnant females and the lower pups viability (LOAEC = 140 mg/m3).

Similarly B6C3F1 mice (20/sex/dose) were exposed at concentrations of 0, 19, 47 and 140 mg/m3 AGE vapors during 8 weeks premating period (6 hours/day, 5 days/week). Mating begun 2 days after the end of the 8 week exposure period: control animals with control animals, exposed males with control females and control males with exposed females. Mortality was low and not treatment-related. At the end of exposure body weight at 47 and 140 mg/m3 was decreased (90 and 89% of control for males, and 92 and 83% of control for females, respectively). At termination body weight was slightly reduced in males (91% of control) and females (96% of control) at 140 mg/m3. No treatment-related effects were seen on sperm motility, number of sperm or abnormal sperm. No effects were seen on the mating rate, the number of pregnant females, duration of gestation, number of implantations and the number of litters when males or females were exposed. Furthermore no treatment-related effects were observed on the pups (litter size, pup weight, sex ratio, viability, external abnormalities). The NOAEL for parental toxicity was considered to be 47 mg/m3 based on decreased body weight gain in males at the highest dose group. The NOAEL for fertility was established to be >= 140 mg/m3.

In a limitedly documented summary (Reliability 4), male rats received intramuscular injections of 400 mg/kg bw AGE on days 1, 2, 8, and 9. The three surviving animals (total number not reported) were sacrificed on day 12 and a focal testicular necrosis was observed in one of them. The same report summarized results for other glycidyl ethers indicating testicular disorders to be a class effect (Lane 1980).

The clear effects on fertility in male rats provide convincing evidence that AGE should be classified as toxic to reproduction. The effects on fertility occurred at the same dose levels as other toxic effects (nasal tract irritation, reduction in body weight gain), but cannot be considered to be a secondary non-specific consequence of these other toxic effects. A category 3 classification is appropriate as the evidence is considered insufficient for category 2. This is because there is a lack of supporting data from other species and no information on the mechanism of action, so it is not possible to make a judgment on the likelihood of the effects on reproduction occurring in humans. Therefore, AGE should be classified as Repro. Cat 3/R62 based on EU standards and as Cat 2 based on GHS standards.


Short description of key information:
The effects on fertility occurred at the same dose levels as other toxic effects (nasal tract irritation, reduction in bodyweight gain), but cannot be considered to be a secondary non-specific consequence of these other toxic effects, therefore AGE should be classified as toxic to reproduction.

Effects on developmental toxicity

Description of key information
Results derived from non-standard development toxicity studies are limited due to exposure of females (and males) during the pre-mating period only. Dams were unexposed during gestation and therefore organogenesis was not adequately studied. Possible teratogenic effects would have been related to exposure of the germ cells during the pre-mating period. A NOAEL for substance related effects during organogenesis can not be established. However, under the conditions of these studies no effects on development were observed in mice and rats.
Additional information

No standard developmental study is available. The same rat and mice studies as described under Fertility were also assessed for development toxicity (NTP, 1990). Half of the pregnant females were used for fetal examinations (killed on day 19 of pregnancy); the remainder was used for postnatal examinations (up to day 21 post-partum). However, as exposure was limited to the 8 weeks pre-mating period, substance related effects on organogenesis were not adequately studied.

In rats, no treatment-related mortality was observed in females during the 8 weeks pre-mating exposure period and thereafter. At the end of the exposure period two days prior to mating, body weight gain of females was decreased at 934 mg/m3 (86% compared to control) and slightly decreased at 140 and 467 mg/m3. When females were mated with exposed males, a statistically significant decrease in gravid uterus weight was observed (45 and 40% of control at 30 and 100 ppm, respectively), due to the lower number of implantations. The number of pregnant females, the number of implantations and live foetuses decreased in a dose-related manner at all dose levels. Fetal weight, sex ratio and external findings including malformations and anomalies were not affected. No external abnormalities were observed in the few pups delivered. 

When females were exposed, no effect on placenta or gravid uterus weight, the number of pregnant females, corpora lutea, implantations, resorptions or live/dead foetuses was observed. Foetal weight, sex ratio and external findings including malformations and anomalies were not affected. No postnatal findings were observed. The NOAEC for maternal toxicity was established to be 467 mg/m3 due to the decreased body weight gain. No NOAEC can be established for developmental toxicity as the dams were not exposed during organogenesis.

In mice, no treatment-related mortality was observed in females during the 8 weeks pre-mating exposure period and thereafter. At the end of the exposure period, the body weight gain of exposed females was decreased at 140 mg/m3 (83 % compared to control) and slightly decreased at 47 and 19 mg/m3.

In the fetuses, weight and sex ratio were also not affected. Isolated occurrences of exencephaly at 47 mg/m3 when males were exposed and at 19 and 47 mg/m3 when females were exposed, were not considered to be treatment-related. In the pups, a single occurrence of spina bifida at 19 mg/m3 was observed when males were exposed and hydronephrosis at 47 mg/m3 when females were exposed. These findings were not considered to be treatment-related due to lack of a dose-response. The NOAEL for maternal toxicity was established to be 47 mg/m3 due to the decreased body weight gain. No NOAEL can be established for developmental toxicity as the dams were not exposed during organogenesis.

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: Cat 3/R62

CLP classification (EC No 1272/2008): Cat 2