Registration Dossier

Administrative data

Description of key information

Inhalation:
NOEC (14 days, 6h/d, whole body, male rat): 0.187 mg/L (corresponding to 132.6 mg/kg bw/d)
NOAEC (14 days, 6h/d, whole body, male/female rabbit): 0.187 mg/L
NOAEC (14 days, whole body, male rat): < 0.374 mg/L
NOAEC (14 days, whole body, pregnant rabbit): 0.374 mg/L
Oral (read across to 2-Methoxyethanol, the metabolite of Ethylene glycol dimethyl ether):
NOEL (14 days, drinking water study, male mouse): 200 mg/kg bw/d
NOEL (14 days, drinking water study, female mouse): 600 mg/kg bw/d
NOAEL (13 weeks, drinking water study, male/female mouse): < 2000 ppm
NOAEL (14 days, drinking water study, male rat): 200 mg/kg bw/d
NOEL (14 days, drinking water study, female rat): 400 mg/kg bw/d
NOAEL (13 weeks, drinking water study, male rat): < 750 ppm

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
187 mg/m³

Additional information

A 14 day inhalation toxicity study was performed in rats. The animals were exposed to 0.037, 0.187 and 0.935 mg/L 6 hours per day (whole body exposure).

All animals survived and no clinical signs were noted at any dose level. No neurological or ophthalmological effects or changes in mucosa were noted. Body weight gain of all animals was not affected. There were no effects upon the mean daily food consumption observed at all dose levels. Water consumption of all females of the 0.037 mg/L dose group was decreased from day 29 until termination of the study. Water consumption of all females of the 0.935 mg/L dose group was decreased on study day 22 and 50. There were no haematological changes noted at any dose level. All determined clinical parameters were within the control range. Relative organ weights were within the control range. No changes occurred at any dose level with the exception of the reduction of cell layers of seminiferous epithelium in male rats of the 0.935 mg/L dose group. This effect was reversible. There were no such findings in the recovery group.

 

 

In a further 14 day inhalation study rabbits were exposed to 0.037, 0.187 and 0.935 mg/L 6 hours per day (whole body exposure). In the control group, one male was found dead on day 10 and in the 0.037 mg/L dose group, one female died on day 11. In the 0.187 mg/L dose group, one male was found dead on day 2 (this animal was replaced by one male of the satellite group) and in the 0.935 mg/L dose group, one female was found dead on day 12. All other animals survived and no clinical signs were noted at any dose level. No neurological or ophthalmological effects or changes in mucosa were noted. Body weight gain of all animals was not affected within the first 15 days of the study. During the 36 days recovery period the body weight gain of the male animals of the 0.935 mg/L dose group was considerably decreased, the body weight gain of the females of this dose group was slightly decreased. With one exception there were no effects upon the mean daily food consumption observed at all dose levels. The food consumption of the animals of the 0.935 mg/L dose level was decreased during the exposure period. Water consumption of all males of the 0.935 mg/L dose group was increased during the recovery period. In case of all other animals the water consumption was not affected. The reticulocyte count of all animals of the 0.935 mg/L dose group and of the females of the 0.187 mg/L dose group was decreased one day after the last exposure. The leucocyte count of the females in the 0.935 mg/L dose group was slightly decreased. These effects were reversible within the recovery period. All determined clinical parameters were within the control range. Relative organ weights were within the control range with the exception of a decreased testis weight of the males in the high dose group after the recovery period. No changes occurred at any dose level with the exception of changes of the seminiferous epithelium in male rabbits of the 0.935 mg/L dose group which caused aspermia. This effect was irreversible within the recovery period of 36 days.

 

Rats (males and pregnant females) were exposed to an atmosphere of 0.374 or 1.87 mg Ethylene glycol dimethyl ether/L daily for up to 14 days. All animals survived and no clinical signs were noted at 0.374 mg/L. No deaths or clinical signs occurred in the rats of the 1.87 mg/L dose group. Body weight gain of the rats at 0.374 mg/L exposure was unaffected. The body weight of the male rats of the 1.87 mg/L dose group was unaffected; the body weight of three female rats was decreased. There were no effects upon the mean daily food consumption observed in the 0.374 mg/L dose group. Food consumption of all females in the 1.87 mg/L dose group was decreased. There were no haematological changes noted at 0.374 mg/L. At 1.87 mg/L the leucocyte count was decreased in all animals. No changes occurred in all rats. The microsopic examination of the testes and epidymis showed oligospermia at 0.374 mg/L and severe lesions of the seminiferous epithelium at 1.87 mg/L exposure. At 0.374 mg/L retardation of foetal development was observed. At 1.87 mg/L an increase of resorptions occurred.

 

Pregnant rabbits were exposed to an atmosphere of 0.374 or 1.87 mg Ethylene glycol dimethyl ether/L daily for 14 days. All animals survived and no clinical signs were noted at 0.374 mg/L. All rabbits of the 1.87 mg/L dose group died (one female died after the 7th exposition, one on the first day after the last application, two on the second day after the last application and one was found dead 8 days after the last application). Four of five rabbits in the 0.374 mg/L dose group had a slightly decreased body weight gain; the body weight of all rabbits was decreased at 1.87 mg/L. There were no effects upon the mean daily food consumption observed in the 0.374 mg/L dose group. Food consumption of all females in the 1.87 mg/L dose group was decreased. There were no haematological changes noted at 0.374 mg/L. At 1.87 mg/L the leucocyte count, the lymphocyte count and reticulocyte count was decreased in the rabbits. The rabbits of the 1.87 mg/L exposure group showed enlarged livers. Exposure to 0.374 mg/L of the test substance resulted in the resorption of all embryos. At 1.87 mg/L no rabbit survived.

 

Since there is a strong evidence in literature that Ethylene glycol dimethyl ether is metabolised to 2-Methoxyethanol a read across to the 2 and 13-week drinking water study with 2-Methoxyethanol in rats and mice might be justified to estimate possible systemic effects of the glycol ether via oral route.

In summary, the major target organs for toxicity of 2-Methoxyethanol were testes in males (decrease in testicular and epididymal weight) and the haematopoetic system (lymphoid depletion) in both species. These effects were also observed via the inhalatory route.


Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: testes

Justification for classification or non-classification

Since no severe changes in pathology and histopathology occurred in a 14 day inhalation studies in rats exposed to the test substance at a concentration up to 0.935 mg/L, Ethylene glycol dimethyl ether does not have to be classified regarding systemic and target organ toxicity after repeated exposure according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC). It can reasonably be deduced that the only severe effects caused by Ethylene glycol dimethyl ether are restricted to the male reproductive system (reduced testes weight, changes in seminiferous epithelium etc.) and the fetal development/viability. The substance is already classified accordingly (R60 – May impair fertility; R61 – May cause harm to the unborn child; H360 – May damage fertility or the unborn child). No other severe systemic effects were observed after repeated applications to test animals. Furthermore the substance is found to be moderately irritating and it is unlikely that higher amounts than tested in the repeated dose toxicity study will be systemically available via the skin barrier. Therefore, toxicity testing via dermal route is not scientifically necessary.