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Description of key information

NOEL (3 weeks, 6h/d, whole body, male/female rat): 200 ppm (corresponding 318.4 mg/kg bw/d)
NOEC (2 weeks, 6h/d, nose only, female rat): 370 ppm (corresponding to 589 mg/kg bw/d); LOAEC (male rat): 110 ppm (corresponding to 175.1 mg/kg bw/d)
NOEC (5 days, 7h/d, whole body, male mouse): 250 ppm
NOEC (2 weeks, 6h/d, nose only, male rat): < 110 ppm (corresponding to 175.1 mg/kg bw/d)
Oral (read across to 2-Methoxyethanol, a metabolite of Diethylene 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:
603.9 mg/m³

Additional information

A 15 day (3 weeks) inhalation toxicity study was performed in rats. The animals were exposed to a Diethylene glycol dimethyl ether atmosphere of 200 ppm and 600 ppm. All animals survived and no clinical signs were noted at any dose level. Body weight gain of the rats at 200 ppm exposure (corresponding 318.4 mg/kg bw/d) was unaffected. The body weight of the rats of the 600 ppm dose group was irregular. There were no changes in haematology and urinalysis noted at any dose level.At 600 ppm the thymus was atrophied.

To assess the inhalation toxicity of Diglyme, groups of 20 male and 10 female rats were exposed by nose-only inhalation 6 hours/day, 5 days/week for 2 weeks to either 0 (control), 110, 370 or 1100 ppm Diglyme. 2-Methoxyethanol was applied as positive control. Rats were sacrificed immediately following exposure, after a 14-day recovery period, or after 42 and 84 days of recovery (males only). Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to Diglyme produced a variety of concentration-related changes. The most striking effect produced in all test groups was cellular injury involving the testes, seminal vesicles, epididymides and prostate. Although these effects were more severe at the higher concentrations tested, partial or complete recovery was seen by 84 days post-exposure. Changes in the haematopoetic system occurred in both sexes and involved the bone marrow, spleen, thymus, leucocytes and erythrocytes. The testicular effects of Diglyme were somewhat less pronounced than those seen with 2-Methoxyethanol. The NOEC for repeated inhalation exposure to Diglyme in female rats is 370 ppm (corresponding to 589 mg/kg bw/d). For males, the NOAEC was derived at 110 ppm (corresponding to 175.1 mg/kg bw/d).


A sperm abnormality test was performed with male mice. The animals were exposed to 0, 250 and 1000 ppm Diglyme for 7 h/d on 5 consecutive days. Sperm head abnormalites were increased in the high dose group leading to a NOEC of 250 ppm.


Male rats were exposed to 0, 110, 370, or 1100 ppm Bis(2-methoxyethyl)ether (Diglyme) 6 h/d, 5 d/week for 2 weeks. Rats were killed after 10 days of exposure and 14, 42, or 84 days post-exposure (PE), respectively. At 110 ppm, spermatocytes in pachytene and meiotic division at spermatogenic stages XII-XIV were mainly affected. At 370 ppm, affected germ cells were similar to those seen at 110 ppm, but round spermatids at spermatogenic stage I-VIII were also affected. The testes regained normal spermatogenesis by 84 days PE. At 1100 ppm, marked testicular atrophy was found affecting all spermatogenic stages. Damaged seminiferous tubules were lined with regenerating pachytene spermatocytes at 14 days PE and with spermatocytes and round spermatids after 42 days PE. Most but not all testes in rats exposed to 1100 ppm Diglyme had normal morphology after 84 days PE.


Since there is a strong evidence in literature that to 2-Methoxyethanol is a metabolite of Diethylene glycol dimethyl ether 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 of organs occurred in inhalation studies in rats and mice exposed to the test substance at a concentration up to 370 ppm (corresponding to 589 mg/kg bw/d; changes in male reproductive organs) and thymus atrophy was observed at dose levels of 600 ppm (corresponding to 955 mg/kg bw/d), Diethylene 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 Diethylene glycol dimethyl ether are restricted to the male reproductive system (reduced testes weight, changes in seminiferous epithelium and spermatogenesis 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 not 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.