2-methoxyethanol

Immunotoxicity

Description of key information

ORAL
Mice: NOAEL: 250, 400, 400mg/kgbw/day.  LOAEL: 500mg/kgbw/day
Rats: NOAEL: 25, 25-30mg/kgbw/day.  LOAEL: 50, 50, 50mg/kgbw/day
DERMAL
rat: NOAEL=150mg/kgbw/day

Key value for chemical safety assessment

Effect on immunotoxicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

25 mg/kg bw/day

Effect on immunotoxicity: via dermal route

Endpoint conclusion

Dose descriptor:

NOAEL

150 mg/kg bw/day

Additional information

Treatment of mice with relatively large doses of methoxyethanol (500 -1000mg/kg) caused a decrease in thymic cellularity and atrophy of the cortex. Thymic markers (CD4 +/CD8 +, Thy+,PNA+), immature thymocytes are relatively decreased. There were also increases in response to other ex-vivo immunological assays (eg. Lympho-proliferative response to concanavalin A.) Overall, the study indicated that methoxyethanol at high doses selectively depletes immature thymocytes

 

All four strains of mice treated with methoxyethanol for 10 days at doses of 50 -400mg/kg were comparatively resistant to adverse effects on the humoral immune system as quantified using an antibody response to TNP-LPS assay. In another study, treatment of mice with methoxyethanol for 10 days at doses of 50 -400mg/kg had no immunosuppressive effects.

 

Exposure of mice to methoxyethanol for two weeks as doses up to 1000mg/kg resulted in a significant reduction in thymus weight (NOAEL=250mg/kg) but no reduction in the effectiveness of the humoral or cell mediated immune system when examined in a number of in vitro assays. No adverse effect was seen in a functional assay either

 

Treatment of rats acutely with methoxyethanol for 2 days significantly suppresses the antibody response to TNP-LPS. The study did not establish a NOAEL since effects were seen at the lowest dose tested (50mg/kg). Benchmark dose analysis of the results indicates that the NOAEL was in the range 25 -30mg/kg. Treatment of rats for 10 days at doses of 25 -200mg/kg caused significant suppression of the antibody response to TNP-LPS in all four strains tested. Statistically, a no effect level of 25mg/kg was established although the results suggest that the biologically significant no effect level could be lower than this.

 

Treatment of rats with methoxyethanol by oral gavage for 10 days at doses of 50 -200mg/kg causes significant suppression of immune system as quantified by a number of assays. The most sensitive changes were lymphoproliferative reduced response to certain mitogens, enhanced PFC response to SRBC and IL2 reduced production at all dose levels. Other assays or the same ones with different mitogens or antibody stimulants were less sensitive or produced negative results. A decrease in thymus weight in the absence of body weight change was also seen at all doses.

 

Treatment of rats with methoxyethanol by oral gavage for 10 days at doses of 50 -400mg/kg causes significant suppression to the humoral and specific cell mediated immune system. The most sensitive changes were reduced lymphoproliferative response to a number of mitogens where effects were seen at all doses. A decrease in thymus weight in the absence of body weight change was also seen at al doses.

 

Oral treatment of rats with a single dose of methoxyethanol as low as 125mg/kg results in a visible increase in the number of thymic apoptotic cells within 3 hours. Prior treatment with phenobarbital reduced the level of thymic toxicity which is likely to be due to a reduction in the capacity of the animal to metabolise methoxyethanol to the active metabolite toxicant methoxyacetic acid.

 

Treatment of rats with methoxyethanol by dermal exposure for 4 days at doses of 150 -1200mg/kg causes significant suppression of the specific cell mediated immune system and the humoral immune system in particular. The no effect level for suppression of the latter was 150mg/kg. A decrease in thymus weight in the absence of body weight change was also seen at higher doses. Effects from dermal exposure mirror those from oral exposure clearly indicating that methoxyethanol is toxic by the dermal route.

In conclusion, 2-methoxyethanol does appear to be toxic to the immune system in both mice and rats. The evidence suggests that effects are only seen at quite high oral doses in mice (LOAEL=500mg/kgbw/day) but that clear suppression of the immune system of rats was seen at oral doses as low as 50mg/kgbw/day.

Justification for classification or non-classification

On the basis of the reported effects showing suppression of the immune system in rats at levels of 50mg/kgkb/day by the oral route, classification with R48 under directive 67/548 would be required. Because the NOAEL for the dermal route was shown to be 150mg/kgbw/day, classification for this route is not required. A classification of R48/22 would be appropriate.

For classification under the CLP regulation 1272/2008, since there is clear evidence for immunosuppressive effects in rats after as few as 2 exposures, classification for specific target organ toxicity for a single dose exposure by the oral route seems appropriate. Since the dermal study only used a four day exposure, this also seems appropriate to consider as a 'single' rather than a 'repeat dose' exposure. The LOAEL for the oral route is 50mg/kgbw/day whilst for the dermal route it is 300mg/kgbw/day. These would trigger a category 1 classification for both routes. There is no data for the inhalation route, but there is no reason to suspect that the same toxicity would not be manifest following dosing by this route, so the hazard phrase should not be route specific. A classification of STOT (single exosure) H370 "Causes damage to organs (immune system)" is therefore recommended.