Registration Dossier

Administrative data

Description of key information

ORAL ROUTE:

NOAEC (6 week, gavage, rat): 900mg/kg

NOAEC (11 day, gavage, rat): 1000mg/kg

NOAEC (20 day, gavage, rat): 500-1000mg/kg - biochemical changes

NOAEC (20 day, gavage, rat): 500mg/kg (LOAEL=1000mg/kg)

DERMAL

NOAEL (90 day, rat) = 40mg/kg

INHALATION

NOAEC>1060mg/m3 (saturated vapour concentration)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
900 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

ORAL

In a 6 week sub-acute gavage study rats were given doses up to 3500mg/kg of 2 -(2 -methoxyethoxy)ethanol. A number of effects were seen in the high dose group, the most notable being adverse testicular changes. The only effects seen in the mid dose group were inconsistent increases and decrease in either relative or absolute organ weights. No treatment related changes were seen in the low dose group (900mg/kg).

In a range finder study for a developmental toxicity, non-pregnant female rats were dosed with 2 -(2 -methoxyethoxy)ethanol at up to 4000mg/kg for 11 consecutive days. At 3000mg/kg, adverse effects were restricted to decreased body weight gain and food consumption, a decrease in blood hematocrit and plasma total protein plus a decrease in the weight of the pituitary . At 2000mg/kg, the only adverse changes were non-statistically significant weight changes to the thymus and pituitary. Progressive reductions in the pH of the urine were seen at all doses, but this can be attributed to the acidic metabolite of the test substance and is not an adverse finding. Based on the biologically significant weight changes to the pituitary and thymus, a no effect level of 1000mg/kg was established.

In studies to examine the effect on the biochemistry of rats given 2 -(2 -methoxyethoxy)ethanol, the substance was given by oral gavage at doses up to 2000mg/kg for up to 20 days. The substance increased hepatic microsomal protein contents and induced cytochrome P-450, but not cytochrome b5 or NADPH-cytochrome C-reductase. A reduction in liver weight was also seen at the highest dose used, leading to a no effect level for this study of 1000mg/kg. A second study found the substance caused no changes in serum levels of the metabolic enzymes (hepatic microsomal mixed function oxidase system and cytosolic alcohol dehydrogenase enzymes GGT, SGOT, SGPT and ALP.) Levels of GGT in a number of organs were also examined. At the highest dose, GGT was seen to increase in the brain and liver and liver weight also decreased. A no effect level of 500mg/kg was established for biochemical changes in the brain (GGT increase activity), the relevance of which was unclear, and 1000mg/kg for all other effects..

In a sub-acute repeat dose study, 2 -(2 -methoxyethoxy)ethanol was given by oral gavage to rats at doses up to 2000mg/kg for up to 20 days. No effects were seen at 500mg/kg but at 1000mg/kg the thymus weight was reduced. At 2000mg/kg, body weight, liver and testes as well as thymus showed weight reductions and the thymus weight change was also accompanied by histopathological changes (lymphocyte reduction.). A no effect level for this study was 500mg/kg due to effects at 1000mg/kg.

DERMAL

In a dermal sub-chronic toxicity study which followed the basic requirements of a guideline study, guinea pigs were exposed occlusively to 2 -(2 -methoxyethoxy)ethanol at doses of 40, 200 and 1000mg/kg for 13 weeks. Exposed animals showed decreased splenic weights in the high and medium dose groups. Isolated but significant changes were also seen in the high dose groups clinical chemistry (LDH level) and haematology (MCHC level). Changes were seen in all animals urine chemistry (calcium concentration) but this was attributed to be a secondary consequence of the elimination of metabolites. Some minor fatty changes were seen in the livers of some animals in all dose groups, but it was difficult to explain the biological significance of these in the absence of any changes to any other liver parameters (eg weight) and were therefore considered to be of minimal significance. Based on this analysis, the no effect level from this study is 40mg/kg, although the suspicion that this is likely to be a very conservative finding (effects seen are not very much more severe at 1000mg/kg) and that the effects are not adverse and certainly not reflective of significant toxicity, which needs to be borne in mind in selecting appropriate assessment factors for the risk characterisation.

INHALATION

In a sub-chronic inhalation toxicity study that closely followed the requirements of a guideline study, male and female rats were exposed to 2 -(2 -methoxyethoxy)ethanol at concentrations up to and included saturated vapour concentrations. No changes were seen in any of the measured parameters, including body weight, haematology, clinical chemistry, urinalysis and gross and histopathological organ examination that could be attributed to substance exposure. Based on this result, a NOAEC of 216ppm or 1060mg/m3 can be established and more importantly, it can be concluded that there is no hazard evident in rats from any conceivable exposure to vapour

Justification for classification or non-classification

No toxic effects are possible through inhalation due to the low vapour pressure of the substance. By the oral route, the substance clearly has low toxicity with no effect levels clearly outside the ranges that would require classification. The no effect level for dermal exposure does fall within the range for potential classification. However, classification is not thought appropriate for the following reasons:

  • The test species was not rat or rabbit but guinea pig.
  • There were limited differences in the findings between the low and high dose groups. No clear dose response relationship.
  • The findings may not reflect an 'adverse' effect and do not constitute 'significant toxicity'.
  • It is difficult to rationally explain why the toxicity should be so much more severe by the dermal route than the oral route

This leads to the conclusion that a NOAEL of 40mg/kg for dermal toxicity could be questioned as not reliable (a conclusion also reached by the CSTEE committee (Opinion on the results of the Risk Assessment of : 2-(2-methoxyethoxy)ethanol [111-77-3] carried out in the framework of Council Regulation (EEC)793/93 on the evaluation and control of the risks of existing substances - Opinion expressed at the 6th CSTEE plenary meeting, Brussels, 27 November 1998) and therefore should not be a basis for classification decisions when there are other repeat dose studies available by different routes. Using extrapolation from the oral data and using a conservative assumption of 100% absorption, would lead to the conclusion that classification is not warranted for the dermal route.