Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
other: review
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: review

Data source

Reference
Reference Type:
other: review report
Title:
Unnamed
Year:
1999

Materials and methods

Type of study / information:
Literature review
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
review study
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
not apllicable

Results and discussion

Any other information on results incl. tables

Human data show that, especially, acute and repeated abuse of alcohol can induce severe damage to the nervous system. Generally, ethanol blood levels exceeding 200 mg/L may cause signs of mild intoxication.

There are no relevant data concerning long-term occupational exposure. In a volunteer study, exposure up to 1500 mg/m³ (750 ppm), for 4 hours, did not cause impairment of performance in neurobehavioural tests or an increase in reporting of subjective symptoms. At exposure levels of 1000-1500 mg/m³ (600-750 ppm), actually measured or predicted (PBPK modelling) concentrations of ethanol in blood were roughly below 15 mg/L, thus far below the levels of 200 mg/L that would induce signs of mild intoxication.

In experimental animals,single inhalation, oral, and intraperitoneal exposure to generally high levels caused nervous system effects. Rats exposed to 15,200 mg/m³ (8000 ppm), for up to 4 hours, showed an impaired performance in behavioural tests which was not seen at 7600 mg/m³ (4000 ppm).

There are no studies on neurotoxic effects following repeated inhalation exposure.

However, no signs of toxicity were seen in male rats exposed up to 30,400 mg/m³ for 6 weeks.

Evaluation:

Generally, reviews on solvent neurotoxicity (see e.g., Arlien-Søborg, 1992); European Centre for Ecotoxicology and Toxicology of Chemicals, 1996) do not address alcohols, probably because occupational exposure to alcohols have not been shown to induce neurotoxic effects in humans (Lington and Bevan, 1994). In a recent Danish evaluation of the neurotoxicity of chemicals, ethanol was classified as being "neurotoxic to humans", mainly based on evidence from ingestion of high oral doses (Simonsen et al., 1995).

In the present literature survey, no data were found in which the relationship between long-term occupational exposure to the alcohols discussed here and the prevalence of CTE has been examined. However, testing of volunteers following acute exposure to ethanol did not show significant changes in behavioural parameters at a concentration of 1500 mg/m³ (750 ppm).

Applicant's summary and conclusion

Conclusions:
The occupational exposure levels for ethanol and therefore, as part of ethyl lactate, will leave a sufficent margin of safety with respect to induction of both acute and long-term neurotoxic effects (see waiving statement section 7.5.2).
Executive summary:

A literature review was prepared concerning the neurotoxic effects of, amongst others, ethanol which is considered to result from instantaneous hydrolysis of ethyl lactate upon inhalation.

Data were obtained from a literature search in the online databases Medline and Chemical Abstracts and from reviews prepared by (inter)national bodies.

In a Danish evalution of the neurotoxicity of chemical (1995), ethanol was classified as being "neurotoxic to humans", mainly based on evidence from ingestion of high oral doses.

In the present literature survey, no data were found in which the relationship between long-term occupational exposure to the alcohols discussed here and the prevalence of Chronic Toxic Encephalopathy (CTE) (or Organo-Psycho Syndrome; OPS) has been examined. However, no impairment of performance in behavioural tests was found in volunteers following acute exposure to ethanol at a concentration of 1500 mg/m³ (750 ppm).

The occupational exposure levels for ethanol and therefore, as part of ethyl lactate, will leave a sufficent margin of safety with respect to induction of both acute and long-term neurotoxic effects (see waiving statement section 7.5.2).