Methyl (R)-lactate

Additional toxicological data

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:

review

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

review study

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethanol

EC Number:

200-578-6

EC Name:

Ethanol

Cas Number:

64-17-5

IUPAC Name:

ethanol

Constituent 2

Reference substance name:

Ethyl lactate

EC Number:

202-598-0

EC Name:

Ethyl lactate

Cas Number:

97-64-3

IUPAC Name:

ethyl 2-hydroxypropanoate

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).

NOAELs of a series of lactate esters have been presented based on animal experiment and a NOAEL of 200 mg/m³ was set for ethyl lactate (Clary and Feron, 1997; Clary et al, 1998). Assuming an instantaneous hydrolysis of theyl lactate into ethanol on an equimaolr basis, the aforementioned levels are equivalent to alcohol levels of 78 mg/m³ for ethanol. This level is far below the NOAEL for neurotoxic effects that can be derived for ethanol.

It is, therefore, concluded that occupational exposure levels for ethyl lactate which could be derived form the NOAEL of 200 mg/m³ will leave a sufficient margin of safety with respect to the induction of neurotoxic effects.

Applicant's summary and conclusion

Conclusions:

The occupational exposure levels for ethyl lactate which could be derived from the NOAEL of 200 mg/m³ will leave a sufficent margin of safety with respect to induction of both acute and long-term neurotoxic effects.

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).

Using the NOAEL of 200 mg/m³ and assuming an instantaneous hydrolysis of ethyl lactate into ethanol on an equimolar basis upon inhalation, the aforementioned level would be equivalent to an ethanol level of 78 mg/m³. This level is far below the NOAEL for neurotoxic effects that can be derived for ethanol.

It is, therefore, concluded that occupational exposure levels for ethyl lactate which could be derived from the NOAEL of 200 mg/m³ for ethyl lactate will leave a sufficient margin of safety with respect to the induction of both acute and long-term neurotoxic effects.