Terms of reference
In the context of Regulation793/93 (Existing Substances Regulation), and on the basis of the examination of the Risk Assessment Report the CSTEE is invited to examine the following issues:
1. Does the CSTEE agree with the conclusions of the Risk Assessment Report?
2. If the CSTEE disagrees with such conclusions, the CSTEE is invited to elaborate on the reasons for this divergence of opinion.
Introduction
Methacrylic acid is used as an internal and external intermediate in the chemical industry for the production of methacrylic acid esters and as monomer in different kinds of polymers. The main use of methacrylic acide is in the preparation of ethyl methacrylate and higher homologues. Methacrylic acid is also used in the preparation of carboxylated polymers and emulsion polymers for paints, adhesives and textile applications.
GENERAL COMMENTS
The environmental part of the document is of good quality. The CSTEE agrees with the conclusion that there is no need for further information and that risk reduction measures may be needed only in particular conditions (use of grouting agents and high release via drainage water).
The CSTEE agrees with the conclusion that there is a need for limiting the risks from short term inhalation exposure in the chemical industry and the intermittent use of adhesives in the skilled trade sector, although the CSTEE questions some of the scientific arguments on which this conclusion is founded. The CSTEE agrees with the conclusions that there is at present no need for further information and/or testing with respect to consumer exposure or man indirectly exposured via the environment.
SPECIFIC COMMENTS
Environment
Exposure assessment
PECs in all environmental compartments seems properly calculated, using conservative worst case scenarios in case of lack of information. Nevertheless, details of calculations are reported in appendices, not provided with the document.
Effect assessment
The toxicity of methacrylic acid is relatively low on aquatic animals. For algae, there are some controversial data, nevertheless the reasons for not considering a surprisingly low figure is acceptable.
No data are available for terrestrial animals, besides mammals. Nevertheless, due to many aspects of environmental fate, methacrylic acid can be considered as a low concern chemical for terrestrial (soil and air) compartments.
Risk characterisation
Low or negligible risk was calculated, with the exception of some very specific conditions. Risk for the atmospheric compartment and for secondary poisoning were not calculated due to the low persistence in the atmosphere and to the negligible bioaccumulation potential. Considering the toxicological and physical-chemical profile of methacrylic acid, the use of the equilibrium partitioning method for the estimation of PNEC for soil organisms is acceptable.
The absorption coefficient (Kp) for methacrylic acid ranging from 0.076 to 0.24 l/kg indicates that it has a high mobility through soils and may leach to groundwater. Thus, the potential for leaching to groundwater should be included in the conclusions of the risk assessment.
Human Health
Exposure assessment
Occupational: Methacrylic acid is a chemical intermediate which is further processed to methacrylic esters, homo- and co-polymers. It is also used in reactive adhesive preparations. Methacrylate esters are used as grouting agents for tunnelling and sewer processes. Methacrylic acid may be formed from hydroxyethylesters in alkaline environment.
Consumers: Polymers manufactured with methacrylic acid as co-monomer are used in consumer products. When using dispersion paints, lacquers and 2-component adhesives, consumers may be exposed by the inhalation route only to residual monomer.
Indirect: There is a possible intake of a total daily dose of 0.15 m g methacrylic acid/kg bw/day from drinking water.
Effects assessment
There is very little long-term toxicity data on methacrylic acid. However, the methyl ester of methacrylic acid can be used as a model substance in toxicological studies, since methyl methacrylate is rapidly hydrolysed in the body to methacrylic acid. Thus, results obtained from the ester can be regarded as worst case assumptions as the ester is likely to be absorbed more readily and to a much higher extent than the acid due to its higher lipophilicity.
Methacrylic acid is a corrosive substance/severe irritant at the site of application. On the other hand, it has low acute toxicity. There is no indication that methacrylic acid has a sensitising potential in guinea pig tests or patch testing in humans. However, it should be noted that there is some evidence for a sensitising effect of methyl methacrylate in experimental animals, Further, there are reports of allergic dermatitis and allergic respiratory reactions in humans.
Irritation of nasal mucosa and degenerative lesions of the olfactory epithelium are seen in 90-day inhalation studies with methacrylic acid in rats and mice. The CSTEE does not agree with the conclusion that no clear-cut experimental NOAEC can be identified and that it is "slightly below 20 ml/m3. The report states that rats had rhinitis from 20 ml/m3 exposure and no lesions of the oflactory epithelium at 300 ml/m3, whereas mice had rhinitis and lesions of the olfactory epithelium at 300 ml/m3. It is noted, however, that control rats also had rhinitis in an incidence comparable to rats in the 20 and 100 ml/m3 groups. Only in male F-344 rats was the severity of rhinitis dose-related, with an increase at 300 ml/m3. The CSTEE would regard 100 ml/m3 as the NOAEC for the rat. The degeneration of olfactory epithelium was already present at 100 ml/m3 in female mice (3/10 animals), thogh not statistically significant. Therefore, the CSTEE would regard 20 ml/m3 NOAEC for the mouse. Overall, a clear NOAEC of 20 ml/m3 has been obtained for local effects.
The CSTEE does not agree with the statement that "It may be assumed that the nasal irritation threshold for methacrylic acid will not substantially change with longer duration of exposure". This fact is illustrated with data on methyl methacrylate, acrylic acid and methyl acrylate. None of these comparisons support the assumption that there would be no change of nasal irritation threshold from subchronic to chronic exposure:
- The methyl methacrylate data show a NOAEL of 500 ml/m3 (LOAEL 1000 ml/m3) subchronic versus 25 ml/m3 (LOAEL 100 ml/m3) chronic for the rat; howdver, the ester data cannot be directly compared to the acid
- For acrylic acid, there is no chronic data to compare to the subchronic data
- For methyl acrylate 20 month results (not 3 month) are compared to 24 month results
Therefore, a decrease in the irritation threshold for chronic exposure is to be expected as a worst-case assumption as long as no chronic toxicity study is available.
The conclusions of the RAR state that the PBPK model (originally developed for acrylic acid and adopted to methacrylic acid) constructed for interspecies extrapolation, is not considered to be valid. Thus, the model has not been taken into account for deriving a NOAEC for humans, instead the NOAECs of the animal studies were used. The model for methacrylic acid has not been published, therefore the CSTEE cannot comment on the model and its reliability. However, the CSTEE understands that the model for acrylic acid was accepted by the US EPA (see minutes TM IV'99). The CSTEE would not put much weight in the argument of missing variability parameters for interindividual and interspecies toxicodynamic differences, as was done in the report. In view of the fact that mice and rats are obligatory nose-breathers, the comparability to humans regarding nasal effects is limited per se. There are even large differences in the irritation thresholds for rats and mice for acrylic acid and methacrylic acid, so the quantitative extrapolation to humans is in any case difficult. According to the above arguments, and the fact that always the most sensitive species is used for evaluating the margins of safety and since methacrylic acid does not require metabolic activation/inactivation, the CSTEE feels that most of the uncertainties in extrapolating stem from fundamental species differences and not from the human variability. Finally, the report itself does not address the above problems when evaluating the MOS values.
The CSTEE agrees with the assumption that there is no concern for carcinogenic properties of methacrylic acid based on structural similarities with methyl methacrylate for which there are acceptable studies available (the cited NTP study cannot be found in the reference list).
With respect to genotoxicity, only a negative bacterial gene mutation test is available for methacrylic acid. High concentrations of methyl methacrylate caused chromosomal aberrations and marginal increases in sister chromatid exchanges in mammalian cells in culture.A bone marrow micronucleus test and a dominant lethal assay in mice was negative with methyl methacrylate, whereas a bone marrow chromosomal aberration test in rats were inconclusive. The CSTEE considers that methacrylic acid will not express genotoxic activity under in vivo conditions.
There are no data on reproductive toxicity of methacrylic acid. However, since methyl methacrylate (without a reproductive toxic potential) is rapidly cleaved to methacrylic acid, no concern in relation to developmental toxicity is assumed based on teratogenicity studies with methyl methacrylate. There is a deficiency in that no data on possible impairment of fertility by methacrylic acid (or methyl methacrylate) are available. Given the low margins of safety with respect to methacrylic acid exposure in a number of occupational settings (vide infra), such data are deemed necessary, although there were no evidence of changes in the reproductive organs of rats after 90-days inhalation. According to the RAR, a 2-generation reproductive study by inhalation is being planned in the US for the near future.
Risk characterisation
Workers: Overall, the CSTEE agrees to the conclusion iii) that there is a need for limiting the risks based on margins of safety of up to 3 for repeated inhalation exposure. But as outlined above, the supporting arguments would in several instances be contrary to those given in the report. On the other hand, the CSTEE does not agree with a conclsion iii) for short or intermediate exposure (Chapter 4.3.1), because in this case the 3 month study is representative for the exposure scenario.
As methacrylic acid is a corrosive substance, it would be expected to produce sensory irritation as well as local lesions when inhaled. The report focuses only on the latter aspect, There are no data on irritation in humans. The RD50 as a measure of sensory irritation in mice is with 22000 ml/m3 surprisingly high. At 4900 ml/m3 there was only minor irritation in mice. Therefore, it seems that the discussed NOAEC of 20 ml/m3 is also protective against sensory irritation in humans.
Consumers: Only a possibility for local effects in the upper respiratory tract from exposure to methacrylic acid has been considered. Due to similarity with methyl methacrylate, no concern for chronic effects or reproductive toxicity is expressed (conclusion ii)). The CSTEE agrees to this conclusion.
Indirect exposure: No concern is expressed for the low exposure from drinking water (conclusion ii)). The CSTEE agrees to this conclusion (possible revision, dependent on data from grouting episodes).
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1 Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of those substances if they are produced or imported into the Community in volumes above 10 tonnes per year. The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission Regulation (EC) 1488/94, which is supported by a technical guidance document.