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In-vitro studies: Bacterial systems

Methyl acrylate was not mutagenic in the Ames test in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, TA97 and TA100, both in the presence and in the absence of S-9 mix from Aroclor 1254 induced rats when tested up to cytotoxic doses (BASF AG 1977, Waegemaekers 1984; Zeiger 1987). In addition, a modified Ames assay (plate gradient assay) was performed in ten tester strains (Salmonella typhimurium G 46, TA 1535, TA 100, C 3076, TA 1537, D 3052, TA 1538,TA 98, E. coli WP2, E. coli WP2uvrA-) with and without metabolic activation. Methyl acrylate was reported to be negative (McMahon 1979)

In-vitro studies: Mammalian cell gene mutation test

Methyl acrylate did not induce increases in mutant frequencies in the Chinese Hamster Ovary (CHO) HGPRT test performed in the absence of metabolic activation (Moore 1991), and no mutagenicity was demonstrated in AS52/XPRT Chinese hamster cells in which the hgprt gene has been largely deleted and replaced by a single copy of the functional xanthine-guanine phosphoribosyl transferase (XPRT) gene from E. coli. This test was also performed only in the absence of metabolic activation (Oberly 1993).

In contrast, methyl acrylate was active at clearly cytotoxic concentrations (≤ 50% cell survival) in the Mouse Lymphoma TK+/- mutation assay using L5178Y cells in the absence of metabolic activation (Moore 1988, 1989). The majority of the mutant colonies were small colonies, suggesting that methyl acrylate did act via a clastogenic mechanism (Moore 1988, 1989, Amtower 1986).

In-vitro studies: Genotoxicity tests

There is a number of chromosome aberration tests in vitro available for MA (Ishidate 1981, Moore et al. 1988, 1989). Assays were performed with CHL cells, L5178Y mouse lymphoma cells and CHO cells with (Ishidate 1981) and without metabolic activation (Ishidate 1981, Moore et al. 1988, 1989). All assays gave positive or equivocal results at doses which reduced cell survival to 50 % or lower. There were no doses tested for chromosome aberrations which resulted in 60 % cell survival or more. Thus, there is no experimental evidence that MA might cause chromosome aberrations at non-cytotoxic doses.

More recent studies have indicated that there is an association between chromosomal aberrations and cytotoxicity at exposure concentrations which reduce cell growth to less than 50% of the control value (Galloway, 2000 and references cited therein). These data suggest that the increase in mutagenicity reported in the cytogenicity assays with methyl acrylate may be an artifact of the experimental method.

Conclusion-In vitro studies

In vitro, methyl acrylate was negative in a variety of studies for point mutation both in the presence (Ames test only) and in the absence of metabolic activation, but induced chromosome aberrations in Chinese hamster cells, Chinese ovary cells and L5178Y mouse lymphoma cells in the absence of metabolic activation.

In vivo studies

Methyl acrylate has been tested in three in vivo micronucleus assays. It did not induce micronuclei in bone marrow cells of male ddY mice exposed for 3 hours to atmospheres containing 1300 or 2100 ppm (4.64 or 7.50 mg/L) methyl acrylate. Bone marrow samples were taken at 18, 24, 30, 48 or 72 hours after exposure. (The group size was not specified) (Sofuni 1984).

No induction of micronuclei was also found in male ddY mice after single oral doses (62.5, 125 or 250 mg/kg bw; 6 mice per group) or repeated dosing (125 mg/kg bw/d for 4 consecutive days; 4 mice). Bone marrow cells were sampled 24 hours after the last dose (Hachiya 1982).

In contrast, exposure of Balb/C mice to 37.5, 75, 150 or 300 mg/kg bw (4 mice/dose; 2 injections, 24 hours apart) by the intraperitoneal route, induced a not clearly dose-dependant increase in micronuclei at toxic dose levels as evidenced by significant reductions in the ratio of polychromatic to normochromatic erythrocytes. Only a short summary of the results is available (Przybojewska 1984). The validity of the results of this study is questionable. In the available publication methyl and ethyl acrylate were tested in parallel and both are described to be positive in the mouse micronucleus test (i.p.). In the case of ethyl acrylate, different laboratories tried to reproduce the positive results reported in Przybojewsla et al. In these well conducted and documented studies the results were negative (Ashby 1989, Kligerman 1991, Hara 1994). Therefore, based on the data available and the questionability of the findings in the Przybojewska et al. study, the weight of evidence indicates that methyl acrylate is negative in vivo in mouse micronucleus studies.

Conclusion-in vivo studies

In vivo, two micronucleus tests using the inhalation and oral route in ddY mice were negative.

Galloway SM (2000). Environmental and Molecular Mutagenesis 35:191-201.

UPDATE FOLLOWING ECHA’S COMPLIANCE CHECK IN NOVEMBER 2014: REQUIREMENT FOR GENOTOXICITY- CLASTOGENICITY (CHROMOSOMAL ABERRATIONS) 

ECHA: ECHA considers that the data used by the Registrant from the in vivo studies cannot be considered equivalent to Article 13(3) data for the reasons set out below.

1)        First, the in vivo studies used do not appear to provide a reliable coverage of the key parameters foreseen to be investigated in the corresponding test methods referred to in Article 13(3).

ECHA: (i)       An inadequate number of animals were used,

LEAD REGISTRANT: The lead registrant agrees that the studies were not compliant to the OECD 474 guideline.

ECHA: (ii)       Too few doses were used, and

LEAD REGISTRANT: The lead registrant does not agree with ECHA on this point. At the time of the study conduct, OECD 474 (1983) only recommended one high dose for the initial assessment.

ECHA: (iii)      Too few numbers of cells were analysed.

LEAD REGISTRANT: The lead registrant does not agree with ECHA on this point. At the time of the study conduct, Hachiya (1982) scored 2000 erythrocytes (it is likely that PCE and NCE were not differentiated). Sofuni (1984) scored 1000 PCEs, which was compliant to OECD 474 (1983).

ECHA: 2)       Second, no adequate and reliable documentation of the in vivo studies are provided.

(i)        No evidence that the test material reached the target tissue. 

LEAD REGISTRANT: The lead registrant agrees that inadequate evidence of the test material reaching the target tissue was available within the study reports. 

However, evidence is available demonstrating that by the inhalation route methyl acrylate is systemically available to reach the bone marrow, therefore the inhalation micronucleus study (Sofuni, 1984) was guideline compliant on this point. Additional details are provided below.

 

The oral gavage micronucleus study (Hachiya, 1982) study would technically not be compliant with the relevant OECD guideline, however based upon the toxicokinetics of methyl acrylate it would be unlikely that the substance would reach the bone marrow by the oral route. Additional details are provided below.

 

 

Specific Comments by the Lead Registrant:

The registrant agrees with ECHA on one of the four concerns that there are aspects of the referred to in vivo genotoxicity studies that do not fit the strict criteria of the OECD guidelines at the time of their conduct, specifically the number of animals used in the Sofuni (1984) study. Other aspects of the referred to in vivo genotoxicity studies, including the number of doses used and numbers of cells analyzed, were compliant with the guideline at the time of the study and should be considered acceptable for this purpose. The registrant has also provided responses above for the lack of evidence that the test material reached the target tissue. Noteworthy about the latter point is that evidence does exist to indicate that exposure to methyl acrylate via inhalation does result in systemic availability of methyl acrylate or a metabolite of methyl acrylate. Methyl acrylate is rapidly absorbed by the oral and inhalation routes and distributed throughout the body. After oral or intraperitoneal administration, greater than 90 % is excreted within 72 hours, primarily via the lungs as CO2 (> 50 %), and kidneys as products of glutathione conjugation reactions (10-50 %) (Delbressine 1981, Sapota 1988 & 1990, Seutter 1981). The predominant pathway of metabolism of methyl acrylate, by many tissues (including lung, liver, kidney and plasma) appears to be hydrolysis to acrylic acid and methanol, which is catalyzed by carboxyl esterase enzymes.Under normal circumstances, a small amount of the intact ester is absorbed into the blood through the lungs. Once in the blood following inhalation exposures there is a high probability that methyl acrylate or a metabolite of methyl acrylate reaches the bone marrow because in vitro experiments have demonstrated that the elimination t1/2 for methyl acrylate (1mM) was ca. 34 min., the estimated t1/2 for the cleavage product acrylic acid was ca. 250 min (BASF SE, 2014). 

 

In contrast to the inhalation route, methyl acrylate exposure via the oral route results in very rapid metabolism to acrylic acid and the alcohol occurs in blood and liver and therefore it would not be possible for the substance to reach the bone marrow with this route of treatment. Studies have been conducted in order to evaluate the possibility that acrylate esters are hydrolyzed to acrylic acid and an alcohol in vivo and in vitro in mammals, and to determine the extent to which acrylic acid and the acrylate esters bind glutathione (GSH) in vitro (Miller et al., 1979). The acrylate esters were found to disappear rapidly in rat whole blood in vitro; the t½ was 3.6 minutes for methyl acrylate. Recent investigations on the in vitro metabolism of acrylates showed a fast esterase cleavage within the first 10 incubation minutes, with a parallel increase of acrylic acid after incubation with S9 fraction of rat liver for methyl acrylate (BASF SE, 2014). The t1/2 was about 3 min for methyl acrylate and would have likely been much shorter were it not for a technical error determined on the acrylic acid formation. By comparison the t1/2 was 0.84 min for butyl acrylate and 1.4 min for ethyl acrylate. In plasma the disappearance was by factor or 10 slower. In conclusion, methyl acrylate exposure by the oral route would lead to pre-hepatic blood and liver exposure but negligible systemic exposure. 

 

Adaptation of available data for the in vivo mutatgenicity endpoint

Column 2 of Annex X, 8.4 indicates the following: “If there is a positive result in any of the in vitro genotoxicity studies in Annexes VII or VIII, a second in vivo somatic cell test may be necessary,depending on the quality and relevance of all the available data.” (registrant added underline). Column 2 of Annex X, 8.4 further indicates: “If there is a positive result from an in vivo somatic cell study available, the potential for germ cell mutagenicity should be consideredon the basis of all available data, including toxicokinetic evidence(registrant added underline). If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.” 

 

We would like to bring to ECHA’s attention available data that did not appear to be considered in the assessment, specifically a Klimisch 1inhalation Carcinogencity study in rats (Inbifo, 1985) which showed no evidence of tumor formation following exposure. Based upon this study additional in vivo genotoxicity testing does not appear scientifically necessary because a clear conclusion can be made that Methyl acrylate is neither a somatic or germ cell mutagen (Annex XI: General rules for adaptation of the standard testing regime sought out in Annexes VII to X). Furthermore, the study meets ECHA’s consideration that it is the most appropriate route to assess local genotoxicity due to MA’s volatility and reactivity. Use of this existing data should be considered to be equivalent to data generated by the corresponding test methods referred to in Article 13(3) as the following conditions are met:

1)        Adequacy for the purpose of classification and labeling and/or risk assessment;

p379 Guidance on the Application of the CLP Criteria: “It is recognized that genetic events are central in the overall process of cancer development.” Therefore, lack of carcinogenicity in vivo in a reliable study would indicate that the substance does not have the potential for genotoxic effects in vivo.

2)  Sufficient documentation is provided to assess the adequacy of the study; and

3)        the data are valid for the endpoint being investigated and the study is performed using an acceptable level of quality assurance. Given that the study was a Klimisch 1 guideline compliant study by the appropriate route conditions 2 and 3 are met.

 

Further justification indicating her testing for genotoxicity is for adaptation of this study for the required endpoint is provided based upon the following weight of evidence:

1)        Lack of tumors indicates no genotoxicity (including mutagenicity or chromosomal aberrations)

2)        The study conforms to ECHA’s weight of evidence consideration of all available data

3)        This in vivo cancer study is more reliable and relevant than the available in vitro study data

1)        Lack of tumors indicates no genotoxicity (including mutagenicity or chromosomal aberrations)

As ECHA’s endpoint specific guidance (August 2014, p337) indicates that “there is considerable positive correlation between the mutagenicity of substances in vivo and their carcinogenicity in long-term studies with animals” it scientifically justified that methyl acrylate’s lack of carcinogenicity also demonstrates a lack of in vivo genotoxicity (chromosomal aberrations and/or mutagenicity) of this substance. Therefore the Carcinogenicity study data indicates that the substance does not have the potential for genotoxic effects in vivo and should be considered to be equivalent to data generated by the in vivo chromosomal aberration and mutagenicity test methods referred to in Article 13(3). 

 

2)        The study conforms to ECHA’s weight of evidence consideration of all available data

In addition to the above justification, ECHA’s endpoint specific guidance (August 2014, p345) indicates that in the evaluation of available information on mutagenicity a weight of evidence evaluation should “include an evaluation of the available data as a whole, i.e. both over and across toxicological endpoints (for example,consideration of existing carcinogenicity data, repeated dose toxicity data and genotoxicity dataall together can help understand whether a substance could be a genotoxic or non-genotoxic carcinogen).” (underline added by registrant). This further supports the suitability of the carcinogenicity study as adequate information for the endpoint of mutagenicity.

 

The guidance on weight of evidence for indicates that particular points should be taken into account when evaluating negative test results (i.e. the methyl acrylate Carcinogenicity study) (August 2014, p346):

- 1) Were the doses high enough (signs of toxicity seen)? Yes, decreased body weight gain and olfactory epithelial degeneration.

- 2) What the test system used sensitive to the nature of the genotoxic changes that might have been expected?Yes, carcinogenicity studies are designed to detect genotoxic carcinogenesis with origins occurring either in a somatic cell or germ cell. The Inbifo (1985) study with methyl acrylate examined both somatic and germ cells for evidence of carcinogenesis in the following tissues histopathologically: adrenal gland, aorta, brain (including sections of cerebrum, cerebellum, and medulla/pons), caecum, cervix, coagulating gland, colon, duodenum, epididymis, eye (including retina), Harderian gland, heart, ileum, jejunum, kidney, lacrimal gland (exorbital), liver, lung, lymph nodes (both superficial and deep), female mammary gland, nasal tissue, oesophagus, olfactory bulb, ovary, pancreas, parathyroid gland, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicle, skeletal muscle, skin, spinal cord (at three levels: cervical, midthoracic, and lumbar), spleen, stomach (forestomach, glandular stomach), testis, thymus, thyroid gland, trachea, urinary bladder, uterus (including cervix), vagina, and a section of bone marrow and/or a fresh bone marrow aspirate).

- 3) For studies in vivo, did the substance reach the target organ?Yes, if one were to exist. A small proportion of inhaled MA reaches the blood intact following absorption through the lungs and is systemically available (see expanded explanation above). 

- 4) For studies in vivo, was sampling appropriate (sufficient numbers of animals, sufficient sampling times, sufficient number of cells scored/sampled)?Yes, the carcinogenicity study was a Klimisch 1 fully guideline compliant study by the appropriate route, inhalation.

 

3)        This in vivo cancer study is more reliable and relevant than the available in vitro study data. Based upon cancer study’s duration and in vivo conduct, this study is more reliable and relevant for adaptation of the in vivo testing than the consideration of the available in vitro study data, further supporting its suitability for adaptation of the mentioned in vivo endpoints.

 

UPDATE FOLLOWING ECHA’S COMPLIANCE CHECK IN NOVEMBER 2014: REQUIREMENT FOR GENOTOXICITY- MUTAGENICITY 

ECHA: The technical dossier contains four in vitro mammalian cell gene mutation non-guideline publications with no information on GLP compliance with the registered substance that show ambiguous results.

LEAD REGISTRANT: The lead registrant suggests that the weight of evidence indicates that methyl acrylate is not a mutagen in vitro or in vivo. Lack of in vitro mutagenesis is supported by four negative bacterial reverse mutation assays and two mammalian gene mutation assays (XPRT and HGPRT (Table 1). Two additional studies were positive for mutagenicity however these studies came from the same laboratory and study data is only available for one of the studies. In the study where data are available to review (Moore, 1988) small colony mutants were observed, which is an indication of clastogenicity rather than mutagenicity of methyl acrylate in vitro. While there was a small increase in large colony mutants at cytotoxic test concentrations in this in vitro assay the authors themselves did not consider the substance mutagenic but rather considered it a clastogen based upon “the negative hgprt results for the clastogenic acrylates under both test protocols are consistent with studies performed by our laboratory and other on agents acting primarily as clastogens.” The study author reiterates this important point when stating that all four acrylates tested in their lab (methyl acrylate, ethyl acrylate, tetraethylene glycol diacrylate, and trimethylolpropane triacrylate) were all “confirmed clastogens” in vitro.

Table 1. Summary of In Vitro Mutagenicity Studies with Methyl Acrylate

In vitro study type

Reference

Klimisch value

Outcome

Ames

McMahon, 1979

2

Negative

Ames

BASF, 1977

2

Negative

Ames

Waegemaekers, 1984

2

Negative

Ames

Zeiger, 1987

2

Negative

XPRT

Oberly, 1993

2

Negative

HGPRT

Moore, 1989

2

Negative

Mouse Lymphoma

Moore, 1988

2

Positive*

Mouse Lymphoma

Amtower, 1986

4

Positive*

While methyl acrylate is clastogenic in vitro, this hazard does not exist in vivo as demonstrated in the two negative micronucleus studies previously discussed. One of these studies was conducted via the inhalation route and data exists to indicate that exposure to methyl acrylate via inhalation does result in systemic availability of methyl acrylate or a metabolite of methyl acrylate thereby supporting that target tissue exposure would have occurred. 

 

ECHA: ECHA considers it necessary to perform an in vivo assay addressing gene mutations, as described in the ECHA Guidance on information requirements and chemical safety assessment (version 2.2, August 2013), Chapter R.7a, Section R.7.7.1. and Figure R.7.7-1. 

 

LEAD REGISTRANT: Weight of evidence indicates that methyl acrylate is not a mutagen in vitro or in vivo. The previously discussed Klimisch 1 inhalation carcinogenicity study demonstrates that additional in vivo genotoxicity testing does not appear scientifically necessary (Annex XI: General rules for adaptation of the standard testing regime sought out in Annexes VII to X). Please refer to the scientific justification and weight of evidence support in the section on clastogenicity above. 

 

ECHA: ECHA considers that testing by the inhalation route is most appropriate. Furthermore, local genotoxicity and route-specific concern of the respiratory system after inhalation exposure due to the volatility and reactivity of this substance may be of concern.

 

LEAD REGISTRANT: The lead registrant agrees that the inhalation route is the most appropriate for assessment of methyl acrylate’s toxicity. The carcinogenicity study referenced previously was conducted via this route and histopathological data demonstrated toxicity (decreased body weight gain and olfactory epithelial degeneration) in the absence of mutagenicity (i.e. tumors) in either somatic cell or germ cells in the following tissues: adrenal gland, aorta, brain (including sections of cerebrum, cerebellum, and medulla/pons), caecum, cervix, coagulating gland, colon, duodenum, epididymis, eye (including retina), Harderian gland, heart, ileum, jejunum, kidney, lacrimal gland (exorbital), liver, lung, lymph nodes (both superficial and deep), female mammary gland, nasal tissue, oesophagus, olfactory bulb, ovary, pancreas, parathyroid gland, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicle, skeletal muscle, skin, spinal cord (at three levels: cervical, midthoracic, and lumbar), spleen, stomach (forestomach, glandular stomach), testis, thymus, thyroid gland, trachea, urinary bladder, uterus (including cervix), vagina, and a section of bone marrow and/or a fresh bone marrow aspirate). This comprehensive in vivo study provides strong weight of evidence to indicate that methyl acrylate is not a mutagen in vivo following inhalation exposure.

References for the update following ECHA’s Compliance Check:

Amtower AL, Brock KH, Doerr CL, Dearfield KL, Moore MM (1986). Genotoxicity of three acrylate compounds in L5178Y mouse lymphoma cells. Envir. Molec. Mutagen. 8 (6): 4

BASF (1977) Ames-Test an den Substanzen Acrylsaeure, Methylacrylat, Butylacrylat,unpublished data: BASF AG, Department of Toxicology. Report date: July 26, 1977

BASF SE (2014).Bachelor thesis Kerstin Roos, unpublished data, Testing laboratory: BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany. Report date: 2014.

Delbressine LPC (1981). Identification of urinary mercapturic acids formed from acrylate, methacrylate and crotonate in rat. Xenobiotica 11: 241-247; cited in: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Some Chemicals Used in Plastics and Elastomers. Vol. 39 p.99-112. WHO, Lyon 1985

Hachiya, N., Taketani, A. & Takizawa, Y.(1982). Ames test and mouse bone marrow micronucleus test on acrylic resin monomer and other additives. Nippon Koshu Eisei Zasshi (Jpn. J. Public Health) 29: 236-239 (1981) (in Japanese, Translation available).

Inbifo (1985). 2-Jahres-Inhalationsstudie mit Methylacrylat an der Ratte. Inbifo GmbH, Koeln, D. Report date: March 4, 1985.

McMahon RE, Cline JC, Thompson CZ. (1979). Assay of 855 Test Chemnicals in Ten Tester Strains Using a New Modification of the Ames Test for Bacterial Mutagens. Cancer Res. 39: 682-693, 1979; cited in: Review Methylacrylat, Dr. Zeller, (1986)

Miller, R.R., Ayres, J.A., and Rampy, L.W., 1979. Metabolism of acrylate esters in rat tissue homogenates in vitro. Unpublished data, The Dow Chemical Company.

Moore MM et al. (1988). Genotoxicity of Acrylic Acid, Methyl Acrylate, Ethyl Acrylate, Methyl Methacrylate, and Ethyl Methacrylate in L5178Y Mouse Lymphoma Cells. Envir. Molec. Mutagen., 11, 49-63, 1988.

Moore MM, Harrington-Brock K, Doerr CL, Dearfield KL (1989). Differential mutant quantitation at the mouse lymphoma tk and CHO HGPRT loci. Mutagenesis 4: 394-403.

Oberly TJ1, Huffman DM, Scheuring JC, Garriott ML (1993). An evaluation of 6 chromosomal mutagens in the AS52/XPRT mutation assay utilizing suspension culture and soft agar cloning.

OECD 474 (1983). Test Guideline 474: Mammalian Erythrocyte Micronucleus Test

OECD 453 (1981). Test Guideline 453: Combined Chronic Toxicity\Carcinogenicity Studies

Sapota A (1988). The disposition of [2,3-14C]-Methyl- and [2,3-14C]-2-Ethylhexyl acrylate in male Wistar albino rats. Arch. Toxicol. 62: 181-184

Sapota A, Jakubowski M (1991). Distribution of Methyl, Butyl, and 2-Ethylhexyl [2,3-14C]-acrylates in Male Wistar Albino Rats. Chemical Abstracts 114: 218

Seutter E and Rijntes NVM (1981). Whole-body autoradiography after systemic and topical administration of methyl acrylate in the guinea-pig. Arch. Dermatol. Res. 270: 273-284

Sofuni T, Hayashi M, Matsouka A, Sawada M, Hatanaka M, Ishidate M Jr. (1984). Cytogenetic Effects of Gaseous and Volatile Chemicals on Mammalian Cells in vitro and in vivo II. Micronucleus tests in mice. Bull National Institute of Hygiene Sciences 102:84-90, 1984 (in Japanese; Translation available)

Waegemaekers THJM and Bensink MPM (1984). Non-mutagenicity of 27 aliphatic acrylate esters in the Salmonella-microsome test. Mutation Research. 137: 95-102, 1984; cited in MAK Begruendung Methylacrylat (1985) (in German).

Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K, Speck W (1987). Salmonella Mutagenicity Tests: III. Results From the Testing of 255 Chemicals. Env. Mutag. 9 (Suppl. 9): 1-110.


Short description of key information:
Methyl acrylate was negative in bacterial mutation tests. In gene mutation assays in mammalian cells, i.e. HGPRT and XPRT assays, MA was clearly negative. MA seems to have some potential for genotoxicity in mammalian cells, presumably by a clastogenic mechanism. Since this effect is limited to doses with moderate to strong cytotoxicity, it is highly unlikely that this potential will be expressed in vivo. Methyl acrylate was negative in several in vivo mouse micronucleus assays. Thus, taking the negative test results in vivo for MA into consideration, it can be assumed that MA will not cause any DNA damage, i.e. genotoxicity in vivo. Furthermore, the carcinogenicity study referenced previously was conducted via the inhalation route (the most relevant route for MA) and histopathological data demonstrated toxicity (decreased body weight gain and olfactory epithelial degeneration) in the absence of mutagenicity (i.e. tumors) in either somatic cell or germ cells in wide array of tissues. This comprehensive in vivo study provides strong weight of evidence to indicate that methyl acrylate is not a mutagen in vivo.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.3, 2009): no classification required