Mutagenicity assessment of acrylate and methacrylate compounds and implications for regulatory toxicology requirements

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<ul><li><p>lao</p><p>,</p><p>ithbCytec Industries, 1937 West Main Street, Stamford, CT 06904, USAc</p><p>similar chemical can be predicted with condence by inclusion within this chemical class, thus avoiding unnecessary testing. 2008 Elsevier Inc. All rights reserved.</p><p>between one acrylic acid moiety (monofunctional) or morethan one acrylic acid moiety (multifunctional) with an alco-hol. Methacrylates are esters formed in a similar manner</p><p>Screening mutagenicity test requirements, for example,for both the U.S. EPA (Environmental Protection Agency)HPV (High Productive Volume) Challenge program andthe broader OECD (Organization of Economic and Coop-erative Development) HPV program consist of a 2-testin vitro mutagenicity battery, which includes: a gene reverse</p><p>* Corresponding author. Fax: +1 203 321 2978.E-mail address: barbara.vogt@cytec.com (B. Vogt).</p><p>Available online at www.sciencedirect.com</p><p>Regulatory Toxicology and PharmacKeywords: Acrylate; Methacrylate; Mutagenicity; Genotoxicity; Regulatory test batteries; Chemical categories; Structure activity; SAR; Mouse lymph-oma assay; Mouse micronucleus assay; Bacterial reverse mutation assay; Carcinogenicity</p><p>1. Introduction</p><p>Acrylates and methacrylates are key raw materials usedin diverse applications, including coatings, printing inks,varnishes, sealants, caulks, adhesives, textiles and plastics,and as chemical intermediates. Acrylates are esters ofacrylic acid, resulting from a catalyzed condensation</p><p>using methacrylic acid. Both the mono- and multifunc-tional acrylate analogs and the methacrylate esters (mono-functional and multifunctional) possess a similar spectrumand pattern of toxicity (Moss et al., 1997).</p><p>The diversity of industrial applications of acrylates andmethacrylates requires that they must meet a variety of reg-ulatory mutagenicity testing requirements (Table 1).Cytec Industries, 1950 Lake Park Drive, Smyrna, GA 30080, USAdCytec Industries, 5 Garret Mountain Plaza, West Paterson, NJ 07424, USA</p><p>Received 3 February 2007Available online 1 February 2008</p><p>Abstract</p><p>Esters of acrylic acid and methacrylic acid, more commonly known as acrylates and methacrylates, respectively, are key raw materialsin the coatings and printing industry, with several of its chemical class used in food packaging. The results of over 200 short-term in vitroand in vivo mutagenicity studies available in the open literature have been evaluated. Despite dierences in acrylate or methacrylate func-tionality or in the number of functional groups, a consistent pattern of test response was seen in a typical regulatory battery of muta-genicity tests. No evidence of point mutations was observed when acrylic acid or over 60 acrylates and methacrylates were investigated inSalmonella bacterial tests or in hprt mutation tests mammalian cells, and no evidence of a mutagenic eect was seen when tested in wholeanimal clastogenicity and/or aneuploidy (chromosomal aberration/micronucleus) studies. Consistent with the in vivo testing results,acrylic acid exhibited no evidence of carcinogenicity in chronic rodent cancer bioassays. In contrast, acrylic acid and the entire acrylateand methacrylate chemical class produced a consistently positive response when tested in the mouse lymphoma assay and/or otherin vitro mammalian cell assays designed to detect clastogenicity. The biological relevance of this in vitro response is questioned basedon the non-concordance of in vitro results with those of in vivo studies addressing the same mutagenic endpoint (clastogenicity). Thus,in short-term mutagenicity tests, the acrylates and methacrylates behave as a single chemical category, and genotoxicity behavior of aMutagenicity assessment of acryand implications for regulat</p><p>F.R. Johannsen a, Barbara Vogt b,*</p><p>aFRJ-TOX, L.L.C., 12346 Coppersm0273-2300/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.yrtph.2008.01.009te and methacrylate compoundsry toxicology requirements</p><p>Maureen Waite c, Randy Deskin d</p><p>Court, St. Louis, MO 63131, USA</p><p>www.elsevier.com/locate/yrtph</p><p>ology 50 (2008) 322335</p></li><li><p>Sta</p><p>In vitro</p><p>Bacterial Mammalianicity</p><p>resu</p><p>logymutation assay in bacteria (Ames assay) and a chromo-somal aberration assay in cultured mammalian cells. Newchemical notications in the European Union (EU) requirea battery of two mutagenicity studies. While most newchemicals do not require premanufacturing testing in theU.S., those chemicals meeting specied volume and expo-sure criteria or are included in specialized chemical catego-ries, require testing in a gene mutation assay and an in vivoclastogenicity assay (Cimino, 2006).</p><p>A number of these acrylates are used in food packagingmaterials and, as such, they must meet the requirements offood contact notications around the world. The U.S.FDA (Food and Drug Administration) Center for FoodSafety and Applied Nutrition (CFSAN, 2002) recommendsa 2-test battery of mutagenicity studies for food contactsubstances with a cumulative estimated daily intake nogreater than 50 ppb in the diet. The European Food SafetyAuthority (EFSA) requires submission of a battery of threemutagenicity tests for materials migrating at levels less than</p><p>mutagenicity mutagen</p><p>OECD SIDS/HPVp</p><p>OU.S. EPA/HPV SIDS/HPV</p><p>pU.S. EPA New Chemicals</p><p>pU.S. FDA Food Contact</p><p>Noticationa</p><p>pO</p><p>EU Dangerous SubstancesDirective, VII A</p><p>Registrationp</p><p>EU EFSA Food Contactap p</p><p>pdenotes a requirement.</p><p>O denotes optional among other optional tests.C denotes conditional if previous in vitro tests are positive for mutagenica Conditional on levels of migration into food 650 ppb.Table 1Mutagenicity requirements for selected regulatory programs in the United</p><p>F.R. Johannsen et al. / Regulatory Toxico50 ppb (EFSA, 2006a). If any single result from these testsis suggestive of mutation or chromosomal disruption, thenat least one in vivo mammalian genotoxicity assay isrequired, most commonly the mouse micronucleus assay.</p><p>Genotoxicity testing has been completed on many of theacrylates and methacrylates. In this paper, we present asummary of published mutagenicity results indicating thatthese compounds should be considered nonmutagenic inthe whole animal. The data clearly support the conceptof a category for mutagenicity behavior for acrylates andmethacrylates. Further, this data oers grounds for re-assessment of the multi-test battery recommended bynumerous regulatory agencies, insofar as this chemical cat-egory is concerned.</p><p>2. Materials and methods</p><p>A number of public literature sources have been investigated to iden-tify all available short-term genotoxicity studies conducted with acrylicacid, methacrylic acid, and members of the acrylic acid ester (acrylates)and methacrylic acid ester (methacrylates) family of chemicals. Studieswere identied which used either of the acids or one of the monofunctionalor multifunctional (including di-, tri- and tetra-functional) derivatives ofthese two acids. The sphere of genotoxicity tests included in this reviewwere those most frequently used by global regulatory bodies for initialhazard screening purposes and tended to follow study designs consistentwith current regulatory guidelines. Study types included as part of thisreview were: Salmonella reverse mutation (Ames test), mouse lymphomaL5178Y tk locus, mouse lymphoma hgprt gene assay, in vitro chromo-somal aberration, sister-chromatid exchange (SCE), Chinese Hamsterovary (CHO/hgprt), V79/hgprt, in vitro cell transformation, in vitrounscheduled DNA synthesis (UDS), in vitro micronucleus, in vivo micro-nucleus, in vivo chromosomal aberration, and in vivo SCE . For in vitroassays, multiple mammalian cell lines, primarily those of rodents andhumans, were considered; multiple animal species and routes of dosingwere included in evaluation of the in vivo studies. Where available, primaryliterature citations have been cited. Multiple ndings in a similar test sys-tem by dierent researchers have been included to provide weight-of-the-evidence of study ndings. In a number of cases, results of short-termgenotoxicity studies by parties involved in either the conduct or authoriza-tion of conduct of these studies were reported in secondary source docu-ments and have also been included in this review, where validity of thendings was judged to be high. Examples of such studies came from (1)</p><p>pC European Commission</p><p>(1992)pC EFSA (2006)</p><p>lts.tes and the European Union</p><p>In vivo References</p><p>Chromosomalaberrations</p><p>Erythrocyte micronucleusor bone marrowchromosomal aberration</p><p>O C OECD (2005)pO Cimino (2006)p</p><p>Cimino (2006)O C CFSAN (2002)</p><p>and Pharmacology 50 (2008) 322335 323testing by the U.S. National Toxicology Program (NTP), the results ofwhich are listed on their ocial website or Technical Documents butnot specically reported or (2) robust summary documentation of a studysubmitted for peer review under voluntary programs to share hazard dataon a national (EPA HPV Challenge program) or global (OECD/ICCAHPV program) basis, often resulting in a nal, documented assessmentand (3) review documents summarizing the decisions of EFSA. In allcases, nal conclusions reached in those studies were taken from thoseof the individual authors or peer-reviewed summary.</p><p>3. Results</p><p>A substantial number of monofunctional and multifunc-tional acrylates and methacrylates have been tested usingstandard test methodology currently found in internation-ally accepted mutagenicity testing guidelines (OECD,1997). As seen in Table 2, acrylic acid, methacrylic acidand the vast majority of acrylates and methacrylates thathave been tested are inactive in the bacterial reverse muta-tion assay, whether tested with or without metabolic acti-vation in a series of standard Salmonella tester strains.</p></li><li><p>Table 2Results of reverse mutation bacterial assay with acrylic and methacrylic acid and their monofunctional and multifunctional acid esters</p><p>Acrylic/methacrylic acid/ester CAS No. Test results Reference(s)</p><p>(I) Acrylic acid</p><p>Acrylic acid 79-10-7 (1) Inactive (1) Zeiger et al. (1987)(2) Inactive (2) Cameron et al. (1991)</p><p>(II) Monofunctional acrylates</p><p>Methyl acrylate 96-33-3 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Zeiger et al. (1987)</p><p>Ethyl acrylate 140-88-5 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Haworth et al. (1983)</p><p>2-Hydroxyethyl acrylate 818-61-1 Inactive Watanabe et al. (1996)n-Butyl acrylate 141-32-2 (1) Inactive (1) Waegenmachers and Bensink (1984)</p><p>(2) Inactive (2) Zeiger et al. (1987)iso-Butyl acrylate 106-63-8 Inactive Zeiger et al. (1987)tert-Butyl acrylate 1663-39-4 Inactive Waegenmachers and Bensink (1984)2-Ethylhexyl acrylate 103-11-7 Inactive Zeiger et al. (1987)Pentyl acrylate 2998-23-4 Inactive Waegenmachers and Bensink (1984)Neopentyl acrylate 4513-36-4 Inactive Waegenmachers and Bensink (1984)Hexyl acrylate 2499-95-8 Inactive Waegenmachers and Bensink (1984)iso-Octyl acrylate 29590-42-9 Inactive Gordon et al. (1991)</p><p>(III) Multifunctional acrylates</p><p>Glycerol propoxydiacrylate 103534-15-2 Inactive Andrews and Clary (1986)Pentaerythritol triacrylate 3524-68-3 (1) Inactive (1) Zeiger et al. (1987)</p><p>(2) Inactive (2) Andrews and Clary (1986)Triethyleneglycol diacrylate 1680-21-3 Inactive Andrews and Clary (1986)Tetraethyleneglycol diacrylate 17831-71-9 Inactive Andrews and Clary (1986)Dipropyleneglycol diacrylate 57472-68-1 Inactive Andrews and Clary (1986)Glycerol propoxytriacrylate 52408-84-1 Inactive Andrews and Clary (1986)Trimethylolpropane ethoxytriacrylate 28961-43-5 Inactive Andrews and Clary (1986)Butanediol diacrylate 1070-70-8 Inactive Waegenmachers and Bensink (1984)1,5-Pentanediyl diacrylate 36840-85-4 Inactive Waegenmachers and Bensink (1984)Ethyleneglycol diacrylate 2274-11-5 (1) Inactive (1) Waegenmachers and Bensink (1984)</p><p>(2) Inactive (2) Zeiger et al. (1987)Trimethylolpropane triacrylate 15625-89-5 (1) Inactive-rat S9 (1) Cameron et al. (1991)</p><p>(2) Positive-hamster S9 (2) Cameron et al. (1991)Hexanediol diacrylate 13048-33-4 (1) Inactive (1) Waegenmachers and Bensink (1984)</p><p>(2) Inactive (2) Andrews and Clary (1986)(3) Inactive (3) Zeiger et al. (1987)</p><p>Neopentanediol diacrylate 2223-82-7 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Andrews and Clary (1986)</p><p>(IV) Methacrylic acid</p><p>Methacrylic acid 79-41-4 (1) Inactive (1) Haworth et al. (1983)(2) Inactive (2) Querens et al. (1981)</p><p>(V) Monofunctional methacrylates</p><p>Methyl methacrylate 80-62-6 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Zeiger et al. (1987)(3) Inactive (3) Querens et al. (1981)(4) Inactive (4) Schweikl et al. (1998)</p><p>Ethyl methacrylate 97-63-2 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Zeiger et al. (1987)</p><p>Hydroxyethyl methacrylate 868-77-9 (1) Inactive (1) Waegenmachers and Bensink (1984)(2) Inactive (2) Schweikl et al. (1998)</p><p>n-Propyl methacrylate 2210-28-8 Inactive Zeiger et al. (1987)iso-Propyl methacrylate 4655-34-9 Inactive Zeiger et al. (1987)Butyl methacrylate 97-88-1 (1) Inactive (1) Waegenmachers and Bensink (1984)</p><p>(2) Inactive (2) Zeiger et al. (1987)(3) Inactive (3) EPA/OTS (1986)</p><p>tert-Butyl methacrylate 585-07-9 Inactive Waegenmachers and Bensink (1984)iso-Butyl methacrylate 97-88-9 Inactive Zeiger et al. (1987)Pentyl methacrylate 2849-98-1 Inactive Waegenmachers and Bensink (1984)Neopentyl methacrylate 2397-76-4 Inactive Waegenmachers and Bensink (1984)Hexyl methacrylate 142-09-6 (1) Inactive (1) Waegenmachers and Bensink (1984)</p><p>(2) Inactive (2) Zeiger et al. (1987)Isodecyl methacrylate 29964-84-9 Inactive Zeiger et al. (1987)</p><p>324 F.R. Johannsen et al. / Regulatory Toxicology and Pharmacology 50 (2008) 322335</p></li><li><p>Tes</p><p>InaInaInaInaInaIna(1)(2)(3)(4)</p><p>InaInaInaInaInaInaIna(1)(2)Ina(1)(2)Ina</p><p>logyAn exception is GMA (glycidyl methacrylate), derivedfrom glycidol which, as a member of the class of epoxides,is mutagenic in the bacterial reverse mutation assay(McCann et al., 1975). Positive responses reported withtrimethylolpropane triacrylate (TMPTA) and trimethylol-</p><p>Table 2 (continued)</p><p>Acrylic/methacrylic acid/ester CAS No.</p><p>Dodecyl (Lauryl) methacrylate 142-90-5Octadecyl (Stearyl) methacrylate 32360-05-7Isobornyl methacrylate 7534-94-3Octyl methacrylate 2157-01-9Allyl methacrylate 96-05-92-Hydroxypropyl methacrylate 27813-02-1Glycidyl methacrylate 106-91-2</p><p>(VI) Multifunctional methacrylates</p><p>1,2-Ethanediol dimethacrylate 97-90-51,4-Butanediol dimethacrylate 2082-81-71,5-Pentanediol dimethacrylate 13675-34-8Neopentanediol dimethacrylate 1985-51-91,6-Hexanediol dimethacrylate 6606-59-3Diethylene glycol dimethacrylate 2358-84-1Urethane glycol dimethacrylate 28654-11-7Bisphenol A-glycidyl dimethacrylate 72869-86-4</p><p>Ethylenegylcol dimethacrylate 97-90-5Trimethylolpropane trimethacrylate 3290-92-4</p><p>Triethyleneglycol dimethacrylate 109-16-0</p><p>F.R. Johannsen et al. / Regulatory Toxicopropane trimethacrylate (TMPTMA) occurred in a singleSalmonella tester strain (TA1535) only when a hamsterliver metabolic activation system was used. Both were inac-tive in all Salmonella strains without metabolic activationand in TA1535 when a conventional rat liver metabolica...</p></li></ul>

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