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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Isobutyl Nitrite, β-Picoline, and Some Acrylates. Lyon (FR): International Agency for Research on Cancer; 2019. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 122.)
4.1. Absorption, distribution, metabolism, and excretion
4.1.1. Humans
Data on absorption, distribution, metabolism, and excretion of methyl acrylate in humans were not available to the Working Group.
4.1.2. Experimental systems
Methyl acrylate has been shown to be readily absorbed in rats (Sapota, 1988, 1993) and guinea-pigs (Seutter & Rijntjes, 1981) after the radiolabelled compound was given by intraperitoneal injection or orally. Dermal absorption has also been demonstrated in guinea-pigs; radiolabelled methyl acrylate had fully penetrated the dermis after 16 hours and was spread throughout the body (Seutter & Rijntjes, 1981).
Methyl acrylate was distributed to all major tissues after oral exposure or intraperitoneal injection in rats (Sapota 1988, 1993) and guinea-pigs (Seutter & Rijntjes, 1981). In rats, the highest concentration of radiolabel was detected in the liver and kidney 1 and 2 hours after intraperitoneal or oral exposure, respectively (Sapota, 1988, 1993). The highest concentrations of radiolabelled methyl acrylate detected using whole-body autoradiography of guinea-pigs were observed in the liver, bladder, and brain, or in the peritoneum and liver, 1 hour after oral exposure or intraperitoneal injection, respectively. Radiolabel quickly disappeared from all tissues, but at a slightly slower rate after intraperitoneal injection than after oral exposure (Seutter & Rijntjes, 1981).
In rats, the major route of excretion of methyl acrylate is via expiration (as carbon dioxide, CO2, > 50%) and urine (10–50%), and, to smaller extent, faeces (1–3%) (Sapota, 1988, 1993). The total radiolabel excreted after oral exposure or intraperitoneal injection of radiolabelled methyl acrylate within 72 hours was approximately 97% and 91% of the administered dose, respectively (Sapota, 1988). A similar excretion pattern was observed in guinea-pigs (Seutter & Rijntjes, 1981).
There are two suggested detoxification pathways for methyl acrylate (Sapota, 1993) (see Fig. 4.1): (i) hydrolysis by carboxylesterases to acrylic acid and methanol, with further hydration of the double bond of acrylic acid to form 3-hydroxypropionic acid that can then be oxidized to malonic acid and further to CO2; and (ii) conjugation with endogenous glutathione and subsequent excretion as mercapturic acid in urine.
These two metabolic pathways are supported by several findings in the literature (Delbressine et al., 1981; Miller et al., 1981; Seutter & Rijntjes, 1981; Vodička et al., 1990; Black et al., 1993; Sapota, 1993). For instance, methyl acrylate has been shown to be hydrolysed by rat tissue carboxylesterases to acrylic acid (Miller et al., 1981). An increase in the amount of excreted mercapturic acid derivatives of methyl acrylate, more specifically thioethers, was also observed in rats and guinea-pigs after intraperitoneal injection, and in guinea-pigs after oral and dermal exposure to methyl acrylate. In rats, the thioethers were identified as N-acetyl-(2-carboxyethyl)-l-cysteine and the corresponding monomethyl ester at a ratio of 20:1 (Delbressine et al., 1981; Seutter & Rijntjes, 1981). This is consistent with the observed chemical reactivity of methyl acrylate with glutathione in vitro, with an estimated half-life of 18.4 minutes (Miller et al., 1981; Vodička et al., 1990).
4.1.3. Modulation of metabolic enzymes
At doses of up to 160 µM, methyl acrylate did not induce mRNA of the endogenous human NAD(P)H:quinone oxidoreductase (HQOR1) gene in the human hepatocarcinoma cell line (HepG2) (Winner et al., 1997). However, at 20 µM, it caused a twofold induction of quinone reductase in the mouse Hepa 1c1c7 cell line (Talalay, 1989).
4.2. Mechanisms of carcinogenesis
This section summarizes the evidence for the key characteristics of carcinogens (Smith et al., 2016). Data were available only for the key characteristic “is genotoxic”.
4.2.1. Genetic and related effects
(a) Humans
No data were available to the Working Group.
(b) Experimental systems
(i) Non-human mammals in vivo
See Table 4.1
There was an increase in the frequency of micronucleated cells in the bone marrow of male BALB/c mice exposed to methyl acrylate by two intraperitoneal injections given 24 hours apart (Przybojewska et al., 1984). However, in ddY outbred mice, methyl acrylate gave negative results in assays for micronucleus formation after oral exposure (a single dose of 250 mg/kg bw) or by inhalation (2100 ppm for 3 hours) (Hachiya et al., 1982; Sofuni et al., 1984).
(ii) Non-human mammalian cells in vitro
See Table 4.2
In Chinese hamster ovary (CHO) AS52 cells, methyl acrylate was not mutagenic in the xanthine-guanine phosphoribosyl transferase (Xprt) assay (Oberly et al., 1993). In addition, no mutagenic effect was reported in the hypoxanthine-guanine phosphoribosyl transferase (Hgprt) assay in CHO cells exposed to methyl acrylate (Moore et al., 1989, 1991). At cytotoxic test concentrations with less than 50% cell survival, methyl acrylate induced mutations at the thymidine kinase (Tk+/−) locus in L5178Y mouse lymphoma cells without metabolic activation (Moore et al., 1988), and increased the frequency of chromosomal aberrations in CHO cells and L5178Y mouse lymphoma cells in the absence of metabolic activation (Moore et al., 1988, 1989). In CHO cells, methyl acrylate increased the frequency of micronucleus formation at cytotoxic concentrations in the presence but not absence of S9 (Kirpnick et al., 2005).
(iii) Non-mammalian systems
See Table 4.3
In Saccharomyces cerevisiae, methyl acrylate significantly increased the frequency of DNA deletions detected in the deletion (DEL) assay in the absence but not the presence of S9, but only at concentrations at which there was less than 5% cell viability (Kirpnick et al., 2005).
Methyl acrylate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538, without or with metabolic activation (Florin et al., 1980; Waegemaekers & Bensink, 1984).
4.2.2. Other mechanisms
(a) Humans
No data were available to the Working Group.
(b) Experimental systems
Dose-related atrophy of the neurogenic epithelial cells and hyperplasia were observed in the nasal mucosa of all male and female Sprague-Dawley rats exposed to methyl acrylate by inhalation at concentrations of 0, 15, 45, and 135 ppm for 6 hours per day, 5 days per week, for 24 months (Reininghaus et al., 1991).
4.3. Other adverse effects
4.3.1. Irritancy and sensitization
(a) Humans
Irritation and sensitization after exposure to methyl acrylate have been described, in some cases with complex exposures; positive patch-test responses to methyl acrylate have also been reported (Cavelier et al., 1981; Kanerva et al., 1994; Lammintausta et al., 2010).
(b) Experimental systems
The immunogenicity of methyl acrylate was investigated by determining the induction of immunoglobulin G antibodies in female Hartley guinea-pigs in vivo (Bull et al., 1987). The injection of 0.25 mL of an emulsion of equal volumes of a 20 mM solution of methyl acrylate and Freund’s complete adjuvant resulted in the induction of antigen-specific antibodies reactive with methyl acrylate.
Methyl acrylate was determined to be a weak sensitizer (effective concentration required to produce a threefold increase in proliferation of draining lymph node cells compared with control values), EC3, 19.6) in a local lymph node assay in female CBA/Ca mice (Dearman et al., 2007).
Figures
Fig. 4.1Proposed metabolic pathways for methyl acrylate, based on identification of acrylic acid, carbon dioxide, and mercapturic acid conjugates
The N-acetyl-(2-carboxyethyl)-l-cysteine conjugate may also stem from glutathione addition to acrylic acid
Compiled by the Working Group
Tables
Table 4.1Genetic and related effects of methyl acrylate in non-human mammals in vivo
| End-point | Species, strain (sex) | Tissue | Resultsa | Dose (LED or HID) | Route, duration | Reference |
|---|---|---|---|---|---|---|
| Micronucleus formation | Mouse, ddY (M) | Bone marrow | − | 250 mg/kg bw | Oral | Hachiya et al. 1982 |
| Micronucleus formation | Mouse, BALB/c (M) | Bone marrow | + | 37.5 mg/kg bw | Intraperitoneal injection, ×2 | Przybojewska et al. (1984) |
| Micronucleus formation | Mouse, ddY (NR) | Bone marrow | − | 2100 ppm | Inhalation, 3 h | Sofuni et al. (1984) |
bw, body weight; h, hour; HID, highest ineffective dose; LED, lowest effective dose; M, male; NR, not reported; ppm, parts per million
a +, positive; –, negative; the level of significance was set at P < 0.05 in all cases
Table 4.2Genetic and related effects of methyl acrylate in non-human mammalian cells in vitro
| End-point | Species, cell line | Resultsa | Concentration (LEC or HIC) (μg/mL) | Comments | Reference | |
|---|---|---|---|---|---|---|
| Without metabolic activation | With metabolic activation | |||||
| Mutation (Tk) | Mouse, L5178Y lymphoma cells | (+) | NT | 14 | Only positive at cytotoxic concentrations | Moore et al. (1988) |
| Mutation (Xprt) | Chinese hamster ovary, CHO-AS52 | − | NT | 25 | Oberly et al. (1993) | |
| Mutation (Hgprt) | Chinese hamster ovary, CHO | − | NT | 80 | Moore et al. (1991) | |
| Mutation (Hgprt) | Chinese hamster ovary, CHO | − | NT | 18 | Moore et al. (1989) | |
| Chromosomal aberrations | Mouse, L5178Y lymphoma cells | (+) | NT | 16 | Only positive at cytotoxic concentrations | Moore et al. (1988) |
| Chromosomal aberrations | Chinese hamster ovary, CHO | (+) | NT | 14 | Only positive at cytotoxic concentrations | Moore et al. (1989) |
| Micronucleus formation | Chinese hamster ovary, CHO | − | (+) | 2109 | Only positive at cytotoxic concentrations | Kirpnick et al. (2005) |
HIC, highest ineffective concentration; LEC, lowest effective concentration; NT, not tested
a –, negative; (+), positive result in a study of limited quality; the level of significance was set at P < 0.05 in all cases
Table 4.3Genetic and related effects of methyl acrylate in non-mammalian experimental systems
| Test system (species, strain) | End-point | Resultsa | Concentration (LEC or HIC) | Comments | Reference | |
|---|---|---|---|---|---|---|
| Without metabolic activation | With metabolic activation | |||||
| Salmonella typhimurium
TA98, TA100, TA1535, TA1537 | Reverse mutation (Ames test) | − | − | 3 μmol/plate | Florin et al. (1980) | |
| Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 | Reverse mutation (Ames test) | − | − | 1250 µg/plate | Waegemaekers & Bensink (1984) | |
| Saccharomyces cerevisiae RS112 | DEL recombination | (+) | − | 500 μg/mL | Significant toxicity (< 5% survival) | Kirpnick et al. (2005) |
DEL, deletion; HIC, highest ineffective concentration; LEC, lowest effective concentration
a –, negative; (+), positive result in a study of limited quality; the level of significance was set at P < 0.05 in all cases