1. Exposure Characterization

2. Cancer in Humans

3. Cancer in Experimental Animals

See Table 3.1.

Table 3.1

Studies of carcinogenicity with ortho-anisidine and ortho-anisidine hydrochloride in mice and rats.

4. Mechanistic Evidence

4.1. Absorption, distribution, metabolism, and excretion

4.1.1. Humans

(a) Exposed humans

ortho-Anisidine was detected in 95% of urine samples in a study of 20 participants without known exposure. The concentration was in the range of 0.05 to 4.2 µg/L, with a median value of 0.22 µg/L and a 95th percentile of 0.68 µg/L (Weiss & Angerer, 2002).

In a cross-sectional study, urinary ortho-anisidine was quantified in 1004 volunteers aged 3–84 years. ortho-Anisidine was detected in 90% of the population at a concentration range of 0.03–8.66 µg/L, with a median value of 0.23 µg/L and a 95th percentile of 1.12 µg/L (Kütting et al., 2009).

No data on absorption after occupational exposure to ortho-anisidine were available to the Working Group.

(b) Human hepatic microsomes

See Fig. 4.1.

Fig. 4.1

Pathways of ortho-anisidine metabolism.

Stiborová et al. (2005) reported that ortho-anisidine (0.1–0.5 mM) incubated with human hepatic microsomes in the presence of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) produced two metabolites, one of which was identified as N-(2-methoxyphenyl)hydroxylamine. In addition, Stiborová et al. (2005) demonstrated the involvement of human cytochrome P450 (CYP) enzymes in the ortho-anisidine oxidation, mainly CYP2E1 and CYP1A2. These findings were supported by the results of three independent assays: (i) the highly significant correlation found between the rate of chlorzoxazone 6-hydroxylation, a marker for CYP2E1, and the levels of N-(2-methoxyphenyl)hydroxylamine in human hepatic microsomes; (ii) the inhibition of N-(2-methoxyphenyl)hydroxylamine formation by diethyldithiocarbamate, an inhibitor of CYP2E1 in human hepatic microsomes; and (iii) the oxidation of ortho-anisidine by recombinant human CYP enzymes in Supersomes, demonstrating that the enzymes CYP1A2, followed by CYP2B6 and CYP2E1, are the most efficient enzymes catalysing the metabolism of ortho-anisidine (Stiborová et al., 2005).

Naiman et al. (2011) reported that human CYP enzymes catalyse the further oxidative and reductive metabolism of N-(2-methoxyphenyl)hydroxylamine, the main metabolite of ortho-anisidine. Using human hepatic microsomes and human recombinant CYP enzymes incubated with N-(2-methoxyphenyl)hydroxylamine, the parent compound ortho-anisidine (major product), the isomer ortho-aminophenol, and two other metabolites were identified. In addition, the human CYP2E1, CYP3A4, and CYP2C enzymes were found to be important in catalysing the reduction of N-(2-methoxyphenyl)hydroxylamine to ortho-anisidine (Naiman et al., 2011).

4.1.2. Experimental systems

(a) In vivo

Sapota et al. (2003) reported on the tissue distribution, excretion, and metabolism of ortho-anisidine in male IMP:WIST rats given a single intraperitoneal dose of ortho-anisidine-ring-U-³H (as a free base, dissolved in olive oil; 10 mg/kg bw). The blood plasma biphasic half-lives for fast and slow phases were about 1.5 hours and 80 hours, respectively, and the erythrocyte biphasic half-lives for fast and slow phases were about 1 hour and 116 hours, respectively. ortho-Anisidine was widely distributed to tissues, with the highest levels found in the liver, kidneys, and muscle tissue. In all examined tissues except for kidney and fat, the highest concentration of radiolabel was found 12 hours after injection. Urine was the main route of excretion. Almost 72% was excreted during the first 72 hours, about 6% of this in the faeces (Sapota et al., 2003). The main urinary metabolites were: (i) N-acetyl-2-methoxyaniline (almost 97% of the total amount excreted in the urine); and (ii) N-acetyl-4-hydroxy-2-methoxyaniline (about 1.5% of the total amount excreted in the urine) (Sapota et al., 2003).

ortho-Anisidine induced methaemoglobinaemia in CBA mice and Alpk:APfSD rats treated by oral administration (Ashby et al., 1991), indicating that ortho-anisidine is distributed and N-oxidized in rodents.

(b) In vitro

See Fig. 4.1.

Oxidation of ortho-anisidine by peroxidases, including the mammalian peroxidases and prostaglandin H synthase (from ram seminal vesicles), has been reported (Thompson & Eling, 1991; Stiborová et al., 2001, 2002). The pattern of metabolites formed after incubation of ortho-anisidine (0.1–1.0 mM) with peroxidases was dependent on the concentration of ortho-anisidine, concentration of peroxidases, incubation time, and pH. Peroxidases oxidized ortho-anisidine to a diimine metabolite, which subsequently hydrolysed to form a quinone imine (Stiborová et al., 2002). [The Working Group noted that diimine and quinone imine are electrophilic species.]

Three studies identified the metabolites formed in incubations of ortho-anisidine (0.1–2.0 mM) with rat and rabbit hepatic microsomes (Rýdlová et al., 2005; Naiman et al., 2008a, b). These studies showed that ortho-anisidine is subject to redox cycling reactions. It is primarily oxidized to N-(2-methoxyphenyl)hydroxylamine (major metabolite), ortho-aminophenol, and an additional metabolite. N-(2-methoxyphenyl)hydroxylamine is either further oxidized to ortho-nitrosoanisole (2-methoxynitrosobenzene) or reduced to parental ortho-anisidine, which can be oxidized again to produce ortho-aminophenol (Rýdlová et al., 2005; Naiman et al., 2008a, b). Using purified rat and rabbit hepatic CYP enzymes, reconstituted with NADPH:P450 reductase, the ability of CYP1A1, 1A2, 2B2, 2B4, 2E1, and 3A6 to catalyse the oxidation of ortho-anisidine was observed (Naiman et al., 2008b). The involvement of CYP2C, CYP2E1, CYP2D, and CYP2A, was observed in the reduction of N-(2-methoxyphenyl)hydroxylamine to ortho-anisidine (Naiman et al., 2010).

4.2. Evidence relevant to key characteristics of carcinogens

This section summarizes the evidence for the key characteristics of carcinogens (Smith et al., 2016), including whether ortho-anisidine is electrophilic or can be metabolically activated to an electrophile; is genotoxic; or alters cell proliferation, cell death, or nutrient supply. For the evaluation of other key characteristics of carcinogens, data were not available or considered insufficient.

4.2.1. Is electrophilic or can be metabolically activated to an electrophile

(a) Humans

(i) Exposed humans

Two studies detected the presence of haemoglobin adducts of ortho-anisidine in blood samples. Richter et al. (2001) detected haemoglobin adducts of ortho-anisidine, using capillary GC-MS, in blood samples of children from three different regions of southern Germany. The levels of ortho-anisidine–haemoglobin adducts were statistically significantly higher in children from an urban area (Munich, 1.3 million inhabitants) than in children from a less urban area (Augsburg, 250 000 inhabitants) and in children from a rural area (Eichstatt, 13 000 inhabitants). The regional differences in levels of ortho-anisidine–haemoglobin adducts were not related to tobacco exposure, since there were no major differences between children from smoking and non-smoking households (Richter et al., 2001). Haemoglobin adducts of ortho-anisidine, analysed by capillary GC-MS, were detected at similar levels in the blood of smoking and non-smoking pregnant women in Germany (Branner et al., 1998).

(ii) Human cells in vitro

No data from studies in human cells in vitro were available to the Working Group.

In two studies it was observed that ortho-anisidine is activated by human hepatic microsomes to form DNA adducts. Stiborová et al. (2005) used two techniques, [¹⁴C]-labelled ortho-anisidine and ³²P-postlabelling, to show that after activation by human hepatic microsomes ortho-anisidine forms N-(2-methoxyphenyl)hydroxylamine and binds to DNA. Using the ³²P-postlabelling technique, Naiman et al. (2011) reported DNA-adduct formation induced by N-(2-methoxyphenyl)hydroxylamine, the main metabolite of ortho-anisidine, when incubated with human hepatic microsomes.

(b) Experimental systems

Covalent binding to DNA was undetectable in B6C3F₁ mouse bladder or liver cells in vivo, after a single oral dose of ortho-anisidine hydrochloride (Ashby et al., 1994; see Table 4.1). ortho-Anisidine–DNA adducts, detected by ³²P-postlabelling, were observed in the urinary bladder, liver, kidney, and spleen (but not in the lung, heart, or brain) of Wistar rats treated with more than one intraperitoneal dose of ortho-anisidine (Stiborová et al., 2005; Naiman et al., 2012; see Table 4.1). The highest total DNA-adduct levels were found in the urinary bladder. The level of adducts in the bladder declined with time, but 39% of the initial level of binding remained even after 36 weeks (Naiman et al., 2012). Covalent binding was much less persistent in the liver, kidney, and spleen. N-(Deoxyguanosin-8-yl)-2-methoxyaniline was the major DNA adduct formed by ortho-anisidine. [The Working Group noted that guanine is also the predominant deoxynucleotide target within DNA for covalent binding by other aromatic amines, such as 4-aminobiphenyl, which is classified in IARC Group 1 (IARC, 2012).] There was formation of DNA adducts, detected by ³²P-postlabelling, in the urinary bladder of Wistar rats exposed orally to ortho-anisidine hydrochloride for 4 weeks (Iatropoulos et al., 2015; see Table 4.1).

Table 4.1

Genetic and related effects of ortho-anisidine and ortho-anisidine hydrochloride in non-human mammals in vivo.

ortho-Anisidine (1 mM) underwent covalent binding to calf thymus DNA (Thompson & Eling, 1991). Metabolites of ortho-anisidine (diimine and quinone imine) were consistently more reactive with protein and glutathione than were metabolites of para-anisidine (Thompson & Eling, 1991). Two subsequent studies using [¹⁴C]-labelled ortho-anisidine and ³²P-postlabelling assays observed that, after peroxidation to diimine and quinone imine, ortho-anisidine binds to calf thymus DNA in the presence of microsomes from ram seminal vesicles (Stiborová et al., 2001, 2002). Using [¹⁴C]-labelled ortho-anisidine, Stiborová et al. (2002) observed substantial peroxidase-dependent covalent binding of ortho-anisidine to DNA, tRNA, and polydeoxynucleotides. Using the ³²P-postlabelling assay, and enzymatic digestion with three times higher concentrations of micrococcal nuclease and spleen phosphodiesterase than in the standard procedure, ortho-anisidine activated by peroxidases was bound to poly(dG)–poly(dC) and to a lesser extent to poly(dA), but binding to poly(dC) or poly(dT) was not detectable, suggesting specificity for purine adduct formation (Stiborová et al., 2002).

Rat and rabbit hepatic microsomal CYP enzymes catalyse both O-demethylation and N-hydroxylation of ortho-anisidine to form a reactive metabolite, N-(2-methoxyphenyl)hydroxylamine (Naiman et al., 2008a, b). As shown in Fig. 4.1, studies using human, rabbit, or rat hepatic microsomes reported CYP-dependent oxidation of ortho-anisidine to its major metabolite, N-(2-methoxyphenyl)hydroxylamine. This N-hydroxy compound can be further oxidized to ortho-nitrosoanisole or reduced back to ortho-anisidine. Moreover, studies in vitro using mammalian peroxidases showed CYP-dependent formation of the electrophilic species diimine and quinone imine. [The Working Group noted that the bioactivation of ortho-anisidine to electrophilic species involves N-oxidation by CYP-associated enzymes, and parallels an established paradigm for aromatic amines such as 4-aminobiphenyl, 2-naphthylamine, and ortho-toluidine, which have been classified as carcinogenic to humans (IARC Group 1) (IARC, 2010, 2012).]

4.2.2. Is genotoxic

Table 4.1, Table 4.2, and Table 4.3 summarize the available studies on the genetic and related effects of ortho-anisidine and ortho-anisidine hydrochloride.

Table 4.2

Genetic and related effects of ortho-anisidine in non-human mammalian cells in vitro.

Table 4.3

Genetic and related effects of ortho-anisidine and ortho-anisidine hydrochloride in non-mammalian and acellular experimental systems.

(a) Humans

(i) Exposed humans

No data were available to the Working Group.

(ii) Human cells in vitro

DNA damage, analysed by the quantification of phosphorylated histone H2AX (γ-H2AX) in protein extracts of cells and by biased sinusoidal field-gel electrophoresis assay, was detected in 1T1 cells (human ureter epithelial cells immortalized by transfection with the human papillomavirus E6 and E7 genes) treated with ortho-anisidine (10 mM) for 4 hours. The generation of γ-H2AX increased in a dose-dependent manner after treatment of 1T1 cells with ortho-anisidine (5 mM) for 4 hours (Qi et al., 2020). Induction of γ-H2AX was also reported in human liver carcinoma HepG2 cells treated with ortho-anisidine (5 mM) for 4 hours. [The Working Group noted that the authors did not present quantification values for induction of γ-H2AX in HepG2 cells. HepG2 cells have low metabolic competence.]

(b) Experimental systems

(i) Non-human mammals in vivo

See Table 4.1.

The effect of ortho-anisidine on DNA damage was evaluated in several studies in rodents, and positive results in several tissues, including urinary bladder, were observed. Iatropoulos et al. (2015) observed a statistically significant increase in the mean percentage values of tail DNA, assessed by comet assay, in the urinary bladder of Wistar rats treated with ortho-anisidine hydrochloride for 1 month. Ashby et al. (1991) did not observe DNA strand breaks in the liver, thymus, testes, kidney, spleen, or urinary bladder of Wistar or Sprague-Dawley rats, after a single oral or intraperitoneal dose of ortho-anisidine. On the other hand, in Wistar rats, ortho-anisidine induced DNA strand breaks in the colon, kidney, bladder, and lung at the 3-hour sampling time; in the stomach, colon, kidney, bladder, lung, and brain at the 8-hour sampling time; and in the colon at the 24-hour sampling time after a single oral dose (Sekihashi et al., 2002). Wada et al. (2012) did not observe an increase in the frequency of DNA strand breaks in the urinary bladder of male and female Sprague-Dawley rats given a single dose of ortho-anisidine. Data from an international validation study on the comet assay technique indicated that a single dose of ortho-anisidine administered to Crl:CD(SD) male rats induced DNA strand breaks in the liver when the median percentage tail DNA, instead of the mean percentage tail DNA, was analysed (Uno & Omori, 2015). [The Working Group noted that the comet assay resulted in equivocal responses in this study, i.e. positive depending on the choice of statistical evaluation method.] Hobbs et al. (2015) reported that ortho-anisidine induced DNA strand breaks in the liver, without a corresponding significant dose–response relationship, but did not induce DNA strand breaks in the stomach of Sprague-Dawley rats. Toyoda et al. (2019) reported that administration of ortho-anisidine hydrochloride to Fischer/DuCrl-Crlj rats for 1 month induced DNA damage, as analysed by the quantification of γ-H2AX-positive epithelial cells in the urinary bladder.

ortho-Anisidine or its hydrochloride form did not induce unscheduled DNA synthesis in Fischer 344 or AP rat liver or kidney (Tyson & Mirsalis, 1985; Ashby et al., 1991).

In ddY mice, ortho-anisidine induced DNA strand breaks in the colon and urinary bladder at the 3- and 8-hour sampling times and in the urinary bladder at the 24-hour sampling time (Sekihashi et al., 2002). In CD-1 mice, a single dose of ortho-anisidine induced DNA damage, assessed by a modified comet assay, in the urinary bladder and colon but not in the stomach, kidney, liver, lung, brain, or bone marrow (Sasaki et al., 1998).

ortho-Anisidine hydrochloride induced gene mutation in the lacI transgene; in the Big Blue^TM mouse, there was a modest effect in the bladder and no effect in the liver (Ashby et al., 1994). ortho-Anisidine did not induce micronucleus formation in AP rat bone marrow or liver (Ashby et al., 1991) or in BDF1 or B6C3F₁ mouse bone marrow (Morita et al., 1997; Ashby et al., 1991).

ortho-Anisidine induced DNA repair in Escherichia coli in a host-mediated assay in male NMRI mice treated by intraperitoneal administration but not when treated by gavage (Hellmér & Bolcsfoldi, 1992b).

(ii) Non-human mammalian cells in vitro

See Table 4.2.

ortho-Anisidine did not induce unscheduled DNA synthesis in primary cultured rat hepatocytes (Thompson et al., 1983; Yoshimi et al., 1988).

Although DNA strand breaks were observed only in the presence of an exogenous metabolic system (Garberg et al., 1988), ortho-anisidine induced gene mutations in mouse lymphoma L5178Y cells in vitro both with and without exogenous metabolic activation (Wangenheim & Bolcsfoldi, 1988). Chromosomal aberrations and sister-chromatid exchange were induced in Chinese hamster ovary cells in vitro both with and without exogenous metabolic activation (Galloway et al., 1987). Structural chromosomal aberrations were observed in Chinese hamster lung cells both with and without exogenous metabolic activation (JETOC, 1997).

(iii) Non-mammalian experimental systems

See Table 4.3.

Three studies were conducted in Drosophila melanogaster (Yoon et al., 1985; Rodriguez-Arnaiz & Aranda, 1994; Rodriguez-Arnaiz & Téllez, 2002). ortho-Anisidine did not induce sex-linked recessive lethal mutations in Drosophila (Yoon et al., 1985), but this compound and its hydrochloride form induced, in a dose-dependent manner, the frequency of light spots in the eyes of an insecticide-sensitive Drosophila strain (white/white somatic assay), suggesting loss of heterozygosity by mitotic recombination (Rodriguez-Arnaiz & Aranda, 1994; Rodriguez-Arnaiz & Téllez, 2002).

ortho-Anisidine induced genotoxic effects by increasing recombination frequency, analysed by DEL recombination assay in Saccharomyces cerevisiae strain RS112 (Brennan & Schiestl, 1999).

ortho-Anisidine induced reverse mutations in Salmonella typhimurium strains TA98, TA100, TA1537, and TA1538, with exogenous metabolic activation (Shimizu & Takemura, 1983; Dunkel et al., 1985; Zeiger et al., 1992). In the presence of exogenous metabolic activation, ortho-anisidine induced reverse mutations in strain YG1029 (but not in strain YG1012, both YG strains having elevated levels of N-acetyltransferase) (Thompson et al., 1992). ortho-Anisidine or its hydrochloride form did not induce reverse mutation in E. coli or in S. typhimurium strains TA98, TA100, TA102, TA1535, TA1537, TA1538, TA2638, G46, C3076, D3052, or YG1012 (Ferretti et al., 1977; Garner & Nutman, 1977; Haworth et al., 1983; Thompson et al., 1983, 1992; Dunkel et al., 1985; Zeiger et al., 1992; Watanabe et al., 1996). ortho-Anisidine induced dose-dependent expression of the umuC gene in S. typhimurium overexpressing N-acetyltransferase type 1 and N-acetyltransferase type 2 (Oda, 2004), but not in S. typhimurium overexpressing O-acetyltransferase (Oda et al., 1995).

ortho-Anisidine, without exogenous metabolic activation, preferentially killed DNA repair-deficient E. coli strains rather than repair-proficient strains (Hellmér & Bolcsfoldi, 1992a).

4.2.3. Alters cell proliferation, cell death, or nutrient supply

(a) Humans

No data were available to the Working Group.

(b) Experimental systems

Cell proliferation was not induced in the urinary bladder of Wistar rats treated with ortho-anisidine hydrochloride (17 mg/kg bw per day, 3 days per week, for 4 weeks) (Iatropoulos et al., 2015). Histopathological evaluation of the bladder of F344/DuCrl-Crlj rats treated with ortho-anisidine hydrochloride (1.0% in the feed, for 2 or 4 weeks) showed hyperplasia with an increase in the frequency of cells that tested positive for the cell proliferation marker, Ki67 (Toyoda et al., 2019).

Male and female Fischer 344 rats given feed containing ortho-anisidine hydrochloride at a concentration of 5000 or 10 000 mg/kg for up to 103 weeks developed non-neoplastic lesions of the thyroid gland and kidney more frequently than did control animals (NCI, 1978).

In female B6C3F₁ mice that received feed containing ortho-anisidine hydrochloride at a concentration of 2500 or 5000 mg/kg for up to 103 weeks, the incidence of cystic hyperplasia of the uterine endometrium was higher than in control mice. There was an increased incidence of hyperplasia of the bladder in male and female B6C3F₁ mice at 5000 mg/kg relative to controls (NCI, 1978).

4.2.4. Evidence relevant to other key characteristics of carcinogens

(a) Humans

In human liver carcinoma cell lines HepG2 and Huh-7 single cultured and co-cultured with human monocytic THP-1 cells, ortho-anisidine induced reactive oxygen species in a concentration-dependent manner, as measured by the 2′,7′-dichlorodihydrofluorescein diacetate assay (Wewering et al., 2017).

(b) Experimental systems

In the absence of exogenous metabolic activation, ortho-anisidine hydrochloride at the lowest effective dose (500 µg/mL) induced cell transformation in Syrian hamster embryo cells in vitro (Kerckaert et al., 1998).

Treatment of primary murine hepatocytes with ortho-anisidine at 2.5 or 10 mM led to a significant increase in levels of reactive oxygen species after 3 hours of incubation (Wewering et al., 2017). Brennan & Schiestl (1999) reported that the genotoxic effects of ortho-anisidine in yeast were reduced in the presence of the free radical scavenger and antioxidant N-acetyl cysteine. In addition, comparing yeast strains with different capacities for the detoxification of oxygen radicals, it was shown that a strain with an inactivating disruption in the superoxide dismutase genes SOD1 and SOD2 was hypersensitive to the lethal effects of ortho-anisidine, which implies a role of the superoxide anion (O₂⁻) in its cytotoxicity (Brennan & Schiestl, 1999). ortho-Anisidine also induced the production in yeast of reactive oxygen species, measured by the oxidation of the free radical-sensitive reporter compound 2′,7′-dichlorodihydrofluorescein diacetate (Brennan & Schiestl, 1999).

The ortho-anisidine metabolite, ortho-aminophenol, induced Cu(II)-dependent DNA damage. This result was achieved using ³²P-labelled human DNA fragments (of c-Ha-RAS and TP53) and calf thymus DNA. In the presence of Cu(II), ortho-aminophenol induced formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) in calf thymus DNA (Ohkuma & Kawanishi, 2001).

ortho-Anisidine (1232 µg/mL) inhibited gap-junctional intercellular communication in mouse keratinocytes in the absence of an exogenous metabolic system, which was related to the decreased intensity of immunocytochemical staining for protein connexin 43 on the cell membrane (Jansen et al., 1996), but did not inhibit gap-junctional intercellular communication in Syrian hamster embryo cells exposed to 0.03–10 mM ortho-anisidine for up to 24 hours (Rivedal et al., 2000).

5. Summary of Data Reported

6. Evaluation and Rationale

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