Mutagenesis Advance Access originally published online on December 29, 2004
Mutagenesis 2005 20(1):3-13; doi:10.1093/mutage/gei005
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Mutagenesis vol. 20 no. 1 © UK Environmental Mutagen Society 2005; all rights reserved.
REVIEW |
Review of the genotoxicity of 4-chloro-2-methylphenoxyacetic acid
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield SK10 4TJ, UK
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Abstract |
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 Top Abstract IntroductionIn vitro genotoxicityIn vivo genotoxicityDiscussionReferences |
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4-Chloro-2-methylphenoxyacetic acid (MCPA) has been examined for genotoxicity in a range of in vitro and in vivo assays, including assays for gene mutation and clastogenicity. MCPA is non-mutagenic in bacterial and mammalian cell gene mutation assays. Increases in percentage aberrant cells were found on analysis of metaphases of human peripheral lymphocytes treated in vitro in the presence of auxiliary metabolic activation (S9), but only at doses approaching 10 mM and causing significant cytotoxicity. These increases may therefore be non-specific. No evidence for clastogenicity in vivo was found in the mouse bone marrow micronucleus assay or the Chinese hamster bone marrow metaphase assay. No evidence for either increases in sister chromatid exchange (SCE) frequency or DNA binding was found in the rat. Very small (less than 1.5 times controls) increases in SCE were observed in vivo in the hamster at toxic or maximum tolerated dose levels. MCPA is not alerting for likely genotoxic activity using established structure–activity relationship principles and it is concluded that, on the weight of evidence from the available data, MCPA is not genotoxic in vivo. This is consistent with its lack of carcinogenicity in rats and mice.
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Introduction |
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TopAbstractIntroductionIn vitro genotoxicityIn vivo genotoxicityDiscussionReferences |
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4-Chloro-2-methylphenoxyacetic acid (MCPA) (Figure 1) is a herbicide. MCPA has been examined in lifetime feeding studies in both rats (at target doses of 20, 80 and 320 p.p.m. for 2 years) and mice (20, 100 and 500 p.p.m. for 2 years) and found to be non-carcinogenic (Bellet et al., 1999
). MCPA has been examined in a number of genotoxicity assays and is reported in the literature to have some evidence of genotoxic activity. In this paper the results from an examination of MCPA in a range of assays including previously unpublished standard genotoxicity assays such as the Salmonella/microsome assay (Ames test) and assays examining for chromosomal aberrations are presented. The activity of three formulations of MCPA, the acid form, the dimethylamine (DMA) salt and the 2-ethyl hexyl ester (EHE) have been investigated in several studies described herein. These formulations have been shown to be metabolically equivalent, at least in the rat (van Ravenzwaay et al., 2004). All the available data are reviewed in the context of whether the chemical should be regarded as posing a genotoxic hazard in vivo.
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In vitro genotoxicity |
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TopAbstractIntroductionIn vitro genotoxicityIn vivo genotoxicityDiscussionReferences |
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MCPA, MCPA as the DMA salt aqueous solution (MCPA.DMAS) and MCPA as the EHE (MCPA-EHE) have been examined in vitro for a range of end-points, including bacterial gene mutation, mammalian cell gene mutation and cytogenetic activity. The available references for MCPA are summarized in Table I and data from unpublished reports are provided in Tables II–X and the text. Reports of unpublished genotoxicity studies on the analogues MCPA.DMAS and MCPA-EHE, conducted in the same laboratories and to the same protocols as MCPA, are summarized in Tables II and III, but the data are not provided except where needed to make specific comparisons.
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Gene mutation
MCPA, MCPA.DMAS and MCPA-EHE have been found to be negative in the Salmonella/microsome assay in Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 at doses up to 5 mg/plate, both in the absence and presence of an auxiliary metabolic activation system (S9) comprising a post-mitochondrial supernatant from rats treated with Aroclor 1254 (Jones et al., 1992
, 1993a,b) (Table IV). MCPA has further been reported to be negative in a range of S.typhimurium and Escherichia coli strains in both the absence and presence of S9 (Nishimura, 1982; Moriya, 1983; Rasanan, 1997; Kappas, 1988) and in the SOS chromotest (Mersch-Sundermann et al., 1989). MCPA as the methyl ester was also negative in Salmonella strains TA98 and TA100 both in the absence and presence of S9 (Zetterberg, 1979).
MCPA was reported to be weakly mutagenic in the presence of S9 only in Salmonella strain TA97a (Kappas, 1988). Statistically significant increases in revertant colonies were observed in the single experiment reported, but these were to a maximum of only 1.3-fold over control values. Activity was reported for samples of a commercial formulation containing MCPA and for MCPA sodium salt, in the absence of S9 only, in the Mutatox bacterial luminescence assay, although only limited details of the assay and the data generated were reported (Vismara and Garavaglia, 1997). This assay is not a generally accepted, validated assay for the evaluation of mutagenicity in bacteria and thus does not have the same status as the standard Salmonella/microsome assay. These two reports of activity of MCPA are considered to be of limited significance and the conclusion from the considerable body of available data is that MCPA should be regarded as non-mutagenic in the standard bacterial mutagenicity screen.
MCPA, MCPA.DMAS and MCPA-EHE have been found to be negative in the CHO HGPRT mammalian cell mutation assay, both in the absence and presence of S9 (Adams et al., 1993a–c) (Table V). MCPA and MCPA.DMAS were examined at maximum doses limited by toxicity (1000 and 2750 µg/ml, respectively), whilst MCPA-EHE was examined at a maximum dose of 200 µg/ml, limited by precipitation of the test material. MCPA has also been reported to be negative in a V79 mammalian cell mutation assay using the 8-azaguanine and ouabain loci (Fiskesjo, 1988). This latter result is considered of limited value, as the top dose reported was only 2 µg/ml, based on effects observed previously in Allium.
Chromosomal aberrations and sister chromatid exchange
MCPA, MCPA.DMAS and MCPA-EHE have been evaluated for chromosomal aberrations using conventional metaphase analysis of human peripheral lymphocytes treated in vitro both in the absence and presence of S9 (Akhurst et al., 1993a–c). MCPA was found to cause limited cell cycle delay in the absence of S9 in an initial investigation, and harvest times of 13 and 21 h were employed for the main study (Akhurst et al., 1993c) (Table VI). In the absence of S9 no significant increases in per cent aberrant cells were observed at doses limited by a reduction in mitotic index, with a maximum concentration of 500 µg/ml causing a reduction in mitotic index of 55%. In the presence of S9 increases in per cent aberrant cells were observed in the two experiments conducted, using doses up to 2000 µg/ml. The increases in aberrant cells were accompanied by increased cytotoxicity, as measured by a reduction in mitotic index and the occurrence of pyknotic figures. At the top dose of 2000 µg/ml, although a value of 12.7% aberrant cells was recorded, one of the two available cultures was found to have too few cells to evaluate and the second only allowed 63 cells to be scored (rather than the 100 target). This dose is therefore considered to have been too cytotoxic to be of value and would not have been selected for evaluation under current guidelines/recommendations as it is excessively cytotoxic. The relationship between concentration of MCPA in the medium, cytotoxicity and per cent aberrant cells is summarized in Table VII. The relevant historical control range for the laboratory for per cent aberrant cells excluding gaps was 0–5.25%. MCPA.DMAS gave a similar picture, in experiments using the same two harvest times, with increases in per cent aberrant cells again only being observed in the presence of S9 (Akhurst et al., 1993a). The top dose evaluated (2000 µg/ml) gave rise to 13.5% aberrant cells with a reduction in mitotic index of 37%, apparently not an excessive level of cytotoxicity. However, the cytotoxicity curve was very steep and a dose of just 2500 µg/ml gave rise to an observed reduction in mitotic index of 96%. The increase in per cent aberrant cells was therefore closely associated with increased cytotoxicity for this material also. MCPA-EHE caused cell cycle delay in the absence of S9, and was evaluated for chromosomal aberrations under these conditions at doses limited by reductions in mitotic index, with a top dose of 160 µg/ml (Akhurst et al., 1993b). In the presence of S9 dose levels were limited by precipitation of the test material and a top dose of 320 µg/ml was used. No significant increases in per cent aberrant cells were observed in either the absence or presence of S9.
A range of cytogenetic studies has been undertaken by a group of workers from Finland, mainly involving measurement of sister chromatid exchange (SCE) following in vitro or in vivo assessments. In the in vitro studies MCPA was reported to produce a small but statistically significant increase in SCE (SCE frequency/cell) in CHO cells treated in vitro in the presence of S9 (Linnainmaa, 1984). However, this increase was only 1.2 times the control value and there was no dose relationship over the concentration range 0.01–1.0 mM. Similar results were obtained with a commercial formulation of MCPA (as the iso-octyl ester; data not shown). The author concluded that MCPA does not act as a DNA-damaging agent. An abstract reported no significant increases for MCPA in an in vitro micronucleus assay using human lymphocytes (Burroughs et al., 1996).
Other in vitro assays
MCPA has been evaluated for mutagenic activity in yeast using Saccharomyces cerevisiae rad18 (Zetterberg, 1978, 1979). Increases in numbers of revertants were observed, but only at concentrations of MCPA that caused 95–99% cell death. The same result was obtained with salicylic acid, and the author concluded that the results were due to the toxicity of the acidic molecules. Kappas reported increased mitotic segregants in Aspergillus nidulans at concentrations of 1500–3000 µM MCPA (Kappas, 1988). These concentrations were also toxic as measured by reductions in colony size.
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In vivo genotoxicity |
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TopAbstractIntroductionIn vitro genotoxicityIn vivo genotoxicityDiscussionReferences |
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MCPA, MCPA.DMAS and MCPA-EHE have been examined in vivo for cytogenetic end-points, including micronucleus formation, chromosomal aberrations and SCEs. The available references for MCPA are summarized in Table I, and data from unpublished reports are provided in the text. Reports of unpublished genotoxicity studies on the analogues MCPA.DMAS and MCPA-EHE, conducted to the same protocols as MCPA, are summarized in Tables II and III, but data are not shown.
Chromosomal aberrations and sister chromatid exchange
MCPA was examined in the mouse bone marrow micronucleus assay in both male and female Swiss CD-1 mice at doses of 96, 192 and 384 mg/kg (Proudlock et al., 1993b) (Table VIII). The maximum tolerated dose (MTD) of 384 mg/kg was confirmed by clinical signs and lethality observed at higher doses. Bone marrow samples were taken at 24, 48 and 72 h following a single oral gavage dose. No significant increase in the frequency of micronucleated polychromatic erythrocytes (MPEs) was seen at any sampling time or dose. A similar result was obtained using the same study design with MCPA.DMAS (doses of 144, 288 and 576 mg/kg, equivalent to 118, 235 and 470 mg/kg MCPA expressed as acid) (Proudlock et al., 1993a) and MCPA-EHE (doses of 450, 900 and 1800 mg/kg, equivalent to 288, 577 and 1154 mg/kg MCPA acid) (Proudlock et al., 1993c). Small increases in MPE frequency were observed at the 72 h sampling time following MCPA-EHE treatment at the two lowest doses only. The MPE frequencies were, however, well within the historical control range and showed no dose–response relationship. These increases were considered not to be significant by the authors, who concluded that MCPA-EHE was negative in the assay. An evaluation of MCPA, MCPA.DMAS and MCPA-EHE in the mouse bone marrow micronucleus assay therefore showed all three materials to be non-clastogenic. MCPA has also been examined in the Chinese hamster bone marrow for possible cytogenetic activity using metaphase analysis. Male and female hamsters were administered MCPA as a single oral gavage dose of 33, 200 or 1200 mg/kg and bone marrow sampled at 6, 24 or 48 h later for the highest dose group and at 24 h for the other groups. The top dose used was an MTD based on significant clinical signs. The mid dose animals showed minimal clinical signs and the low dose animals showed no signs. No significant increases over control were observed (Gelbke and Engelhardt, 1985a,b) (Table IX).
An investigation of MCPA for the induction of SCEs using Chinese hamsters and doses of 33, 200 and 1200 mg/kg was reported by Gelbke and Engelhardt (1985c) (Table X). A sampling time of 24 h after dosing was used and 30 metaphases per animal were examined. The authors reported a small but statistically significant increase in SCE frequency over controls at the top two doses. However, these increases were only 1.16 and 1.37 times the control value. The positive control (20 mg/kg cyclophosphamide) resulted in a >7-fold increase over controls. A repeat study was undertaken, using just the 1200 mg/kg dose, and the SCE frequency evaluated, again in 30 metaphases (Gelbke and Engelhardt, 1985d) (Table X). A similar very small (1.48 times control) but statistically significant increase was observed, whilst the positive control induced a >11-fold increase in SCE frequency. The authors reported that the animals dosed with 1200 mg/kg MCPA showed clear signs of toxicity, including piloerection, apathy, atony, irregular respiration and trembling. The general state of the animals was described as poor. Linainmaa (1984) investigated the ability of MCPA (a commercial formulation of the iso-octyl ester) to induce SCEs in vivo in both the rat and the Chinese hamster. Male Wistar rats were administered 100 or 150 mg/kg MCPA as a daily gavage dose on each of 5 days per week, for 2 weeks. Blood was sampled 24 h after the last dose. Higher doses than 150 mg/kg could not be used owing to adverse clinical signs in the animals, and the 150 mg/kg dose level yielded insufficient metaphases for evaluation. The dose of 100 mg/kg was therefore an MTD for this assay. Male Chinese hamsters were administered 100 mg/kg MCPA as a daily gavage dose for 9 consecutive days and blood was sampled 24 h after the last dose. No statistically significant increase in SCE frequency over control was found in the treated rats. In the treated hamsters a small but statistically significant increase in SCE frequency (1.36 times control) was observed. The author concluded that these weak increases did not indicate that MCPA was acting as a direct DNA-damaging agent. The lack of SCE induction in the rat was confirmed by Mustonen et al. (1989) with the administration of 100 mg/kg MCPA as a daily gavage dose on 5 days per week for 2 weeks to male Han/Wistar rats. Blood was sampled 24 h after the last dose and no significant increase in SCE frequency over the control was observed.
Linnainmaa (1983) and Mustonen et al. (1986) examined the peripheral lymphocytes of forestry workers spraying foliage in an investigation of the ability of herbicides to cause SCE or chromosomal aberration in man. MCPA and 2,4-dichlorophenoxyacetic acid (both formulated as the iso-octyl esters) were the herbicides used, and an estimate of exposure was made by analysis of concentrations in the urine. Levels of MCPA reported in the urine of subjects ranged from 0 to 1.84 (Linnainmaa, 1983) and 0 to 9.54 mg/l (Mustonen et al., 1986). Appropriate non-exposed controls were used. No significant increases in SCE frequency or in the incidence of chromosomal aberrations were found compared with controls. A difference in SCE frequency between smokers and non-smokers was observed, demonstrating the sensitivity of the techniques employed.
MCPA (as the sodium salt) was reported to cause an increased incidence of SCE compared with controls when injected into a developing chick embryo for a period of 4 days (Arias, 1992). The increase over controls was 1.28-fold (from 1.19 to 1.52 SCEs/cell), and the dose used was 2.8 mg/egg, with a dose of 5.6 mg/egg reported as toxic. In a follow-up study the same worker reported a similar small increase when injecting MCPA into eggs and sampling after 4 or 10 days with doses of up to 4.2 mg/egg (Arias, 1996). Even at these higher doses the increases observed were to just 1.37 and 1.40 times control for the 4 and 10 day exposures, respectively.
Other in vivo assays
The ability of MCPA as the sodium salt to bind to DNA, RNA or proteins was investigated by dosing radiolabelled material by oral gavage to groups of three male CD rats and examining the livers at 0.5, 1.5 and 4.5 h after dosing (McGregor, 1986). Doses of 44 or 455 mg/kg MCPA were used, with 4-chloro-2-methyl[ring-U-14C]phenoxyacetic acid (67 mCi/mmol) as the radiolabel. Phenol/chloroform extraction of liver homogenate followed by salt precipitation of RNA and then ethoxyethanol precipitation of DNA was undertaken. No significant association of radiolabel with either the DNA or RNA fractions from liver was observed at any time point. Radioactivity was, however, found to be associated with the acetone-precipitated proteinaceous fraction at all sampling times (data not shown).
An evaluation in the Drosophila sex-linked lethal assay at concentrations of 5 and 10 mM was reported to give rise to small increases in lethal frequencies (Vogel and Chandler, 1974). However, these were found to be statistically significant only when all of the MCPA data were pooled and compared with the lower of two control values obtained. These data are considered not to indicate a mutagenic action of MCPA. This work was further extended by Magnusson et al. (1977), who examined MCPA for the induction of non-disjunction, chromosome loss and exchange in Drosophila at dose levels up to 500 p.p.m. MCPA was found to have no effect on any parameter.
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Discussion |
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TopAbstractIntroductionIn vitro genotoxicityIn vivo genotoxicityDiscussionReferences |
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The activity of the three formulations of MCPA, the acid form, the DMA salt and the EHE have been investigated in several studies described above. These formulations have been shown to be metabolically equivalent, at least in the rat, and to be rapidly absorbed after oral dosing and with maximum plasma concentrations within 2–4 h after dosing (van Ravenzwaay et al., 2004
). The in vivo genotoxicity studies will therefore have been under conditions where the target organ will have been adequately exposed to test material. At physiological pH MCPA (pKa 3.73) is essentially fully dissociated and any differences between acid and salts must reflect the influence of the counterion. The position with the ester is less simple. Although there are many non-specific esterases in intact organisms which can rapidly hydrolyse most esters (MCPA is excreted exclusively as the acid in kinetic studies), these may not be present in high concentration in cell cultures. The ester also has very low water solubility (<1 µg/l) and so distribution of added chemical in the cell cultures may be impaired. Nevertheless, there is generally good agreement between the results obtained from acid and ester studies, so this appears not to be an issue.
MCPA is not extensively metabolized in mammalian systems, but a proportion is transformed into 2-hydroxymethyl-4-chlorophenoxyacetic acid (HMCPA), which is excreted even more rapidly than MCPA (van Ravenzwaay et al., 2004).
The chemical structure of MCPA (and that of HMCPA) is not alerting for genotoxic activity when considered using standard structure–activity relationship (SAR) principles (Tennant and Ashby, 1991; interrogation with DEREK version 7.0). This evaluation is supported by the negative results from the bacterial Salmonella/microsome assay across a range of tester strains, and is based on data for MCPA, MCPA.DMAS and MCPA-EHE. The isolated reports of activity for MCPA in Salmonella TA97a (maximum of 1.3 times control) and in the Mutatox bacterial luminescence assay are considered insufficient to qualify this conclusion. The same three formulations have also been examined in the CHO HPRT mammalian cell gene mutation assay, and again found to be negative. A literature report of a negative result in V79 cells evaluating the azaguanine and ouabain loci is of limited value, as the top dose appears to have been inadequate.
Activity has, however, been reported for MCPA when evaluating for cytogenetic effects, with data available for the end-points of chromosomal aberrations in vitro and SCE formation. In the absence of S9 no significant increases over controls were observed when human peripheral lymphocytes were treated in vitro with MCPA at concentrations up to 500 µg/ml, limited by cytotoxicity. In the presence of S9 the lymphocytes tolerated higher concentrations of MCPA and the top doses evaluated were 2000 and 1500 µg/ml in the two experiments conducted. Examination of the dose–response characteristics for both per cent aberrant cells and cytotoxicity (measured by the reduction in mitotic index) (Table VII) shows a steep curve for cytotoxicity. Meaningful increases in per cent aberrant cells occur only when there is significant measured cytotoxicity to the cultured cells and the doses are on the steep part of the cytotoxicity curve.
A similar profile of response, of increased per cent aberrant cells only in the presence of S9 and only at cytotoxic concentrations, was observed for MCPA.DMAS. It is noted that the report for MCPA contains an observation that in a pre-test, the pH of the medium with 2000 µg/ml MCPA was found to be 6.0–6.5. No measurement of the pH in the main studies appears to have been undertaken. It is known that pH and osmolality changes can result in increases in per cent aberrant cells in culture and, thus, in this experiment MCPA may have decreased the pH sufficiently to contribute to an increased level of aberrations. A concentration of 2000 µg/ml is 
10 mM, and this is a high concentration with regard to possible osmolality-induced events. The current limit dose for in vitro cytogenetic studies is 10 mM, in order to minimize such possible artefacts. An investigation in this laboratory of the effect of 2000 µg/ml MCPA on the pH and osmolality of culture medium showed that a change in pH is indeed induced (a dose-related pH decrease of 0.66 units at 2000 µg/ml over a control of 7.48, but no significant dose-related change in osmolality), but that the magnitude of this change is too small to have been solely responsible for the increases in aberrations observed. Under the experimental conditions in the cytogenetic cultures an additional acidification is likely due to normal cellular metabolism, and this may have reduced the pH to a level where an effect was apparent. The observation of increases in per cent aberrant cells with MCPA.DMAS might similarly have a contribution from pH, since the DMA is significantly volatile and its loss would predispose to a level of acidification. The observation of activity in vitro that is due to effects of the acidic function rather than to a specific genotoxic activity of MCPA are illustrated by the finding that in yeast (Zetterberg, 1979) MCPA and salicylic acid are both able to induce mutation of S.cerevisiae, coincident with the acidic functionality and significant cell death. A steep toxicity curve is seen in the cytogenetic assays and this, coupled with the pH changes, provides a plausible explanation for the high dose effects observed.
In vivo MCPA has been shown to be non-clastogenic using end-points of micronucleus induction in the mouse bone marrow and metaphase analysis in the Chinese hamster bone marrow. Both studies were conducted at doses up to an MTD and using both male and female animals. MCPA.DMAS and MCPA-EHE have similarly been shown to be inactive in the mouse bone marrow micronucleus assay. These data indicate that the increases in per cent aberrant cells observed following treatment in vitro with MCPA and MCPA.DMAS do not translate into clastogenic activity in vivo.
Increases in SCE frequency have been reported for MCPA in vitro in CHO cells in the presence of S9. The increases were very small, being 1.2 times controls. Similar levels of increase have also been reported in vivo in Chinese hamsters, after single or repeat dose oral gavage studies. In all cases the increases reported were very small, being no more than 1.5 times controls. In studies in the rat with both MCPA acid and a commercial formulation of MCPA as the iso-octyl ester no increases in SCE frequency have been observed following repeated oral gavage administration. It appears, therefore, that the increases in SCE frequency are limited to the hamster and that only SCE changes are observed, since there were no increases in aberrant cells in this species, as measured by conventional chromosomal metaphase analysis. It is interesting that when administered to developing chick embryos MCPA was reported to increase SCE frequency to a similar extent (1.3 times control) at a dose level on the limit of toxicity. The range of mechanisms by which SCEs may be induced and their relevance as a predictor of any expression of carcinogenicity or mutagenicity in vivo is not known. The SCE end-point is known to be very sensitive to statistical analysis, as demonstrated in this instance by the observation that an increase of just 1.16 times the control value (3.42 to 3.98 SCEs/cell) can be statistically significant (Gelbke and Engelhardt, 1985c) (Table X). There is a clear emphasis in current regulatory guidelines for the interpretation of data from genotoxicity assays (OECD Guideline 474, 1997) that statistical significance should not be the only determining factor for a positive response and that biological relevance of the results should be considered first. The biological relevance of such small increases in SCE frequency (e.g. 1.3 times control), although statistically significant, is considered to be at best limited. The determination of the ability of a material to induce SCEs is not currently in any core regulatory or scientific, guidelines for the evaluation of genotoxic activity and there was no revision of the OECD guideline for SCE determination at the last round of OECD Guideline updates in 1997. In cases where increases are identified, an evaluation of the magnitude of effect and support from other relevant end-points may assist in the interpretation of their relevance. It appears that MCPA, at MTD or cytotoxic concentrations, may cause an increase in SCE frequency, but only in the hamster. However, the small extent of the increases, the absence of clastogenic activity in the hamster and lack of SCE activity in other species (mouse and rat) indicate that these minimal changes do not indicate a significant genotoxic or mutagenic hazard. This is supported by the lack of carcinogenic response in lifetime feeding studies in both rats and mice (Bellet et al., 1999).
An evaluation in the rat using radiolabelled MCPA showed no detectable binding in the liver to DNA or RNA at sampling times up to 4.5 h after dosing, although significant association of radiolabel with the protein fraction was identified. It is interesting to note that MCPA has been reported to bind reversibly to plasma albumin (Arnold and Beasley, 1989) and these findings may be of interest in the context of the observed chromosomal effects at high concentrations.
In summary, MCPA has been shown to be clastogenic in vitro at high and cytotoxic concentrations, although MCPA is not structurally alerting for likely genotoxic activity and the data from gene mutation assays show no evidence of mutagenicity. Furthermore, as MCPA has shown no evidence for the induction of chromosomal aberrations in vivo, other factors, including physicochemical perturbations in the test medium and chromosomal damage as a secondary consequence of cytotoxicity, may be responsible for the activity observed in vitro.
In conclusion, evaluating all of the relevant available data with the considerations displayed above, the weight of evidence from the available data is that MCPA is not mutagenic or genotoxic in vivo.
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Acknowledgments |
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This review was undertaken on behalf of the MCPA Task Force III, who provided copies of the unpublished reports for review.
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* Tel: 01625 515 426; Fax: 01625 510 762; Email: barry.elliott{at}syngenta.com
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References |
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Received on August 9, 2004; revised on November 30, 2004; accepted on December 6, 2004.
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