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The in vitro genetic toxicity of sodium methylparaben was investigated in a bacterial reverse mutation assay (Ames test) according to OECD 471 and GLP (Donath, 2012). The test was conducted with S. typhimurium strains TA 1535, TA 1537, TA 98, TA100 and TA 102 at concentrations up to 5000 µg/plate with and without metabolic activation. No reversion was noticed in any of the strains tested. Cytotoxic effects were observed in both experiments. In the first experiment, cytotoxicity was observed in the highest dose group in tester strains TA 100, TA 1535 and TA 1537 without metabolic activation and in TA 102 with and without metabolic activation. In the second experiment, cytotoxicity was noted in all strains treated with and without metabolic activation at concentrations of 1000 µg/plate and higher. Precipitation of the test substance was not observed.

 

The induction of gene mutations by sodium methylparaben was assessed in a HPRT test according to OECD 476 and GLP (Wallner, 2012). The test was conducted in V79 cells with metabolic activation at concentrations up to 700 µg/mL and without metabolic activation at concentrations up to 1100 µg/mL. No genotoxicity was observed up to the highest dose tested. Cytotoxic effects were observed in both experiments conducted at concentrations of 200 µg/mL and higher without metabolic activation and at concentrations of 150 µg/mL and higher with metabolic activation. The used positive controls were valid.  

There are no data available on in vivo genetic toxicity for sodium methylparaben. However, there are reliable data on methylparaben which is considered suitable for read-across using the analogue approach.

Sodium methylparaben (sodium 4-(methoxycarbonyl)phenolate) is the sodium salt of methylparaben (methyl 4-hydroxybenzoate). The substance is highly water soluble (418 g/L), dissociates in aqueous solutions and is hydrolysed to sodium hydroxide and the source substance methylparaben. Based on the assumption that upon oral and dermal administration, sodium methylparaben dissociates and is hydrolysed to methylparaben and sodium hydroxide, it was predicted that after exposure the primary effect is local irritation/corrosion at the site of contact due to sodium hydroxide.

Target and source substance are of low acute toxicity. No systemic or local effects were found up to single doses of 5000 mg/kg bw for sodium methylparaben and 2100 mg/kg bw for methylparaben. A dermal absorption of 80% was calculated for sodium methylparaben using QSAR and the available physico-chemical properties. For methylparaben, the dermal absorption was estimated in an in vitro test to be 84.7% in human skin (Fasano, 2004).

Therefore, it can reasonably be deduced that no higher amounts than tested in the acute oral toxicity study will be systemically available via the intact skin barrier. Inhalation is of no concern for the target as well as the source substance because of the low vapour pressure.

The results of several repeated dose toxicity studies indicate a low toxicological concern for methylparaben. Methylparaben caused no systemic toxicity and no effects on fertility or developmental toxicity. Moreover, toxicokinetic data have shown that methylparaben is completely absorbed after oral and dermal administration, hydrolysed, conjugated and rapidly excreted in urine. Thus, there is no evidence of accumulation.

As bioavailability and metabolism and therefore mammalian toxicity of sodium methylparaben were considered to be comparable to that of methylparaben, the assessment of in vivo genetic toxicity based on analogue approach can be considered as justified. 

The read across substance Methylparaben was tested in a dominant-lethal test in rats according to OECD 478 (Litton Bionetics Inc, 1974). Methylparaben was applied to male rats in doses up to 5000 mg/kg bw/d by oral gavage in a single treatment and daily on 5 consecutive days. During the post exposure period (8 week for the single treatment group and 7 weeks for the subacute group), the male rats were sequentially mated to 2 females per week. Two weeks after mating, the females were sacrificed and at necropsy the uteri were examined for corpora lutea, early deaths, late fetal deaths and number of total implantations.

No dose response relationship or time trend pattern was observed across the groups. Therefore, methylparaben was considered to be non-mutagenic in rats in the Dominant-Lethal assay applying dosages up to 5000 mg/kg bw/d.

 

In an in vivo Mammalian Bone Marrow Chromosome Aberration test performed in male rats according to OECD 475, Methylparaben did not induce chromosome aberrations up to 500 mg/kg bw/d.


Justification for selection of genetic toxicity endpoint
No single study was selected, since all available in vitro and in vivo genetic toxicity studies were negative.

Short description of key information:
Bacterial reverse mutation assay, Ames test (OECD 471): negative
Mammalian Cell Gene Mutation Test, HPRT test (OECD 476): negative
Rodent Dominant Lethal Test (OECD 478): negative

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available data on genetic toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.