Abstract
This article presents the outcomes of higher-tier repeated-dose toxicity studies and developmental and reproductive toxicity (DART) studies using Wistar rats requested for methyl paraben and propyl paraben under the European Union chemicals legislation. All studies revealed no-observed adverse effects (NOAELs) at 1000 mg/kg body weight/day. These findings (absence of effects) were then used to interpolate the hazard profile for ethyl paraben, further considering available data for butyl paraben. The underlying read-across hypothesis (all shorter-chained linear n-alkyl parabens are a ‘category’ based on very high structural similarity and are transformed to a common compound) was confirmed by similarity calculations and comparative in vivo toxicokinetics screening studies for methyl paraben, ethyl paraben, propyl paraben and butyl paraben. All four parabens were rapidly taken up systemically following oral gavage administration to rats, metabolised to p-hydroxybenzoic acid, and rapidly eliminated (parabens within one hour; p-hydroxybenzoic acid within 4–8 h). Accordingly, for ethyl paraben, the NOAELs for repeated-dose toxicity and DART were interpolated to be 1000 mg/kg body weight/day. Finally, all evidence was evaluated to address concerns expressed in the literature that parabens might be endocrine disruptors. This evaluation showed that the higher-tier studies do not provide any indication for any endocrine disrupting property. This is the first time that a comprehensive dataset from higher-tier in vivo studies following internationally agreed test protocols has become available for shorter-chained linear n-alkyl parabens. Consistently, the dataset shows that these parabens are devoid of repeated-dose toxicity and do not possess any DART or endocrine disrupting properties.
Highlights
IntroductionRegistration, Evaluation, Authorisation and Restriction of Chemicals (REACH; EP and Council 2006)
Any deliberations to conduct higher-tier studies for longer-chained linear n-alkyl parabens—for the sole purpose to substantiate read-across for ethyl paraben - would contradict the 3Rs principle implemented in Directive 2010/63/European Union (EU) (EP and Council 2010) or the provisions of Article 25(1) of the REACH Regulation (EP and Council 2006) that requires that testing on vertebrate animals shall be undertaken only as a last resort
As discussed by Barlow et al (2015), it is an essential aspect of the EU REACH Regulation to use the collated data for hazard-based substance classification and labelling following the provisions of Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging of substances and mixtures (EP and Council 2008)
Summary
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH; EP and Council 2006). The REACH registration procedure includes preparation of a dossier presenting all relevant data to identify the substance and to assess any potential risks related to it. As per REACH Annexes VII–X, the extent of information to be included in the dossiers depends on the annual tonnage at which the given substance is manufactured or imported (EP and Council 2006). This set of Annexes contains increasingly comprehensive standard information requirements, and specific rules for their adaptation. The applicable REACH Annexes differ between the parabens since methyl paraben is manufactured or imported at > 1000 tonnes per year (tpy), ethyl paraben and propyl paraben each at > 100 tpy, and butyl paraben at 1–10 tpy (Table 1)
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