Toxicology – Active Substances
Pesticide (chemical) active substances are evaluated by HSE in accordance with the requirements of Regulation (EC) 1107/2009. Where appropriate, HSE refers to and uses relevant international guidance documents.
Specific guidance relating to individual active substances may be delivered directly to applicants via pre-submission meetings, which may be organised as part of the application process.
The following subsections are included on this page:
- Data Requirements
- Endocrine Disruption
- Technical Equivalence
For the approval of pesticide (chemical) active substances, the toxicology data requirements are described in Section 5 of Regulation (EC) 283/2013.
Where it is necessary to perform toxicological studies, they should be conducted according to the appropriate and current OECD test guideline and in accordance with GLP. The current OECD test guidelines can be accessed on the OECD website.
In addition, in accordance with Regulation (EC) 1107/2009, a summary of all relevant data from the scientific peer-reviewed open literature on the active substance, metabolites and breakdown or reaction products and plant protection products containing the active substance shall be submitted. A guidance document on the submission of peer-reviewed open literature is available on the EFSA website.
Testing on Vertebrate Animals
Regulation (EC) 1107/2009 applied from 14 June 2011 and lays down a number of requirements aimed at 1) avoiding unnecessary testing on vertebrate animals, where alternative methods are available; 2) avoiding duplicate testing; and 3) prescribing sharing of tests and studies involving vertebrate animals.
Article 62 of Regulation (EC) 1107/2009 states that:
'testing on vertebrate animals for the purposes of this Regulation shall be undertaken only where no other methods are available'.
In practice the Regulation prescribes that no new studies shall be conducted in vertebrate animals where validated alternative methods are available. HSE interprets validated alternative methods as in vitro methods which allow the prediction of in vivo apical endpoints and for which OECD Test Guidelines have been adopted. When new OECD Test Guidelines for alternative in vitro methods fully or partially replacing an in vivo test are adopted, any new studies should be conducted using these alternative methods. This is particularly relevant to the assessment of skin and eye irritation / corrosion (see following sections).
In accordance with the Regulation, dossiers submitted for the approval of active substances and authorisation of plant protection products should include 'for each test or study involving vertebrate animals, a justification of the steps taken to avoid animal testing and duplication of tests and studies on vertebrate animals' (Article 8(1)(d) and Article 33(3)(c) respectively).
In vivo tests conducted either before the implementation date of Regulation (EC) 1107/2009 or before alternative OECD Test Guidelines were adopted may be submitted, subject to the requirements of Article 62 regarding data sharing and duplicate testing.
More detailed information on submitting vertebrate studies is given in the HSE CRD Pesticides Applicant Guide.
In vitro alternatives to the assessment of skin and eye irritation / corrosion
Skin irritation / corrosion studies
To fulfil the data requirement for skin irritation / corrosion, testing should be conducted as described by Regulation (EC) 283/2013 . Section 5.2.4 of Regulation (EC) 283/2013 requires the application of a tiered testing strategy; this should be implemented in accordance with the recommendations of the OECD Guidance on an integrated approach on testing and assessment (IATA) for skin corrosion and irritation. The IATA is available on the OECD website.
A validated in vitro test for skin irritation (OECD Test Guideline 439) has been available since 2010. A number of validated in vitro tests for skin corrosion have been available since 2004. These tests should be used alongside all other available information (including information from dermal toxicity studies, physical / chemical properties, non- testing methods) in a weight of evidence approach, ahead of any in vivo testing. In vivo testing for skin irritation / corrosion (for example, OECD Test Guideline 404) should only be performed as a last resort and where no other options remain. Should testing in vivo be deemed necessary, a full justification must be provided that explains the need to perform the test, with reference to the IATA.
Eye irritation / damage studies
To fulfil the data requirement for eye irritation / damage, testing should be conducted in accordance with Regulation (EC) 283/2013 . Section 5.2.5 of Regulation (EC) 283/2013 requires the application of a tiered testing strategy; this should be implemented in accordance with the recommendations of the OECD Guidance on an integrated approach on testing and assessment (IATA) for serious eye damage and eye irritation. The IATA for serious eye damage is available on the OECD website .
Validated in vitro / ex vivo eye irritation / damage tests (for example, OECD Test Guidelines 437 and 438) have been available since 2009. The available in vitro tests are able to identify substances classified for serious eye damage (category 1) and those not classified for serious eye damage / eye irritation, in accordance with Regulation (EC) 1272/2008 . These tests should be used alongside all other available information (including information from physical / chemical properties, non- testing methods) in a weight of evidence approach, ahead of any in vivo testing.
In vivo testing for the potential to cause serious eye damage / eye irritation (for example, OECD Test Guideline 405) should only be conducted as a last resort, where it is not possible to conclude on serious eye damage / eye irritation hazard categorisation and in accordance with the IATA. Should testing in vivo be deemed necessary, a full justification must be provided that explains the need to perform the test, with reference to the IATA.
(Quantitative) Structure-Activity Relationship ((Q)SAR) analyses may be required as part of the toxicological assessment of chemical active substances, in particular their metabolites and/or impurities under Regulation (EC) 1107/2009.
There is no specific guidance on submission of (Q)SAR analysis for pesticide (chemical) active substances, but generally accepted principles should be followed. Some critical elements that should be included in the submitted (Q)SAR report include:
- Details of the identity of the (Q)SAR software application(s), the version and any alterations which have been made to the default settings
- A detailed summary of all alerts identified for both the chemical structure which is to be assessed, and any molecular structure to which a comparison is to be made
- Fully reasoned comments supporting all alerts and a list of references
- The original report generated by the software application for each (Q)SAR analysis
- SD files (*.sdf or *.sd) containing all the chemical structure data, or a MOL file (*.mol), individual to each chemical molecular structure
General guidance on how to perform and report (Q)SAR is available for the purposes of REACH and can be found on the ECHA website. Guidance on use of (Q)SAR for regulatory purposes from the OECD can be found on the OECD website. The general principles described in these documents are applicable to applications for approval of pesticide (chemical) active substances.
Regulation (EC) 1107/2009 requires specific consideration of the potential for pesticide (chemical) active substances to cause endocrine disruption.
The relevant scientific criteria for determination of endocrine disrupting properties was agreed in 2018. The assessment of endocrine disrupting properties must be performed in accordance with the criteria and the Guidance for the identification of endocrine disruptors in the context of Regulations (EC) No 528/2012 and (EC) No 1107/2009. The assessment of endocrine disruption must be presented according to Appendix I of the Administrative guidance on peer-review of pesticide active substancesand must include the Excel spreadsheet (Appendix E1 of the guidance).
The toxicological equivalence of pesticide technical materials (pure active substance plus impurities) from sources other than the approved source (for example, from different manufacturers) must be assessed.
Technical material from different sources may contain different impurities or different levels of impurities. The assessment is performed to establish whether a different technical material is comparable to the reference or approved source, with respect to its toxicological hazard.
HSE performs the assessment of the equivalence of pesticide technical materials in accordance with the guidance document on the assessment of the equivalence of technical materials of substances regulated under Regulation (EC) 1107/2009 – SANCO/10597/2003.