Toxicology – Active Substances
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HSE's Chemicals Regulation Division (CRD) refers to the appropriate European guidance documents for most parts of the toxicological assessment of pesticide active substances.
Links to the European guidance documents can be found on the Toxicology useful links page.
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. Link to Applicant Guide Active Substances guidance document: EU Decision Making Process for Active Substances.
The following subsections are included on this page:
For the approval of pesticide active substances, toxicology data requirements are laid down in the following regulation:
Commission Regulation (EU) No 283/2013, which can be accessed via The EU Commission Website.
Where it is necessary to perform toxicological studies, they should be conducted according to the appropriate and current OECD test guideline or EU test method and in accordance with GLP.
OECD test guidelines can be found on the OECD Website.
EU test methods can be found on the ECHA Website.
In addition to any toxicological studies, and 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 via the EFSA Publications Website.
Testing on Vertebrate Animals
Regulation (EC) No 1107/2009 applied from 14 June 2011 and lays down a number of requirements aimed at avoiding unnecessary testing on vertebrate animals, including the avoidance of duplicate testing, and for sharing of tests and studies involving vertebrate animals.
In addition, The Regulation states in Article 62 (1) that:
'testing on vertebrate animals for the purposes of this Regulation shall be undertaken only where no other methods are available'.
The Regulation states that 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).
When new OECD Test Guidelines become available that can replace in vivo tests, any new studies submitted for the purposes of plant protection regulation should be conducted using these alternatives. In vivo tests conducted before alternative Test Guidelines were adopted by the OECD may be submitted, subject to the requirements of Article 62 regarding data sharing, but no new vertebrate studies should be conducted for the purposes of fulfilling the requirements of the Regulation when there are alternative methods available.
More detailed information on submitting vertebrate studies is given in the pesticides Applicant Guide: Vertebrate Testing Requirements.
Skin irritation/corrosion studies
Guidance on an integrated approach on testing and assessment (IATA) for skin corrosion and irritation is available in OECD GD No. 203 (2014).
A validated in vitro test to determine skin irritation (OECD guideline 439) has been available since July 2010. A number of validated In vitro tests to determine skin corrosion have been available since 2004. These tests are able to determine the classification of test substances to meet the requirements of Regulation (EC) No. 1272/2008 for skin irritation and corrosion. Therefore in vivo skin irritation/corrosion studies in the rabbit (OECD Test Guideline 404) should no longer be conducted.
Eye irritation/corrosion studies
Validated in vitro/ex vivo eye irritation/corrosion OECD Test Guidelines (OECD 437 and 438) have been available since September 2009 for the detection of Category 1 eye irritants, and were revised in July 2013 to take account of new data showing they could identify non-irritants too. In addition, any test substance that is classified as corrosive to the skin is automatically classified as a severe eye irritant, and does not require further testing for eye irritation/corrosion. Therefore in vivo eye irritation/corrosion studies in the rabbit (OECD Test Guideline 405) should only be conducted as part of an integrated testing strategy. In all cases validated in vitro and ex vivo tests for eye irritation/corrosion should be conducted first, and may provide a definite classification for eye irritation/corrosion without the need for an in vivo test.
Details of any in vitro or ex vivo tests performed prior to an in vivo test should be provided either within the in vivo study report or as supporting documentation.
As an alternative to experimental testing, classification of mixtures of chemicals such as plant protection products (PPPs) can be performed using the calculation method. See the Classification by Calculation section for more information.
(Quantitative) Structure-Activity Relationship ((Q)SAR) analyses may be submitted for the purposes of assessment of equivalence of technical materials of substances regulated under Regulation (EC) 1107/2009, and sometimes for other purposes.
HSE's Chemicals Regulation Division (CRD) requests that (Q)SAR reports submitted for evaluation include the following information:
- The identity of the (Q)SAR software application, the software version used, 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. In the case of technical equivalence assessment, this refers to the new/increased impurities, and the active ingredient.
- 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
Regulation (EC) No 1107/2009 calls for specific scientific criteria for the determination of endocrine disrupting properties. The finalised criteria were expected from the Commission in December of 2013, but this was not realised.
It is anticipated that a scientific criteria for determination of endocrine disrupting properties of substances will be agreed in 2016/17. Until such a point where these criteria are finalised and adopted, the Regulation enacts the so-called 'interim criteria'. The interim criteria laid down in Point 3.6.5 of Annex II of the Regulation states that:
Pending the adoption of these criteria, substances that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as carcinogenic category 2 and toxic for reproduction category 2, shall be considered to have endocrine disrupting properties.
In addition, substances such as those that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as toxic for reproduction category 2 and which have toxic effects on the endocrine organs, may be considered to have endocrine disrupting properties.
Assessment of the equivalence of pesticide technical materials (pure active substance plus impurities) from sources other than the EU approved source, eg from different manufacturers, is a requirement under EU legislation. Technical material from different sources may contain different impurities or different levels of impurities. It is important to establish that, for the same active substance, technical materials from different sources pose a comparable degree of hazard for human health and for the environment.
HSE's Chemicals Regulation Division (CRD) 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, which can be accessed via the EC Pesticides guidance website.
- Applicant Guide Active Substances process guidance document: EU Decision Making Process for Active Substances