Toxicology - Plant Protection Products
Plant protection products (PPPs) are evaluated by HSE in accordance with the requirements of Regulation (EC) 1107/2009. Where appropriate, in this assessment, HSE uses relevant international guidance documents.
Specific guidance relating to individual product applications may be delivered directly to the applicant in pre-submission meetings, organised as part of the application process; further information is available on the CRD Applicant Guide.
The following subsections are included on this page:
- Amateur Products
- Combined Toxicity
- Data Requirements
- Testing on Vertebrate Animals
- Dermal Absorption
- Safety Data Sheets (SDS)
- Groundwater metabolites
Considerations regarding classification of amateur products
All PPPs, including those intended for amateur use, must be classified in accordance with Regulation (EC) 1272/2008 (GB/NI CLP).
Authorisation will not normally be granted for amateur products that are classified for human health effects in:
- Category 1, 2 or 3 for acute toxicity
- Category 1 (1A or 1B) for carcinogenicity, mutagenicity, reproductive toxicity or Specific Target Organ Toxicity (STOT SE/RE)
- Category 1 (1A, 1B or 1C) for skin corrosion
- Category 1 for eye damage
- Category 1, 1A or 1B for skin sensitisation
Considerations regarding PPE for amateur products
Authorisation will not normally be granted for amateur products where the risk assessment determines that the use of personal protective equipment (PPE) is required for safe use. Amateur products may be authorised where there are standard recommendations for PPE in accordance with Regulation (EC) 1272/2008, but PPE was not a requirement for an acceptable risk assessment.
Combined Toxicity for products with multiple active substances
Where two or more active substances (including safeners, agonists and synergists) are present in a formulated product, consideration should be given to the potential for combined toxicity. Combined toxicity should be considered for all areas of the risk assessment, including dietary and non-dietary elements.
CRD has produced a Combined Toxicity Guidance Document, which provides further information.
The Scientific Report of EFSA – 'International Frameworks Dealing with Human Risk Assessment of Combined Exposure to Multiple Chemicals' (2013) provides further information.
In accordance with Article 62 of Regulation (EC) No.1107/2009, testing in vertebrate animals should only be conducted where there are no reliable alternative methods (for example, the calculation method of GB/NI CLP). Further information is available in the following section on Testing on Vertebrate Animals. In addition, HSE has recently developed detailed guidance on how to apply the toxicology data requirements for the authorisation of plant protection products, in line with the provisions of Article 62 of Regulation (EC) No.1107/2009 on minimising animal testing when unnecessary.
All toxicological studies should be conducted according to the appropriate and current OECD test guidelines and in accordance with GLP (Good Laboratory Practice).
OECD test guidelines can be found on the OECD website .
Testing on Vertebrate Animals
Regulation (EC) 1107/2009 lays down a number of requirements aimed at:
- avoiding unnecessary testing on vertebrate animals, where alternative methods are available
- avoiding duplicate testing
- 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).
For the purposes of fulfilling the toxicological data requirements for Plant Protection Products (PPPs) (Section 7 of Regulation (EC) No), the calculation method of Regulation (EC) 1272/2008 (GB/NI CLP) may be also an acceptable alternative method. Application of the calculation method of GB/NI CLP should always be considered before conducting any testing in vertebrate animals.
In accordance with the Regulation, dossiers submitted for the approval of active substances and authorisation of PPPs 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 14 June 2011 or before alternative OECD Test Guidelines where 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 pesticides Applicant Guide: Vertebrate Testing Requirements.
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) 284/2013. Section 7.1.4 of Regulation (EC) 284/2013 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) The IATA for skin corrosion and irritation for skin corrosion and irritation 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 (eg 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 or damage, testing should be conducted in accordance with Regulation (EC) 284/2013. Section 7.1.5 of Regulation (EC) 284/2013 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 and eye irritation is available on the OECD website.
Validated in vitro/ex vivo eye damage or irritation tests (eg 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 or 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 or irritation (eg OECD Test Guideline 405) should only be conducted as a last resort, where it is not possible to conclude on serious eye damage or 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.
The determination of appropriate values for the dermal absorption of pesticide active substances from a formulated product is a critical part of the non-dietary risk assessment of PPPs.
Dermal absorption values should be determined in accordance with the current EFSA guidance on dermal absorption (2017).
HSE frequently requests further information from applicants, or make amendments to proposed dermal absorption values, when evaluating PPPs. Issues which commonly arise are:
- Incorrect interpretation of experimental data:
- Inappropriate exclusion of material found in tape strips
- Unjustified exclusion of outliers
- Failure to make necessary corrections for high experimental variability
- Inappropriate extrapolation to dermal absorption values which were derived for a different formulation, or absence of an acceptable reasoned case to justify any extrapolation.
HSE runs regular dermal absorption workshops which provide further information on this topic. More information can be found on HSE's Chemicals Regulation Division Events page on the Health and Safety Laboratory (HSL) website.
Some PPP formulations may include dyes or colouring agents. Owing to concerns over the potential for genotoxicity and/or carcinogenicity of certain classes of dyes, HSE requires that any dyes used in pesticide formulations do not present unacceptable risks.
Acceptable risk can be demonstrated in 2 ways:
- If the dye used is one that is already approved within GB/NI for use in cosmetics or foodstuffs, it is considered that the assessment performed for food or cosmetic uses will adequately cover pesticide uses. Applicants should provide the name, appropriate Colour Index (C.I.) number, or E number of the approved dye, and a description of the uses for which it is currently approved.
Dyes approved for use in cosmetic products can be found in Annex IV of Regulation (EC) 1223/2009.
Colours approved for use in foodstuffs can be found in Part B of Annex II of Regulation (EC) 1333/2008.
- If the dye is not already approved within GB/NI for use in cosmetics or foodstuffs, the applicant needs to address the potential toxicity of the dye. In particular a reasoned case or data will need to be provided to show an absence of genotoxicity. In most instances this will require negative genotoxicity data to be available on the dye or a closely related compound; in the majority of cases an Ames assay will be sufficient. No evidence of genotoxicity as a consequence of a particular dye not having been appropriately tested is unlikely to be sufficient without additional scientific argument.
Safety Data Sheets (SDS)
HSE requests that applicants who need to submit SDS for the various ingredients of a formulated PPP, present them according to the following:
- In English
- In compliance with the GB/NI format (ie according to Annex II and articles 31 & 32 of Regulation (EC) 1907/2006 REACH)
Resulting from the use of some PPPs, metabolites of the active substance may occur in soil. These have the potential to reach groundwater and pose a risk to the consumer through consumption of drinking water. For metabolites occurring in groundwater at levels ≥ 0.1 µg/L, a human health hazard and risk assessment should be carried out to determine their toxicological relevance/non-relevance.
This should be performed in line with the EU SANCO (2021) guidance, revision 11 as applicable in GB .
These revisions are minor and apply only to the toxicology area of the assessment. References to hazard classification have been updated to reflect the entry into force of the CLP Regulation in 2008.
Stage 2 of Step 3 on the screening for genotoxicity has been amended to require an in vitro micronucleus test (OECD 487) in lieu of an in vitro chromosome aberration study (OECD 473). This was amended to reflect scientific progress in the area of genotoxicity testing, noting that the in vitro micronucleus test, compared to the in vitro chromosome aberration assay, provides an assessment of aneugenicity over and above investigation of clastogenicity.
Whilst GB accepts the translation of the hazard classification system, GB does not agree with the changes introduced in the area of genotoxicity testing. GB deems that, in line with modern genotoxicity testing strategies (EFSA Journal 2011;9(9):2379) including the advice from the UK Committee on Mutagenicity (COM, 2021), an Ames test and an in vitro micronucleus test are sufficient to investigate adequately the genotoxic potential of chemicals and that the in vitro mammalian cell gene mutation assay provides no additional useful information. The updated EU guidance still retains the in vitro mammalian cell gene mutation assay, which is a test that, according to recent technical and scientific progress, provides no additional valuable information on the genotoxic potential of a chemical.
On this basis, GB proposes that the updated EU guidance is adopted in GB but with amendments to the genotoxicity testing requirements. At Stage 2 of Step 3 of the assessment (genotoxicity screening), HSE will require only an Ames test (OECD 471) and an in vitro micronucleus assay (OECD 487).
HSE, in consultation with its Expert Committee on Pesticides (ECP) has developed a paper describing the use of the TTC (Threshold of Toxicological Concern) CCIII (Cramer Class III) value at step 5 of the groundwater metabolite relevance assessment of PPPs under certain circumstances. At step 5, in accordance with the SANCO (2003) guidance, a repeated dose toxicity test in experimental animals may be required to establish a metabolite-specific acceptable daily intake (ADI) for the subsequent dietary risk assessment. The paper explains how, for groundwater metabolites which are not structurally or toxicologically similar to the parent active substance or for which a read-across from a data-rich analogue is not possible, the TTC CCIII value (1.5 µg/kg bw/day) could be used as the reference value for the risk assessment, in place of testing in vertebrate animals, so as to reduce unnecessary animal testing.