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Essential Oil-based Personal Insect Repellents - Report of an External Advisory Panel

For further information on the Essential Oil-based Personal Insect Repellent External Advisory Panel, please refer to the membership list and biographies.

6 December 2016

(PDF Version - 336 K)

Introduction

Pest control products are registered in Canada by Health Canada’s (HC) Pest Management Regulatory Agency (PMRA). One of the key requirements of registration is that there be reasonable certainty of no risk of harm to human health or the environment from the proposed use of the pest control product.

In October 2010, the PMRA published for consultation its revised Regulatory Proposal for the Registration of Non-Conventional Pest Control Products (Health Canada, 2010). The PMRA revised approach recognized that the registration framework that was developed for conventional well-defined pesticides might not be appropriate for non-conventional products. The PMRA also recognized that the varied nature of these non-conventional pest control products pose unique regulatory challenges in order to demonstrate important thresholds of safety and efficacy. In 2012, the PMRA issued its Regulatory Directive and Guidelines for the Registration of Non-Conventional Pest Control Products (Health Canada, 2012). This Directive outlines an approach for non-conventional products with reduced risk profiles that allows innovation and flexibility in assessing whether they pose unacceptable risks to human health or the environment and have value for their proposed uses.

In order to ensure that only pest control products with reduced toxicity are considered under this initiative, products considered under this Directive must have at least some of the following characteristics:

In January 2016, the PMRA convened an expert External Advisory Panel (EAP) to review its 2012 Guidelines for the Registration of Non-Conventional Pest Control Products in the context of data requirements for personal insect repellents containing plant-derived essential oils.

Although the Guidelines for the Registration of Non-conventional Pest Control Products DIR2012-01 are applicable to essential oil-based personal insect repellents (EOPIR), human exposure to these types of products is significantly different from other types of non-conventional pest control products (Health Canada, 2012). In general, they are applied directly to the skin and can often be applied repeatedly in a single day.

The Panel was asked to confirm that the tiered approach to data requirements in DIR2012-01 can be applied to EOPIRs. The Panel was also asked to provide input on potential data gaps either through modifications to the existing tiered approach or through an alternative approach suggested by the Panel. Specifically, the Panel was asked to provide the PMRA with guidance on the following:

The guidance requested by the PMRA was framed as a series of charge questions to be addressed by the panel which are listed below.

The report, which follows, is the product of the review and recommendations of the Panel.

1. HC-PMRA’s current, tiered approach for evaluating EOPIRs, in terms of toxicology data requirements, is outlined in DIR2012-01.

a) Does the Panel support HC-PMRA’s position of continuing to use this approach for evaluating the toxicity of EOPIRs?

The Panel agrees with the general principles of a tiered approach, as outlined in DIR2012-01; however, the Panel felt that several modifications to the tiered approach are warranted. As a general point, as approaches to toxicological and exposure assessment continue to evolve, the PMRA will need to regularly review its guidance and information requirements to ensure they are reflective of the latest scientific and 3R (animal replacement, reduction and refinement) best practices, both for EOPIRs and more broadly. The Panel is of the view that dermal absorption for a topically applied repellent is fundamental to an understanding of its potential hazard and risk, and so should be included as a Tier I requirement. The Panel also recommends that the substance to be tested for dermal absorption should be the mixture of active ingredients, in the proportions that would typically be included in the end-use product. The Panel does not consider the assessment of dermal absorption of individual components of the active ingredient to be an acceptable alternative to assessment of the mixture of actives. In this context, the Panel is aware that formulants included in the end-use product may influence dermal absorption. This said, the Panel notes that the guidelines for the assessment of EOPIRs specify that these chemicals will be expected to be of low inherent toxicity, thereby substantially reducing the potential toxicological significance of enhanced absorption attributable to the formulants, per se. The Panel, nevertheless, encourages the PMRA to carefully consider the potential importance of formulants when assessing the absorption of active ingredients in EOPIRs. While the Panel is not comfortable with specifying a cut-off for what percentage of dermal absorption represents high versus low, the Panel felt that the PMRA should carefully consider the Threshold of Toxicological Concern (TTC) approach (Munro et al., 2008) where a minimal threshold of exposure could be defined below which the potential for a toxicologically relevant response could be considered to be negligible. In this context, the Panel noted that the “acceptable” absorption would be dependent on the mixture/active ingredient in question. Notwithstanding, the Panel was of the view that it may be possible to establish minimum absorption levels below which toxicological hazards and risk would be considered negligible.

The Panel noted that EOPIRs naturally constitute a mixture rather than a single component – and that component proportions could be expected to vary from batch to batch. The Panel therefore expressed the view that all actives in the mixture, and not individual components, should be tested together, which is what PMRA currently requires for EOPIRs. The Panel noted that citronella registrants did not provide data on the whole oil mixture, except for some acute studies. The Panel defined the active ingredient as meaning the whole oil extracted from the plant and the end use product as the mixture of active ingredient(s) and added formulants (which could include emulsifiers, carriers, surfactants, etc.). The Panel noted that toxicological assessment of components may be misleading in that the most abundant component may not be the most toxic and, similarly, the least abundant may present the most important toxicological hazard and risk.

As discussed above, the Panel carefully reviewed the tier structure adopted by the PMRA and supports the continued application of a flexible, sequential testing approach, but with modifications from the current scheme.

Due to the intended direct application of EOPIRs to the skin to repel insects, and the potential for both dermal and systemic toxicity of EOPIR components, evaluation of dermal absorption is considered to be an essential part of Tier I. Consistent with the PMRA (2005) commitment “to reducing or replacing, wherever possible, the numbers of animals used for testing by incorporating in vitro (non-animal) test methods or other alternative approaches that have been scientifically validated and have received regulatory acceptance”, the Panel recommends that an appropriate in vitromethodology be specified for this endpoint, for example, Organisation for Economic Co-operation and Development (OECD) Test Guideline 428 (Health Canada 2005; OECD 2004). The panel recognizes that this recommendation does not preclude consideration by PMRA of phys-chem properties or read-across from similar substances/mixtures. The panel is of the view that non-animal testing should be given precedence over in vivo methods while also recognizing that in vivo methods may, as a last resort, occasionally be necessary. Likewise, a range of valid and internationally recognized in vitrotest methods are now available for the endpoints of eye irritation (OECD 2013; 2015a), skin irritation (OECD 2015b), skin sensitization (OECD 2015c; OECD 2015d), and mutagenicity, and preferential use of these methods should be specified.

In relation to dermal acute toxicity, the Panel recognizes the findings of several extensive retrospective reviews illustrating the redundancy of this data requirement (Creton et al., 2010; Seidle et al., 2011; Moore et al., 2013), and waiver criteria adopted by some regulators, for example, where the oral LD50 is greater than 2000 mg/kg (Official Journal of the European Union, 2013) and recommends a concordant approach under Tier I. The Panel further recommends that the separate Tier I endpoint requirements for short-term toxicity and a rodent prenatal developmental toxicity study requirement be replaced by a single combination 28-day repeated dose/reproduction/developmental toxicity screening study according to the recently revised OECD 422 (2015e) protocol for maximum efficiency as well as inclusion of reproductive parameters currently absent from Tier I. Nevertheless, it was noted that this test does not provide complete information on all aspects of reproduction and development. Specifically, it does not substitute for the prenatal developmental study (OECD 414) because fetuses are not examined prior to birth and the number of pregnant females is relatively low. It also may not provide complete information on male reproductive toxicity since males are exposed for four weeks and histological examination of the testis may not reveal any effects on the quality of pre-meiotic germ cells (for example, germ stem cells, spermatogonia, early spermatocytes).

The Panel understands that endpoints listed under Tier II may be conditionally required based on Tier I findings. This could include one or more of the following: 90-day repeated dose toxicity, in vivomutagenicity (where possible in combination with a general toxicity study; United States Environmental Protection Agency (US EPA) 2015a), or more comprehensive assessment of reproductive or developmental toxicity. With regard to immunotoxicity, the Panel is mindful of the findings arising from a US EPA (2013) retrospective analysis and echoes the recommendation that an assessment of this endpoint be carried out, in the first instance, in combination with a general toxicity (for example, 90 day) study rather than as a separate, additional in vivostudy requirement.

The Panel noted that positive outcomes in Tier II would send the product to a conventional evaluation, thereby eliminating Tier III for evaluating non-conventionals. The Panel concluded that only Tiers I & II are necessary, as Tier III could never be invoked.

b) If yes, specifically for citronella, could a lower tier study (for example, Tier I: Prenatal developmental toxicity in rats) be used to satisfy the data gaps?

The Panel is of the view that a lower tier study (for example, Tier I: prenatal developmental toxicity) should not be used to address the data gaps for citronella. The Panel also notes that this discussion is not limited to citronella. The Panel noted that the current Tier I does not address reproductive fertility concerns and that a “history of safe use” is not a toxicologically reliable endpoint. The Panel considered adoption of OECD study guideline 422 in Tier I to screen for reproduction and fertility effects, as discussed above. The Panel also noted that if reproduction and /or fertility effects were noted in a Tier I screen, then comprehensive reproduction and fertility testing, for example, extended one-generation study (OECD 2012) and/or a prenatal developmental toxicity study would need to be carried at Tier II, thereby eliminating the relevance of Tier III.

c) Could integrated and validated, alternative approaches to toxicity testing be used to satisfy certain gaps in data requirements for EOPIRs?

Yes; validated and internationally recognized OECD in vitro/in chemicoguideline tests are available and ripe for use in a number of Tier I endpoint areas as discussed above. International guidance regarding application of waiver criteria for acute endpoints is also under development through the OECD, applicable both for active ingredients and formulated end-use products (OECD 2015f). Additionally, the Panel notes that the Globally Harmonized System (GHS) for Classification and Labelling of Chemicals (GHS; United Nations 2015) provides a calculation approach (additivity formula) for the classification of end-use products for acute oral, dermal and inhalation toxicity based on the toxicity of their ingredients, and that pesticide regulators in other jurisdictions have accepted such acute toxicity estimates in lieu of in vivotest data for end-use products (Official Journal of the European Union, 2013).

d) For EOPIRs (including citronella) with identified toxicology data gaps, should HC-PMRA consider the adoption of risk mitigation statements such as a contraindication to not allow the use of the product in the subpopulation of concern until such time that the data gaps are addressed? For example, “Do NOT use if you are pregnant or planning to become pregnant”.

The primary characteristic of any EOPIR is that it must be of “low inherent toxicity to human and non-target organisms (for example, fish, birds, wildlife) with minimal environmental and health risks even if exposure is extensive.” This “low inherent toxicity to human” requirement implies there is sufficient knowledge of the toxicity to make this determination. Risk management would then be directed at low risk health concerns for those products with these essential oils, e.g. sensitivity.

Adoption of risk mitigation statements like those used in some over the counter drugs, to address potential risks in a specific subpopulation, such as  ‘do not administer to pregnant women’, is NOT, in the Panel’s opinion, an effective strategy to mitigate risk. The Panel is concerned that without proper medical and supervisory intervention, as in prescription drugs, at risk groups may be unable to adequately recognize or adopt precautionary measures (for example, a woman may not know she is pregnant when applying a EOPIR which is contraindicated in pregnancy). Moreover, the Panel is of the view that precautionary statements are not adequate to resolve the need for data where important data gaps are present. Furthermore, the Panel is of the view that extended to its illogical end, it could be argued that precautionary label statements could entirely eliminate the need for hazard and risk assessment of several toxicological endpoints. This said the Panel does, in selected circumstances, support the use of additional uncertainty factors to address non-pivotal limitations in study design or outcome.

e) If the Panel does not support the tiered approach for evaluating the toxicology of EOPIRs, what does the panel recommend?

As noted above, the Panel does, in general, support the use of a tiered approach for the safety evaluation of EOPIR. However, the Panel does not support the existing tiered approach recommended by the PMRA and has offered several suggestions above, which, if incorporated, would make the PMRA tiered approach more robust in terms of addressing potential data gaps with respect to dermal absorption, reproductive toxicity, and the use of alternative methods.

2. HC-PMRA’s current, tiered approach for EOPIRs, in terms of exposure data requirements, is also outlined in DIR2012-01.

a) Does the Panel support HC-PMRA’s position of continuing to use this approach for evaluating the exposure of EOPIRs?

As noted above (see 1a), the Panel does support, in general, a tiered approach for EOPIRs. However, in terms of exposure; the Panel does not support the specific tiered approach recommended by the PMRA. Given the unique nature of EOPIRs and their direct application to humans for extended periods, the Panel recommends that dermal absorption (in vitro) be included as a Tier I data requirement which, except under exceptional circumstances, cannot be waived. In the same vein, the Panel also recommends, as discussed above, that in the context of the TTC approach, thoughtful consideration be given to minimum thresholds of exposure below which toxicological concerns would be deemed to be negligible.

b) If not, should other data/information regarding exposure be required for a full assessment (e.g. dermal absorption data)?

Please see (1a) above.

c) If the Panel recommends that further exposure data/information should be requested, does it also recommend conducting quantitative risk assessments for EOPIRs?

The Panel recognizes that the PMRA does not routinely carry out quantitative risk assessment for non-conventional products. The Panel is also aware that the Margin of Exposure approach (MOE) is not a substitute for a quantitative risk assessment. This said, the Panel is of the view that deriving a MOE might be helpful in characterizing hazard – but only in those cases where there is a toxicological endpoint of concern, and only if no observed adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) have been identified from the available data. This approach would then provide a basis for the PMRA to express a safe level of exposure based on outcomes of laboratory toxicology studies.

d) Does the Panel have any other recommendations on the exposure evaluation of EOPIRs?

Please see (2a) and (2c) above.

References

Appendix I - EOPIR EAP Meeting Charge Questions, EAP Responses

As part of the 6 January 2016 EAP meeting, the panel was asked to provide responses and recommendations to a series of charge questions concerning the existing tiered toxicology and exposure information requirements for EOPIRs. Outlined below are the charge questions put to the EAP, a summary of the EAP’s recommendations with respect to each question, and PMRA’s response to the recommendations.

Question 1. HC-PMRA’s current, tiered approach for evaluating EOPIRs, in terms of toxicology data requirements, is outlined in DIR2012-01.

a) Does the Panel support HC-PMRA’s position of continuing to use this approach for evaluating the toxicity of EOPIRs?

Summarized EAP Response and Recommendations:

“The Panel agrees with the general principles of a tiered approach, as outlined in DIR2012-01; however, the Panel felt that several modifications to the tiered approach are warranted.”

“As a general point, as approaches to toxicological and exposure assessment continue to evolve, the PMRA will need to regularly review its guidance and information requirements to ensure they are reflective of the latest scientific and 3R (animal replacement, reduction and refinement) best practices, both for EOPIRs and more broadly.”

“The Panel is of the view that dermal absorption for a topically applied repellent is fundamental to an understanding of its potential hazard and risk, and so should be included as a Tier I requirement.”

“The Panel also recommends that the substance to be tested for dermal absorption should be the mixture of active ingredients, in the proportions that would typically be included in the end-use product. The Panel does not consider the assessment of dermal absorption of individual components of the active ingredient to be an acceptable alternative to assessment of the mixture of actives.”

“The Panel, nevertheless, encourages the PMRA to carefully consider the potential importance of formulants when assessing the absorption of active ingredients in EOPIRs.”

“Consistent with the PMRA (2005) commitment “to reducing or replacing, wherever possible, the numbers of animals used for testing by incorporating in vitro (non-animal) test methods or other alternative approaches that have been scientifically validated and have received regulatory acceptance”, the Panel recommends that an appropriate in vitro methodology be specified for this endpoint, for example, OECD Test Guideline 428 (Health Canada 2005; OECD 2004). The panel recognizes that this recommendation does not preclude consideration by PMRA of phys-chem properties or read-across from similar substances/mixtures. The panel is of the view that non-animal testing should be given precedence over in vivo methods while also recognizing that in vivo methods may, as a last resort, occasionally be necessary.”

“While the Panel is not comfortable with specifying a cut-off for what percentage of dermal absorption represents high versus low, the Panel felt that the PMRA should carefully consider the TTC approach (Munro et al., 2008) where a minimal threshold of exposure could be defined below which the potential for a toxicologically relevant response could be considered to be negligible.”

“The Panel noted that EOPIRs naturally constitute a mixture rather than a single component – and that component proportions could be expected to vary from batch to batch. The Panel therefore expressed the view that all actives in the mixture, and not individual components, should be tested together, which is what PMRA currently requires for EOPIRs.”

“… a range of valid and internationally recognized in vitro test methods are now available for the endpoints of eye irritation (OECD 2013; 2015a), skin irritation (OECD 2015b), skin sensitization (OECD 2015c; OECD 2015d), and mutagenicity, and preferential use of these methods should be specified.”

“In relation to dermal acute toxicity, the Panel recognizes the findings of several extensive retrospective reviews illustrating the redundancy of this data requirement (Creton et al., 2010; Seidle et al., 2011; Moore et al., 2013), and waiver criteria adopted by some regulators, for example, where the oral LD50 is greater than 2000 mg/kg (Official Journal of the European Union, 2013) and recommends a concordant approach under Tier I.”

“The Panel further recommends that the separate Tier I endpoint requirements for short-term toxicity and a rodent prenatal developmental toxicity study requirement be replaced by a single combination 28-day repeated dose/reproduction/developmental toxicity screening study according to the recently revised OECD 422 (2015e) protocol for maximum efficiency as well as inclusion of reproductive parameters currently absent from Tier I.”

“With regard to immunotoxicity, the Panel is mindful of the findings arising from a US EPA (2013) retrospective analysis and echoes the recommendation that an assessment of this endpoint be carried out, in the first instance, in combination with a general toxicity (for example, 90 day) study rather than as a separate, additional in vivo study requirement.”

“The Panel noted that positive outcomes in Tier II would send the product to a conventional evaluation, thereby eliminating Tier III for evaluating non-conventionals. The Panel concluded that only Tiers I & II are necessary, as Tier III could never be invoked.”

PMRA Response:

PMRA continues to participate in and contribute to a range of initiatives related to 21st Century Toxicology and integrated approaches to testing and assessment (IATA). Examples include contributing to a North American Free Trade Agreement (NAFTA) (quantitative) structure activity relationship guidance document, leading the development of an OECD extended one generation reproductive toxicity testing guideline, sponsoring a Council of Canadian Academies (CCA) report on integrating emerging technologies into chemical safety assessment, acting as a co-lead on the development of an OECD acute toxicity testing waiver guidance document, and participating in multi-stakeholder working group analyzing in vitro alternatives to in vivo acute toxicity testing. The goal of these initiatives and others is to lessen the reliance on complex regulatory animal tests through the use of robust, validated predictive models, in vitro tests, and other approaches.

PMRA agrees that information on dermal absorption should be a Tier I exposure information information requirement for EOPIRs. PMRA also agrees that the substance to be tested for dermal absorption should be the TGAI containing the whole, intact essential oil or mixture of oils in the same proportion as used in the end-use product (EP). As is the case for other pest control products, PMRA will assess the potential impacts of the formulants in an EP on the dermal absorption of any TGAIs containing essential oils. In terms of approaches to be used for determining the dermal absorption of an essential oil, PMRA recommends the use of a weight of evidence approach that could include consideration of data from in vitro studies of dermal absorption (i.e. in accordance with OECD TG 428), physical-chemical property information on the essential oil(s), read across information from similar substances, and if necessary data from in vivo studies of dermal absorption. PMRA does not recommend the use of the TTC approach for EOPIRs. The TTC approach was originally designed for use with structurally defined chemicals rather than complex mixtures such as EOPIRs. Also, the TTC approach requires a reliable quantitative estimate of exposure to the chemical in question which is not likely to be available for an EOPIR unless Tier II exposure information requirements are invoked.

Although the current Tier I toxicology information requirements for eye irritation, skin irritation, and skin sensitization for both general non-conventional pesticides and EOPIRS are based on in vivo studies, PMRA will consider scientific waiver rationales for these endpoints based on weight of evidence approaches that include the use of corresponding in vitro assays for which OECD test guidelines have been developed. For general non-conventional pest control products and EOPIRs, Tier I genotoxicity information requirements include a requirement for bacterial reverse mutation testing and an in vitro mammalian cell mutagenicity assay.

With respect to waiver criteria for acute dermal toxicity and other acute toxicity endpoints (i.e. oral and inhalation toxicity, eye and skin irritation, and skin sensitization), PMRA published a document in December 2013 entitled, Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides. This document and a similar one published by the US EPA formed the basis of the published OECD Guidance Document on Considerations for Waiving or Bridging of Mammalian Acute Toxicity Tests.Footnote 1

PMRA agrees with the panel’s recommendation to replace the requirements for separate short-term toxicity and developmental toxicity tests on EOPIRs with a combined repeated dose toxicity study with reproductive/developmental toxicity screening test to be conducted in accordance with OECD test guideline number 422 (US EPA OPPTS 870.3650). If this combined study provides evidence of repeated dose and/or reproductive/developmental toxicity then separate short-term (i.e. 90 day), reproductive and developmental toxicity studies of the EOPIR may be required (i.e. Tier II testing).

In those cases where Tier II immunotoxicity testing is identified as required, waiver rationales based on short-term toxicity testing (i.e. 90 day) that include the assessment of immunotoxicity endpoints would be considered for review by PMRA.

PMRA is in agreement with the panel’s recommendation to eliminate Tier III toxicology information requirements for EOPIRs. If toxicity is identified in Tier II tests and additional long-term or specialized studies are required, at that point the EOPIR would be moved into the conventional pest control product stream and would be subject to the information requirements associated with conventional pest control products.

b) If yes, specifically for citronella, could a lower tier study (for example, Tier 1: Prenatal developmental toxicity in rats) be used to satisfy the data gaps?

Summarized EAP Response and Recommendations:

“The Panel is of the view that a lower tier study (for example, Tier I: prenatal developmental toxicity) should not be used to address the data gaps for citronella. The Panel also notes that this discussion is not limited to citronella. The Panel noted that the current Tier I does not address reproductive fertility concerns and that a “history of safe use” is not a toxicologically reliable endpoint. The Panel considered adoption of OECD study guideline 422 in Tier I to screen for reproduction and fertility effects, as discussed above. The Panel also noted that if reproduction and /or fertility effects were noted in a Tier I screen, then comprehensive reproduction and fertility testing, for example, extended one-generation study (OECD 2012) and/or a prenatal developmental toxicity study would need to be carried at Tier II, thereby eliminating the relevance of Tier III.”

PMRA Response:

PMRA is in agreement with the panel’s recommendation. PMRA has already completed a re-evaluation of citronella oil and identified information requirements that correspond to higher tiered studies than those required at Tier I for non-conventional pest control products. PMRA’s re-evaluation of citronella oil including the identification of information requirements is presented in the Proposed Acceptability for Continuing Registration document, PACR2004-36 Re-evaluation of Citronella Oil and Related Active Compounds for Use as Personal Insect Repellents and the Re-evaluation Note, REV2008-03 Review of the 2004 Re-evaluation of Citronella Oil and Related Active Compounds for Use as Personal Insect Repellents. The information requirements for citronella oil include the following (i.e. taken from REV2008-03):

“As the toxicities of most concern are reproductive and developmental, data submitted to address the uncertainties in the current risk assessment must address these endpoints. Separate or combined reproduction and developmental studies may be conducted, by either the oral or the dermal route. Study options are presented below. The preferred option is to conduct a combined study via the dermal route of exposure because this will directly assess the endpoints of concern by the most relevant route and does not need to include a complex determination of dermal absorption.”

Option 1:
Two-generation rat reproduction study by oral route of exposure with whole citronella oil; and

Option 2:  
One-generation reproduction study with developmental toxicity endpoints by the dermal route of exposure with whole citronella oil. A study of dermal dosing tolerance may be necessary to ensure it is possible to conduct the main study without having to remove animals due to adverse skin irritation.

Prior to conducting any study, the registrant is required to discuss the study protocols with the PMRA. The conduct of these studies will require modification of traditional study design protocols.”Footnote 2

Based on input from the EOPIR EAP, it is recommended that the risk assessment conclusions and the health information requirements for citronella oil and related active compounds used as personal insect repellents identified in PACR2004-36 and REV2008-03, and outlined above should not be reconsidered at this time.

c) Could integrated and validated, alternative approaches to toxicity testing be used to satisfy certain gaps in data requirements for EOPIRs?

Summarized EAP Response and Recommendations:

“Yes; validated and internationally recognized OECD in vitro/in chemico guideline tests are available and ripe for use in a number of Tier I endpoint areas as discussed above. International guidance regarding application of waiver criteria for acute endpoints is also under development through the OECD, applicable both for active ingredients and formulated end-use products (OECD 2015f).”

“Additionally, the Panel notes that the GHS for Classification and Labelling of Chemicals (GHS; United Nations 2015) provides a calculation approach (additivity formula) for the classification of end-use products for acute oral, dermal and inhalation toxicity based on the toxicity of their ingredients, and that pesticide regulators in other jurisdictions have accepted such acute toxicity estimates in lieu of in vivo test data for end-use products (Official Journal of the European Union, 2013).”

PMRA Response:

See the response to question 1a) above.

As noted above, PMRA has contributed to the development of an OECD guidance document on waiving acute toxicity tests for pesticides. This document includes a discussion of the GHS additivity formula for the classification of end-use products for acute oral, dermal, and inhalation toxicity. PMRA will consider for review waiver rationales based on weight of evidence approaches that include information such as the results of internationally accepted, validated in vitro alternative assays and the GHS additivity approach.

d) For EOPIRs (including citronella) with identified toxicology data gaps, should HC-PMRA consider the adoption of risk mitigation statements such as a contraindication to not allow the use of the product in the subpopulation of concern until such time that the data gaps are addressed? For example, “Do NOT use if you are pregnant or planning to become pregnant”.

Summarized EAP Response and Recommendations:

“Adoption of risk mitigation statements like those used in some over the counter drugs, to address potential risks in a specific subpopulation, such as  ‘do not administer to pregnant women’, is NOT, in the Panel’s opinion, an effective strategy to mitigate risk.”

“Moreover, the Panel is of the view that precautionary statements are not adequate to resolve the need for data where important data gaps are present.”

“This said the Panel does, in selected circumstances, support the use of additional uncertainty factors to address non-pivotal limitations in study design or outcome.”

PMRA Response:

PMRA is in agreement with the panel’s recommendation against the use of label risk mitigation statements to allow the use of an end-use product in a subpopulation of concern until the identified data gaps for the end-use product are addressed.

PMRA’s approaches to the use of uncertainty factors in the human health risk assessment of pesticides are outlined in the Science Policy Note, SPN2008-01, The Application of Uncertainty Factors and the Pest Control Products Act Factor in the Human Health Risk Assessment of Pesticides.

e) If the Panel does not support the tiered approach for evaluating the toxicology of EOPIRs, what does the panel recommend?

Summarized EAP Response and Recommendations:

“As noted above, the Panel does, in general, support the use of a tiered approach for the safety evaluation of EOPIR. However, the Panel does not support the existing tiered approach recommended by the PMRA and has offered several suggestions above, which, if incorporated, would make the PMRA tiered approach more robust in terms of addressing potential data gaps with respect to dermal absorption, reproductive toxicity, and the use of alternative methods.”

PMRA Response:

See PMRA’s responses to questions 1a), b), c), and d) above.

Question 2. HC-PMRA’s current, tiered approach for evaluating EOPIRs, in terms of toxicology data requirements, is outlined in DIR2012-01.

a) Does the Panel support HC-PMRA’s position of continuing to use this approach for evaluating the exposure of EOPIRs?

Summarized EAP Response and Recommendations:

“…the Panel does support, in general, a tiered approach for EOPIRs. However, in terms of exposure; the Panel does not support the specific tiered approach recommended by the PMRA. Given the unique nature of EOPIRs and their direct application to humans for extended periods, the Panel recommends that dermal absorption (in vitro) be included as a Tier I data requirement which, except under exceptional circumstances, cannot be waived. In the same vein, the Panel also recommends, as discussed above, that in the context of the TTC approach, thoughtful consideration be given to minimum thresholds of exposure below which toxicological concerns would be deemed to be negligible.

PMRA Response:

See PMRA’s response to question 1a) above.

b) If not, should other data/information regarding exposure be required for a full assessment (for example, dermal absorption data)?

Summarized EAP Response and Recommendations:

See the response to question 1a) above.

PMRA Response:

See the response to question 1a) above.

c) If the Panel recommends that further exposure data/information should be requested, does it also recommend conducting quantitative risk assessments for EOPIRs?

Summarized EAP Response and Recommendations:

“… the Panel is of the view that deriving a MOE might be helpful in characterizing hazard – but only in those cases where there is a toxicological endpoint of concern, and only if NOAEL and LOAEL have been identified from the available data. This approach would then provide a basis for the PMRA to express a safe level of exposure based on outcomes of laboratory toxicology studies.”

PMRA Response:

In general, human health risk assessments for EOPIRs that are based on Tier I information requirements for toxicology and exposure, are qualitative or semi-quantitative. Because of the characteristics of non-conventional pesticides, and specifically EOPIRs, toxicological endpoints of concern are not usually identified and MOEs are not usually estimated. If higher Tier (i.e. II) toxicity testing and quantitative exposure estimates are required, MOEs could be estimated.

d) Does the Panel have any other recommendations on the exposure evaluation of EOPIRs?

Summarized EAP Response and Recommendations:

See the responses to questions 2a) and 2c) above.

PMRA Response:

See the response to questions 2a) and 2c) above.

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2024-05-06