Response to comments received on the consultation for proposed maximum residue limits for mefentrifluconazole (PMRL2023-41)

Health Canada's Pest Management Regulatory Agency (PMRA) published the Proposed Maximum Residue Limit PMRL2023-41, Mefentrifluconazole, for a 75-day public consultation period ending on 21 November 2023. Health Canada proposed several new maximum residue limits (MRLs) for mefentrifluconazole on various food commodities. Multiple comments were received from an environmental non-government organization. A summary of the comments and Health Canada's responses are presented below. The comments do not change the scientific basis of the proposed MRLs, and the MRLs will be specified in the MRL database. Further details are provided below on the purpose of setting MRLs, and how MRLs are determined. More information on MRLs can also be found on the Maximum residue limits, human health, and food safety webpage.

Comments

In general, the comments questioned the authority of Health Canada to specify MRLs for imported food commodities for unregistered pesticide uses. In addition, there were some specific questions on pesticide residue data generation, how MRLs are calculated and reporting levels of pesticide residues for dietary exposure.

Health Canada responses

Maximum residue limit (MRL) definition

A pesticide MRL is the maximum amount of pesticide residue that may legally remain on a food commodity that is either grown and produced domestically, or imported into Canada, when the pesticide is used according to label directions. Health Canada routinely sets science-based MRLs to help ensure the foods Canadians eat are safe. The MRL for each pesticide-crop combination is set at levels well below the amount that could pose a health concern. (See Overview of the dietary risk assessment process).

Authority to establish MRLs for imported food commodities

Health Canada regulates how pesticides are used in Canada. Authority also exists to specify MRLs for unregistered products and uses - that is, uses, including different use patterns in other countries that are not registered in Canada, - in accordance with sections 10 and 11 of the Pest Control Products Act. Health Canada receives these applications under section 10 of the Pest Control Products Act. As such, Health Canada may specify MRLs for foods that are treated with pesticides approved in other countries and imported into Canada; or for pesticides with a Canadian registration, but for a different use or use pattern that is not registered in Canada.

Establishing a higher MRL based on a food commodity imported into Canada does not change the way the pesticide must be used in Canada (domestic use). Growers still must comply with the use directions specified on the Canadian registered label, which is a legal requirement. This increased MRL for food imported into Canada will not change the Canadian registered labels, how the pesticide is used in Canada, or increase the amount of pesticide residues on the foods grown in Canada.

Health Canada's responsibility in pesticide regulation

Health Canada's priority is to protect the health and safety of Canadians, the environment and the food supply. This includes setting the conditions for approval of each specific pesticide use in Canada, including the levels of pesticide residues that may be present in food commodities grown in Canada or that may be imported into the country. These conditions are set based on Health Canada's independent review of scientific data. Health Canada's role is to make sure that the amount of residues that may be present in or on food commodities grown or imported to Canada does not pose a human health concern to any segment of the Canadian population including infants and toddlers, pregnant and nursing people, and the elderly.

Pesticide residues in or on food commodities

Pesticides are used on food commodities that are grown using conventional and organic practices to maintain food quality or prevent damage caused by pests, including insects, weeds, and fungal diseases. This helps ensure Canada has a secure supply of healthy food.

Pesticide residues are small amounts of conventional or organic pesticides that may stay on or in the food. Residues are measured in parts per million (or ppm). One ppm is equal to a single granule of sugar in 273 cubes of sugar (or 1 granule in one million granules). Therefore, 1 or even 50 ppm of residue on a food commodity from a pesticide is exceedingly small.

Pesticide residues can get in or on our food when:

• they are applied to crops we eat, like fruits and vegetables,
• we make processed foods, like juice, from crops treated with pesticide, or 
• we eat dairy or meat products from livestock animals that have eaten crops treated with pesticides.

Pesticide residues also break down over time, so by the time the food reaches the market there can be very small amounts of pesticide residues left on the food. Typically, the amount of pesticide residue on a food or crop is lower than the MRL set for that specific combination of pesticide and food or crop. Nevertheless, Health Canada must be satisfied that the amount of residue that could be present on a food commodity, once a crop has been treated with a pesticide according to label instructions, is not a health concern.

Reason MRLs for mefentrifluconazole are being proposed in PMRL2023-41

As noted in PMRL2023-41, new MRLs are proposed for the pesticide mefentrifluconazole, as part of the following applications under submission number 2021-1865 for specific Canadian uses, and under submission number 2021-2499 for imported commodities. The new MRLs proposed in PMRL2023-41 are not increases to previously specified MRLs.

The purpose of submission number 2021-1865 is to amend the registered Canadian label of the commercial-class end-use product Cevya (Registration Number 33405) by adding several crops within each of the following crop groups/subgroups: bulb onions and green onions (crop subgroups 3-07A and 3-07B), leafy vegetables (crop group 4-13), fruiting vegetables (crop group 8-09), melon and squash/cucumber (crop subgroups 9A and 9B), bushberries (except gooseberries) (crop subgroup 13-07B) and low growing berries (crop subgroup 13-07G). These crops are new to the Cevya label, and MRLs for mefentrifluconazole have not been previously specified for these crops.

The purpose of submission number 2021-2499 is to specify new MRLs on several crops for import into Canada. These will not be listed on the Cevya label. These crops are part of the following crop groups/subgroups: root vegetables (except sugar beet) (crop subgroup 1B), leaves of root and tuber vegetables (crop group 2), bulb onions and green onions (crop subgroups 3-07A and 3-07B), leafy vegetables (except head lettuce) (crop group 4-13), fruiting vegetables (crop group 8-09), sunflowers (crop subgroup 20B, revised); and the individual commodities of bananas, coffee, cotton and sugarcane. MRLs for mefentrifluconazole have not been previously specified for these crops.

As noted in PMRL2023-41, the full list of commodities included in each crop group/subgroup can be found on the Residue Chemistry Crop Groups webpage in the Pesticides and pest management section of Canada.ca.

Overview of the dietary risk assessment process

Before approving the Canadian registration of a pesticide for a specific use or allowing the importation of a pesticide-treated food, Health Canada thoroughly assesses the risks to human health to make sure that the level of human exposure, when the pesticide is used according to the label directions, is well below the level that would be of health concern. Only pesticides for which health risks are shown to be acceptable are approved.

To do this assessment, Health Canada combines scientific information on pesticide toxicity with information on the degree and duration of dietary exposure to the pesticide residue from food. As noted in PMRL2023-41, the risk assessment process involves four distinct steps:

1. Identifying the toxicology hazards of a pesticide
2. Determining the "acceptable dietary level" for Canadians (including all vulnerable populations) that is protective of adverse health effects, by setting the acceptable level at least 100-fold below the level where no effects are observed in animal studies;
3. Estimating how much of a pesticide people may be exposed to in their diet from all possible sources (domestic and imported commodities), based on how much residues remain in or on the food and the amount of treated food an individual may consume; and
4. Characterizing health risk by comparing the estimated dietary exposure to the acceptable dietary level set in Step 2.

If estimated human exposure from Step 3 is less than or equal to the acceptable level (developed in Step 2), Health Canada concludes that consuming residues resulting from use according to approved label directions is not a health concern. This quantity of residue is then subject to consultation to legally specify it as an MRL. If risks to human health from the consumption of treated food are not shown to be acceptable, the pesticide product will not be permitted for sale or use in Canada, and an MRL will not be established.

Each MRL applies to a specific food commodity and food processed from that commodity

An MRL applies to the identified raw agricultural food commodity as well as to any processed food product that contains that commodity, unless a specific MRL is proposed for the processed food. For example, in the case of mefentrifluconazole, the MRL of 0.9 ppm for tomatoes applies to processed commodities derived from the treated tomatoes, such as juice, paste and puree, but not dried tomatoes. The MRL proposed for dried tomatoes is 4.0 ppm, as residues were shown to concentrate in that processed fraction by a factor of 9.2×.

As noted, Health Canada establishes MRLs only when there are no health risks of concern to consumers; in other words, the risks are shown to be acceptable. This approach is consistent with the international approach to health risk assessment and is considered protective, as exposure to pesticide residues in the diet must be below levels that could pose a health concern.

Summary of the dietary risk assessment results for mefentrifluconazole showing acceptable risk

The dietary risk assessment was updated to support the proposed MRLs under submissions 2021-1865 and 2021-2499 (see results in Table 1 and Table 2).

Dietary exposure assessments are conducted using a database called the Dietary Exposure Evaluation Model - Food Commodity Intake Database (DEEM-FCID) which is explained in Science Policy Note SPN2014-01, General Exposure Factor Inputs for Dietary, Occupational, and Residential Exposure Assessments. This is a food recipe and consumption database used by Canada and the United States (U.S.) for dietary exposure modelling that incorporates food consumption data from the United States National Health and Nutritional Examination Survey, What We Eat in America (NHANES/ WWEIA) dietary survey. This survey is made available through the National Center for Health Statistics (NCHS), which is part of the Centers for Disease Control and Prevention (CDC). The NHANES survey, which uses interviews and physical examinations to assess the health and nutritional status of adults and children in the United States, is updated periodically and is also reflective of the large variety of food consumption patterns in the Canadian population.

The acute dietary risk assessment results showed that exposure to mefentrifluconazole is 8% or less of the ARfD. This means that acute exposure to mefentrifluconazole will not affect your health.

• Health Canada considers acute risk may be of concern when exposure is greater than 100% of the ARfD. When the acute dietary risk assessment is lower than 100% of the ARfD, it means that on any given day there are no human health concerns from eating foods treated with mefentrifluconazole.

Table 1: Summary of acute dietary risk analysis for mefentrifluconazole

Population subgroup	ARfD (mg/kg bw)	95th Percentile  Food alone	95th Percentile Food and drinking water
		%ARfD (Basic assessment)	%ARfD (Basic assessment)
General Population	2.0	3.0	3.1
All Infants		4.8	5.1
Children 1-2 years old		7.9	8.0
Children 3-5 years old		5.7	5.8
Children 6-12 years old		3.1	3.2
Youth 13-19 years old		1.9	2.0
Adults 20-49 years old		2.1	2.2
Adults 50+ years old		2.2	2.3
Females 13-49 years old		2.1	2.2
ARfD = Acute Reference Dose; mg/kg bw = milligrams per kilogram of body weight

The chronic dietary risk assessment results showed that exposure to mefentrifluconazole is 19% or less of the ADI. This means that chronic exposure to mefentrifluconazole will not affect your health.

• Health Canada considers chronic risk may be of concern when exposure is greater than 100% of the ADI. When the chronic dietary risk assessment is lower than 100% of the ADI, it means that there are no human health concerns from eating foods treated with mefentrifluconazole every day over a person's lifetime.

Table 2: Summary of chronic dietary risk analysis for mefentrifluconazole

Population subgroup	ADI (mg/kg bw/day)	Food alone	Food and drinking water
		% ADI  (Refined assessment)	% ADI  (Refined assessment)
General Population	0.04	5.9	7.6
All Infants		7.3	13.7
Children 1-2 years old		16.6	19.0
Children 3-5 years old		11.6	13.5
Children 6-12 years old		6.6	8.0
Youth 13-19 years old		3.7	5.0
Adults 20-49 years old		5.2	6.9
Adults 50+ years old		5.5	7.1
Females 13-49 years old		4.9	6.6
ADI = Acceptable Daily Intake; mg/kg bw = milligrams per kilogram of body weight

Crop field trial data were generated according to the directions for use

Health Canada relies on the PMRA's Updated Residue Chemistry Guidelines to assess the scientific robustness and acceptability of the residue chemistry data submitted by pesticide manufacturers. Residue chemistry data are required to support an application for the registration of conventional pest control products for use on human food and animal feedstuffs in Canada or to support the establishment of an MRL for residues in/on a food imported into Canada.

The directions for use on the Cevya label on selected fruiting vegetables (crop group 8-09), melon and squash/cucumber (crop subgroups 9A and 9B), and low growing berries (crop subgroup 13-07G) include a rate of 0.25-0.375 L product/ha/application (100-150 g a.i./ha/application) with up to 4 applications per year, for a maximum rate of 1.125 L product/ha/year (450 g a.i./ha/year); while on bushberries (crop subgroup 13-07B, except gooseberries) they include a rate of 0.25 L product/ha/application (100 g a.i./ha/application), also with up to 4 applications per year, for a maximum rate of 1.0 L product/ha/year (400 g a.i./ha/year). The dietary risk assessment was conducted using the maximum yearly application rates.

As per Table A1 of PMRL2023-41^{Reference *}, crop field trials for cherry tomatoes, tomatoes, bell peppers, and non-bell peppers were conducted at 417-468 g a.i./ha (0.9-1.0-fold Good Agricultural Practice (GAP) for fruiting vegetables); crop field trials for muskmelons, cucumbers, and summer squash were conducted at 446-467 g a.i./ha (1.0-fold GAP for melon and squash/cucumber); crop field trials for strawberries were conducted at 445-469 g a.i./ha (1.0-fold GAP for low growing berries); and crop field trials for blueberries were conducted at 437-464 g a.i./ha (1.1-1.2-fold GAP for bushberries). Therefore, the crop field trial data used in the determination of the MRLs were based on rates comparable to GAP, rather than exaggerated rates.

Table 3: Summary of field trial and processing data used to support the MRLs

Commodity	Application Method/Total Application Rate (g a.i./ha)Table 3 footnote 1	Preharvest Interval (days)	Lowest Average Field Trial Residues  (ppm)	Highest Average Field Trial Residues (ppm)	Experimental Processing Factor
Cherry tomatoes	Foliar application/ 417-446	0	0.125	0.405	Dried tomato: 9.2×  Juice: 0.1×  Paste: 0.5×  Puree: 0.3×
Tomatoes	Foliar application/ 443-468	0	0.026	0.370
Bell peppers	Foliar application/ 445-454	0	0.044	0.729	Not applicable
Non-bell peppers	Foliar application/ 445-446	0Table 3 footnote 2	0.188	0.602	Not applicable
Table 3 footnote 1 g a.i./ha = grams of active ingredient per hectare Return to table 3 footnote 1 Table 3 footnote 2 Residues from a 3-day decline trial sample were used in the OECD MRL Calculator for non-bell peppers, to account for higher residues at the longer PHI. Return to table 3 footnote 2

Use of residue data from decline trials

As noted in Table A1 of PMRL2023-41, when determining MRLs for carrot roots, non-bell peppers, bananas and coffee, residue decline data generated as part of the crop field trial studies were used in the OECD MRL Calculator. Residues from a 14-day decline trial sample were used for carrot roots (PHIs of 6-7 days); residues from a 3-day decline trial sample were used for non-bell peppers (PHI of 0 days); residues from 1, 3, and 7-day decline trial samples were used for bananas (PHI of 0 days); and residues from 30, 45, and 60-day decline trial samples were used for coffee (PHIs of 9-15 days). Residues from decline trial samples were only used when they were higher than those found in crop field trial samples collected at shorter PHIs. This is considered appropriate in order to prevent underestimating potential residues present on crops at harvest. Therefore, MRL calculations are based on the most conservative (i.e., highest) anticipated residue concentrations on crops. This is a health protective approach, as health risks must be acceptable with the higher MRLs proposed.

How MRLs are calculated for smaller datasets

The OECD MRL Calculator is internationally endorsed by an expert group of OECD scientists and used by OECD countries. This calculator is used internationally, including by the Codex Alimentarius Commission,a joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) body to protect consumer health and promote fair practices in food trade which represents over 100 countries, and it is also used by the European Union and the United States Environmental Protection Agency. The OECD White Paper, which explains this calculator, notes that for smaller datasets (i.e., less than 10 points), such as the ones for mefentrifluconazole on radish roots, radish leaves, turnip greens, head lettuce without wrapper leaves, green onions, mustard greens, and non-bell peppers, there is a possibility that the MRL proposed by the statistical methods will be greater than the highest residue in the data set to ensure that the MRL is not underestimated. For these dataset sizes, where the uncertainty is high, this outcome is expected, especially when there is a great deal of variability within the data set.

This calculation is therefore conservative and health protective, as health risks must be acceptable with the higher MRL proposed. That is, once the MRL is calculated by Health Canada, a health risk assessment is conducted to determine if this MRL would represent a health concern. Health Canada establishes MRLs only when there are no health risks of concern for the public.

It should be noted that while residue data on head lettuce without wrapper leaves (with a small dataset) were put into the OECD MRL Calculator, residue data on head lettuce with wrapper leaves (with a larger dataset) were also put into the OECD MRL Calculator. The residues for head lettuce with wrapper leaves ranged from 0.12-2.15 ppm, which were higher than the residues for head lettuce without wrapper leaves, which ranged from <0.01-1.55 ppm. Consequently, the OECD MRL Calculator determined a higher MRL for head lettuce with wrapper leaves (at 5 ppm) compared to head lettuce without wrapper leaves (at 4 ppm). The final determination of the MRL for head lettuce was thus based on head lettuce with wrapper leaves to be protective.

Assessment of formulated products

Health Canada's assessment of pesticides includes an assessment of the formulated (end-use) products. Toxicity studies on formulated products define the hazard statements that must appear on each product label and are specific to each formulated pesticide product. Individual formulated products are also used in other studies, such as in the generation of residue chemistry data including field trials for MRL setting, which are considered during the exposure and risk assessment phase.

Health Canada assessed the acute systemic (oral, dermal and inhalation) toxicity and the potential for eye irritation as well as skin irritation and sensitization of all formulated products containing mefentrifluconazole (please see Proposed Regulatory Decision PRD2019-09). Because the technical grade active ingredient mefentrifluconazole is a known dermal sensitizer, the formulated product Cevya (Registration Number 33405) is also considered a potential dermal sensitizer. The appropriate hazard statement is included on the product label.

The allergen soy may be present at very low levels in certain formulated products containing mefentrifluconazole. The labels for those products display the appropriate allergen warning statements as directed in DIR2006-02, Formulants Policy and Implementation Guidance Document. In addition, Health Canada aims to restrict the food-use application of allergenic formulants to the same or similar crop from which the commodity is derived, unless it has been demonstrated that the source of the formulant contains negligible residues of the allergenic protein resulting in a level that would not pose a health risk. For the implicated mefentrifluconazole products, either their approved uses are such that exposure to the allergen on non-allergenic food commodities is not likely to occur, or the allergen is present at such a low level, that there is no anticipated health risk for the general population. Additional information related to food allergies and food intolerances can be found at the following resources: Food allergies - Canada.ca;Food Allergies and Intolerances - Canada.ca; Food Allergy Canada.

A full hazard assessment was conducted as part of the risk assessment for mefentrifluconazole in 2019 (please see PRD2019-09). No new data or published scientific literature have been identified that would have an impact on the current hazard assessment. The dietary risk assessment was updated to support the proposed MRLs under submissions 2021-1865 and 2021-2499 (see results in Table 1 and Table 2).

Pest Control Products Act factor (PCPA Factor) considerations

The toxicity reference values determined for mefentrifluconazole at the time of the initial evaluation were derived from endpoints based on treatment-related effects that occurred at much lower doses than the serious reproductive effect observed in presence of maternal toxicity in the 2-generation reproductive toxicity study in rats (decreased number of implantation sites in F1 dams). The acceptable daily intake (ADI) is based on a no observed adverse effect level (NOAEL) of 3.5 mg/kg bw/day from the 18-month mouse study. The NOAEL for the serious reproductive effect is 73 mg/kg bw/day. Thus, the NOAEL used to derive the ADI is 20-fold lower than the NOAEL for the reproductive effect.

In addition, variability in the human population is addressed in the risk assessments performed by Health Canada through use of a 10-fold uncertainty factor for intraspecies variability that is applied to the NOAEL. This factor is in addition to the 10-fold uncertainty factor also applied to the NOAEL to account for differences between humans and animals (interspecies variability).

An additional margin of safety is included through retention of another factor (the PCPA factor) if there are any residual concerns for potential sensitivity of the young. However, the reproductive NOAEL was not selected to establish the toxicology reference value (that is, the ADI) as it was determined that the ADI based on a NOAEL of 3.5 mg/kg bw/day from the 18-month mouse study with a PCPA factor of 1-fold and both 10-fold uncertainty factors (100-fold) yielded a margin of 1825-fold to the NOAEL for the serious reproductive effect, which is protective. Moreover, the selected toxicology reference value is more protective than if the NOAEL from the 2-generation reproductive toxicity study, with relevant uncertainty and PCPA factors, was used to derive the ADI.

The same considerations were applied to the selection of the occupational reference values, and the occupational risk assessment must be acceptable for a domestic MRL to be approved.

Scientific literature review

In animal studies used to assess the long-term effects of a pesticide, including the potential to cause cancer, the animals are exposed to the pesticide at high dose levels over their entire lifetime and potential effects on all tissues and organ systems are investigated. Effects evaluated in these studies include clinical signs of toxicity, effects on body weight, organ weights and pathology, effects on hematology and clinical chemistry parameters, and the potential to cause gene mutations and tumour formation. There was no evidence of carcinogenicity and/or other concerns (for example, sensitivity of the young) in the mefentrifluconazole database that have not already been considered in the human health risk assessment. The toxicology profile is described in the published document PRD2019-09.

The commenter provided citations from Zhang et al., (2023) that were not referenced in PMRL2023-41. However, these citations only mention mefentrifluconazole in the introduction to the articles and do not relate to adverse effects of mefentrifluconazole. A cursory review of the scientific literature identified in Pubmed^® (National Institutes of Health, National Library of Medicine) using the key word "mefentrifluconazole" yielded 41 results. These studies did not impact the current risk assessment. Nevertheless, these articles and any additional relevant scientific information that becomes available will be taken into consideration at the time of the next assessment of mefentrifluconazole.

Conclusion

Dietary risks from the consumption of mefentrifluconazole residues in or on various Canadian-grown and imported crops were shown to be acceptable when mefentrifluconazole is used according to the supported Canadian and foreign label directions. As such, the food commodities containing these residues are safe to eat, and the MRLs will be specified as proposed.

For more information

PRD2019-09, Mefentrifluconazole and related end-use products - publication request page.