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Federal Register / Vol. 86, No. 183 / Friday, September 24, 2021 / Rules and Regulations other substances. For the purposes of this action, therefore, EPA has not assumed that mefenoxam has a common mechanism of toxicity with other substances.
D. Safety Factor for Infants and Children 1. In general. Section 408b2C of FFDCA provides that EPA shall apply an additional tenfold 10X margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor SF. In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor.
2. Prenatal and postnatal sensitivity.
There was no evidence of increased susceptibility in offspring in the prenatal developmental or the 2generation reproductive toxicity studies.
In adult rats treated with metalaxyl or mefenoxam, clinical signs and abnormal functional observation battery FOB
findings were noted after a bolus gavage dose but not in repeated dose studies.
3. Conclusion. EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF
were reduced to 1X. That decision is based on the following findings:
i. The toxicity databases for metalaxyl and mefenoxam are adequate to assess the potential for prenatal and postnatal toxicity for infants and children.
ii. In the rat prenatal developmental toxicity with metalaxyl, maternal animals exhibited clinical signs indicative of neurobehavioral effects as previously discussed. In the rangefinding acute neurotoxicity study with mefenoxam, females exhibited abnormal FOB findings at doses lower than in males. In the subchronic neurotoxicity study with mefenoxam, there were no indications of neurotoxicity up to the HDT. In metalaxyl and mefenoxam treated adult animals, clinical signs and abnormal FOB findings were noted.
However, a developmental neurotoxicity DNT study is not required for metalaxyl or mefenoxam because 1 there are no indications of increased susceptibility for infants or children; 2 the convulsions observed in the rat prenatal developmental toxicity study occurred in the maternal animals with no effects being observed
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in the young; 3 the convulsions occurred only after a bolus dose; 4 the available developmental and rangefinding acute neurotoxicity studies provided clear NOAELs and LOAELs for evaluating effects; 5 the current POD is below the level at which any effects were seen in either study, and 6 there were no other indications of neurotoxicity in the mefenoxam or metalaxyl databases, which include a subchronic adult rat neurotoxicity study for mefenoxam. Therefore, there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity. See Metalaxyl, Mefenoxam metalaxyl-m Human Health Draft Risk Assessment for Registration Review docket ID
number EPAHQOPP20090863
0023.
iii. As discussed above in Unit III.D.2., there is no evidence that metalaxyl results in increased susceptibility in the developmental or reproductive toxicity studies; and iv. There are no residual uncertainties in the exposure database. Dietary exposure analysis was performed incorporating all existing and proposed uses using tolerance level values to estimate residues in food commodities and anticipated residues in livestock commodities. Drinking water estimates were generated based upon conservative inputs and modeling. Similarly, potential residential post application exposures are based upon conservative, default assumptions. EPA made conservative protective assumptions in the ground and surface water modeling used to assess exposure to metalaxyl in drinking water. EPA used similarly conservative assumptions to assess postapplication exposure of children as well as incidental oral exposure of toddlers.
These assessments are not expected to underestimate the exposure to metalaxyl.
E. Aggregate Risks and Determination of Safety EPA determines whether acute and chronic dietary pesticide exposures are safe by comparing aggregate exposure estimates to the acute PAD aPAD and chronic PAD cPAD. For linear cancer risks, EPA calculates the lifetime probability of acquiring cancer given the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the appropriate PODs to ensure that an adequate MOE
exists.
1. Acute risk. An acute aggregate risk assessment takes into account acute exposure estimates from dietary
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consumption of food and drinking water. Using the exposure assumptions described in this unit for acute exposure, EPA has concluded that acute exposure to metalaxyl from food and water will utilize 52% of the aPAD for children 1 to 2 years old, the population subgroup with the highest exposure estimate.
2. Chronic risk. There is no increase in hazard from repeat exposures to metalaxyl/mefenoxam; therefore, a chronic dietary POD was not selected.
Due to the lack of a chronic endpoint, a chronic dietary risk is not expected.
The acute endpoint and dietary exposure assessment are protective of potential effects from chronic duration dietary exposures.
3. Short-term risk. Short-term aggregate exposure takes into account short-term residential exposure plus chronic exposure to food and water considered to be a background exposure level. Mefenoxam and metalaxyl are currently registered for uses that could result in short-term residential exposure, and the Agency has determined that it is appropriate to aggregate chronic exposure through food and water with short-term residential exposures to mefenoxam and metalaxyl.
Using the exposure assumptions described in this unit for short-term exposures, EPA has concluded the combined short-term food, water, and residential exposures result in an aggregate MOE of 270 for children.
Because EPAs level of concern for mefenoxam is a MOE of 100 or below, this MOE is not of concern.
4. Intermediate-term risk.
Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water considered to be a background exposure level. An intermediate-term adverse effect was identified; however, metalaxyl and mefenoxam are not registered for any use patterns that would result in intermediate-term residential exposure.
5. Aggregate cancer risk for U.S.
population. Metalaxyl is classified as Not Likely to Be Carcinogenic to Humans; therefore, EPA does not expect metalaxyl exposures to pose an aggregate cancer risk.
6. Determination of safety. Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to metalaxyl residues.

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