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Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Rules and Regulations
occurred in the nasal cavity at lower doses in a 28-day inhalation study in rats USEPA, 2018d. Systemic toxicity effects were not observed in this study.
Immunotoxicity effects were not observed in mice exposed to Smetolachlor USEPA, 2018d.
While some prenatal developmental studies in the rat and rabbit with both metolachlor and S-metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals, decreased pup body weight was observed in a two-generation study Page, 1981, USEPA, 2018d. Though there was no evidence of maternal toxicity, decreased pup body weight in the F1 and F2 litters was observed, indicating developmental toxicity Page, 1981; USEPA, 1990b. Therefore, sensitive lifestages to consider include infants, as well as pregnant women and their fetus, and lactating women.
Although treatment with metolachlor did not result in an increase in treatment-related tumors in male rats or in mice both sexes, metolachlor caused an increase in liver tumors in female rats USEPA, 2018d. There was no evidence of mutagenic or cytogenetic effects in vivo or in vitro USEPA, 2018d. In 1994 USEPA, 1995b, EPA
classified metolachlor as a Group C
possible human carcinogen, in accordance with the 1986 Guidelines for Carcinogen Risk Assessment USEPA, 1986. In 2017 USEPA, 2018d, EPA reassessed the cancer classification for metolachlor in accordance with EPAs final Guidelines for Carcinogen Risk Assessment USEPA, 2005, and reclassified metolachlor/S-metolachlor as Not Likely to be Carcinogenic to Humans at doses that do not induce cellular proliferation in the liver. This classification was based on convincing evidence of a constitutive androstane receptor CAR-mediated mitogenic MOA for liver tumors in female rats that supports a nonlinear approach when deriving a guideline that is protective for the tumor endpoint USEPA, 2018d.
A recent OPP HHRA identified a twogeneration reproduction study in rats as the critical study USEPA, 2018d. OPP
proposed an RfD for metolachlor of 0.26
mg/kg/day, derived from a NOAEL of 26
mg/kg/day for decreased pup body weight in the F1 and F2 litters. A
combined UF of 100 was used based on interspecies extrapolation 10, intraspecies variation 10, and an FQPA
Safety Factor of 1. This RfD is considered protective of carcinogenic effects as well as effects observed in chronic toxicity studies USEPA, 2018d. The decreased F1 and F2 litter pup body weights in the absence of maternal toxicity were considered
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indicative of increased susceptibility to the pups. Therefore, a rate of 0.15 L/kg/
day was selected from the Exposure Factors Handbook USEPA, 2011 to represent the consumers-only estimate of DWI based on the combined direct and indirect community water ingestion at the 90th percentile for bottle fed infants. This estimate is more protective than the estimate for pregnant women 0.033 L/kg/day or lactating women 0.054 L/kg/day. DWI and BW
parameters are further outlined in the Exposure Factors Handbook USEPA, 2011.
EPA OW calculated an HRL for metolachlor of 300 mg/L rounded from 0.347 mg/L. The HRL was derived from the oral RfD of 0.26 mg/kg/day for bottle fed infants ingesting 0.15 L/kg/day water, with the application of a 20%
RSC.
b Occurrence EPA has determined that metolachlor does not occur with a frequency and at levels of public health concern at PWSs based on the Agencys evaluation of available occurrence information. The primary occurrence data for metolachlor are from the UCMR 2 screening survey.
A total of 11,192 metolachlor samples were collected from 1,198 systems. Of these systems, three 0.25% had metolachlor detections 1 mg/L and none of the detections were greater than 12 the HRL 150 mg/L or the HRL 300
mg/L USEPA, 2015; USEPA, 2021a.
Supplementary sources of finished water occurrence data from UCM Round 2 indicate that the occurrence of metolachlor in PWSs is likely to be low to non-existent USEPA, 2021a.
Metolachlor occurrence data for ambient water from NAWQA and NWIS are consistent with those for finished water USEPA, 2021a.
c Meaningful Opportunity The Agency has determined that regulation of metolachlor does not present a meaningful opportunity for health risk reduction for persons served by PWSs based on the estimated exposed populations, including sensitive populations. UCMR 2 findings indicate that the estimated population exposed to metolachlor at levels of public health concern is 0%. As a result, the Agency finds that an NPDWR for metolachlor does not present a meaningful opportunity for health risk reduction.
d Summary of Public Comments on Metolachlor and Agency Responses EPA received several comments on the Agencys evaluation of metolachlor under section 1412b1A of SDWA,
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all of which were in support of its preliminary determination not to regulate metolachlor. EPA agrees with the comments that are in support of the negative regulatory determination.
F. Nitrobenzene 1. Description Nitrobenzene is a synthetic aromatic nitro compound and occurs as an oily, flammable liquid. It is commonly used as a chemical intermediate in the production of aniline and drugs such as acetaminophen. Nitrobenzene is also used in the manufacturing of paints, shoe polishes, floor polishes, metal polishes, aniline dyes, and pesticides.
Nitrobenzene is expected to have a moderate to high likelihood of partitioning to water and moderate persistence in water USEPA, 2021a.
2. Agency Findings The Agency is making a determination not to regulate nitrobenzene with an NPDWR.
Nitrobenzene does not occur with a frequency and at levels of public health concern. As a result, the Agency finds that an NPDWR does not present a meaningful opportunity for health risk reduction.
a Adverse Health Effects The Agency finds that nitrobenzene may have adverse effects on the health of persons. NTP 1983 conducted a 90day oral gavage study of nitrobenzene in F344 rats and B6C3F1 mice. The rats were more sensitive to the effects of nitrobenzene exposure than the mice, and changes in absolute and relative organ weights, hematologic parameters, splenic congestion, and histopathologic lesions in the spleen, testis, and brain were reported. Based on statistically significant changes in absolute and relative organ weights, splenic congestion, and increases in reticulocyte count and methemoglobin metHb concentration, a LOAEL of 9.38 mg/kg/
day was identified for the subchronic oral effects of nitrobenzene in F344
male rats USEPA, 2009. This was the lowest dose studied, so a NOAEL was not identified. The mice were treated with higher doses and were generally more resistant to nitrobenzene toxicity, the toxic endpoints were similar in both species.
The testis, epididymis, and seminiferous tubules of the male reproductive system are targets of nitrobenzene toxicity in rodents. In male rats F344/N and CD and mice B6C3F1, nitrobenzene exposure via the oral and inhalation routes results in histopathologic lesions of the testis and
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