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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: William Cutchin, 703

- 305

- 7990

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA

- Remove” and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply re place the instructions that appear in green , i.e., “ [ insert company

name ] ,” with the information specific to your action.

TEMPLATE:

Clariant Corporation

I N

- 10661

EPA has received a pesticide petition
, IN

- 10661, from Exponent ( 1150 Connecticut Ave., NW Suite 1100 , Washington, DC 20036 ) on behalf of Clariant Corporation (4000 Monroe Road, Charlotte, NC 28205 ) requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from the requirement of a tolerance for C.I. Pigmen t Yellow 1 (CAS RN 2512

- 29

- 0) ; b utanamide, 2

- (4

- methyl

- 2

- nitrophenyl) azo

- 3

-
oxo

- N

- phenyl

- , for use as a pesticide i nert s eed t reatment i ngredient not to exceed 10% wt/wt, under 40 CFR §180. 920 pursuant to Section 408(d)(l) of the Federal Food, Drug,2

and Cosmetic Act (FFDCA). EPA has approved C.I. Pigment Yellow 1 as an inert ingredient for non

- food use pesticide formulations.

EPA has determined that the petition contains data or information regar ding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on th e petition.

A. Residue Chemistry

1. Plant metabolism. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients.

2. Analytical method. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients.

3. Magnitude of residues. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients.

B. Toxicological Profile

1. Acute toxicity. The Clariant Monoazo Chemical Safety Report (2012) report submitted under the auspices of the EU Reach regulatory initiative reported t he following acute toxicity data for C.I. Pigment Yellow 1: OECD 401 (rat acute oral) LD 50 > 10,000 mg/kg/day (EPA Toxicity Category IV, practically non

- toxic); OECD 402 (rat acu te dermal) LD 50 > 2,000 mg/kg (EPA Toxicity Category III); OECD 404 (rabbit dermal irritation) non

- irritating; OECD 405(rabbit acute eye irritation) non

- irritating; OECD 429 (mouse local lymph node assay) non

- sensitizing.

2. Genotoxicty. C.I. Pigment Yel low 1 did not display mutagenic activity in the following assays: AMES bacterial (OECD 471) assay with and without metabolic3

activation; Chinese hamster lung fibroblast cell micronucleus test (OECD 487, version 3) with and without metabolic activation and negative and the mammalian cell gene mutation assay (OECD 476) with and without metabolic activation.

3. Reproductive and developmental toxicity. C.I. Pigment Yellow 1 was administered to Wistar rats (11/sex/dose) by gavage in a Combin ed Repeated Dose
To xicity Study with a Reproduction/Developmental Toxicity Screening (OECD 422) at dose levels of 0 (vehicle control), 100, 300 and 1000 mg/kg bw/day (actual amount ingested). Based on these, the NOAEL (No Observed Adverse Effect Level) for general toxicity in males and females and for reproduction/developmental toxicity was considered t o be 1000 mg/kg bw/day, the highest dose level used.

All animals survived the scheduled study period. Clinical effects included yellow stained feces in all treated animals. No effects were seen in locomotor activity or in the functional observational battery. Body weight gain of male animals in the 300 and 1000 mg/kg bw/day dose groups were dose

- dependently and significantly reduced in the pre

mating period. No differences in body weight gain were noted at any dose level during the remaining study period. Body weights of males in all dose groups were similar to the respective control values during the entire study period. Because reduction in body weight gain at the high

- and mid

- dose levels was reversible and did not cause significant changes in body weights, this effect was considered not to be adverse. Body weights and body weight gain of females were not affected by the treatment at any dose level. Food consumption was not affected by the treatment at any dose level. No test substance

- related effects on hematology, clinical biochemistry, urinalysis, organ weights or histopathology were noted at any dose level.

Mating performance, fertility, corpora lutea count, duration of gestation, implantation rate and post

- implantation loss, litter size or postnatal loss were not affected by the treatment with the test item. At the dose level of 1000 mg/kg bw/day, reduction in mean count of progressive sperms and increase in mean count of not motile sperms were noted. At the dose level of 300 mg/kg bw/day, increase in mean count of not motile sperms was noted. A significant dose dependent trend could not be established. In the absence of any findings during necropsy or histopathological examination of male reproductive organs as well as absence of any effects on reproduction, the differences in sperm motility were considered not to be adverse.4

Sperm morphology and sperm count were not affected by the treatment at any dose level. No test item related findings were noted in pups during first litter check and during lactation at any dose level. No test substance

- related findings were reported in sex ratio or pup weight and no findings were noted upon gross pathology.

4. Subchronic toxicity

. The general systemic toxicity NOAEL from the 28

- Day OECD 422 Combined Repeated Dose Tox icity Study with a Reproduction /Developmental Toxicity Screening Test in rats was 1000 mg/kg body weight/day.

5. Chronic toxicity. No chronic toxicity data for C.I. Pigment Yellow 1 are available. Based on the Federal Register Notice (August 9, 2006, Volume 71, Number 153, pages 45415

- 45424), the Agency stated that the preferred test for repeat

- dose toxicity is the ''Combined Repeated Dose Toxicity Study with the
R epr oduction/Developmental Toxicity Screening Test (OECD Test Guideline 422)." Therefore, an OECD 422 study has been submitted and the results are summarize d under the Reproductive and Developmental Toxicity, Section 3 , of this document.

6. Animal metabolism. There are no publically available mammalian metabolism d a ta reported for C.I. Pigment Yellow 1, but it is unlikely that metabolism would result in the production of toxic or carcinogenic metabolites (Levine, 1991). In the 2012 monoazo pigment R EACh CSR Clariant proposed the following rationale to addr ess the potential animal metabolism in humans. The rationale was published was based on toxicokinetic data for a structurally related monoazo pigment, C.I. Pigment Yellow 74 ; b utanamide, 2

- [(2

- metho xy

- 4

- nitrophenyl)azo]

- N

- (2

- methoxyphenyl)

- 3

- oxo

- , (CAS RN 6358

- 31

- 2).

"Toxicokinetic behaviour (absorption

- distribution

- metabolism

- excretion) of the Monoazo Yellow Pigments has been investigated for Pigment Yellow 74 after single oral application, but no investigations have been performed with the other members of this category. The findings for Pigment Yellow 74 as well as the observations made in several toxicity studies together with the physico

- chemical properties of the pigments of this category w ill be addressed in the following section and the impact of these findings on the toxicokinetic behavior of the Monoazo Yellow Pigments will be discussed.5

Toxicokinetics of Pigment Yellow 74 has been investigated in male Fischer 344 rats which received 1 2.6 mg/kg Pigment Yellow 74 by gavage. Urine, feces, stomach contents, intestinal contents and various tissues have been collected 1, 4, 24 and 48 hours after dosing. One and 4 hours after dosing most of the administered material was present in the gut contents and none was in the feces. 24 and 48 after dosing, most part of the admi nistered substance was in the f eces (about 86% after 48 hours). Detectable amounts (>3%) were only in those tissues directly in contact with the compound. No test compound was found in samples of plasma, whole blood, liver, kidney, or lungs, even after administration of doses ten times larger. These data indicate that Pigment Yellow 74 is not bioavailable after oral application.

The findings from several toxicity studies with Monoazo Yellow Pigment 74 and the absence of any toxic effect in these studies also indicate that the members of this category are not bioavailable by either the oral or dermal routes of
exposure.

The conclusion that the members of this category are not b ioavailable after oral or dermal application is supported by the data on the physicochemical properties: Monoazo Yellow Pigments are nearly insoluble in water (1.9 to 19.3 ug/L) and only marginally soluble in octanol (0.12 to 14.9 mg/L). Due to this low

so lubility the members of this category are (nearly) not existent in a dissolved form on the skin or mucous membranes after dermal, oral or inhalative exposure, i.e. they could not be absorbed through the skin or mucous membrane..."

Additionally, the weight of the evidence of the experimental toxicology mutagenicity studies indicate that C.I. Pigment Yellow 1 is not mutagenic and likely not metabolized to any great extent. These data infer that the azo

- group is stable and not cleaved and ; oxidation of the aromatic amine is not oxidized to generate carcinogenic metabolites6

7. Metabolite toxicology

. Not required

.

8. Endocrine disruption

. C.I. Pigment Yellow 1 does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system.

C. Aggregate Exposure

1. Dietary exposure. While no specific crop residue information is available for C.I. Pigment Yellow 1, on the basis of the proposed tolerance exemption and the physical chemical and environme ntal properties analysis, environmental persistence with resultant crop residues are not likely from the use of C.I. Pigment Yellow 1 as pesticide inert ingredients in seed treatment formulations under 40 CFR §180.920 at
concentrations not to exceed 10%. T he seed treatment formulations containing C.I. Pigment Yellow 1 will be applied directly to the seeds and if released into the environment, experimental Koc data (log Koc = 5.1) indicate that the pigment will bind tightly to soil and sediment and not be soluble in water. Under these conditions, it is unlikely that the pigment will be taken up by the germinated seedlings and translocated within the plant vascular system to result in crop residues and dietary exposures.

The conservative I

- DEEM screening le vel model analysis for food + drinking water indicates that the exposure to C.I. Pigment Yellow 1 would be 0.4% of the c hronic population adjusted dose (cPAD) for the U.S. general population while the highest exposure would be to children 1

- 2 yrs old at 1. 4 % cPAD.

i. Food. The chronic dietary exposures estim ated using I

- DE EM ar e well below 100% of the cPAD, and are therefore below EPA's established level of concern for all U.S. subpopulations

.

ii. Drinking water

. Drinking water is included in the I

- DEEM exposure assessment and based on anticipated concentrations expected to be negligible.7

2. Non

- dietary exposure

. None

D. Cumulative Effects

EPA has not determined that C.I. Pigment Yellow 1 has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Based on the conservative exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population from the aggregate exposure to C.I. Pigment Yellow 1 used at 10% concen tration in seed treatment formulations with chronic dietary exposure estimated to be 0.4% c PAD for the general
U

. S

. population

.

2. Infants and children

. The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safet y factor may be reduced or removed.

Based on available information discussed herein, Clariant, Inc. requests reduction of the FQPA safety factor to IX and that the additional tenfold safety factor for the protection of infants and children be removed. As described above the default 10X FQPA safety factor may be reduced to IX, and the cRfD is the refore equivalent to the
cPAD

. • The availability of a scientifically sound and robust mammalian toxicology database that includes acute, subchronic, and genotoxi city data. These test data did not result in adverse developmental, reproductive or neurological endpoints

or genotoxic effects.8

• Soil application and physicochemical/environmental properties indicate that
crop residues and resultant dietary exposures are unlikely when C.I. Pigment Yellow 1 is used in seed treatment formulations at concentrations not to exceed 10% wt./wt.

• I

- DEEM modeling supports that the estimated dietary exposures to C.I. Pigment Yellow 1 (used at 10% concentration in seed treatments) for children 1

- 2 year s of age, the potentially most exposed population, is 1.4 % and thus well below 100% of the cPAD.
• C.I. Pigment Yellow 1 does not belong to a class of chemicals that is known or suspected to affect the estrogen receptor or having any adverse effects on the endocrine system.]

F. International Tolerances

There are no known international tolerances for C.I. Pigment Yellow 1

.