Document ID: EPA-HQ-OPP-2012-0585-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-27T05:00Z

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

EPA Registration Division contact: [Mark Dow (703) 305-5533]

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 replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

Pennzoil-Quaker State Company 

[2E8049]

	EPA has received a pesticide petition ([2E8049]) from Pennzoil-Quaker State Company, 700 Milam Street, Houston, TX 77002 c/o Wagner Regulatory Associates, 7217 Lancaster Pike, Suite A, Hockessin, DE 19707  proposing, 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 180.910 to establish an exemption from the requirement of a tolerance for Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear, CAS No. 848301-69-9 when used as an inert ingredient in pesticide formulations as a solvent, diluent and dust suppressant without limitations in pesticide formulations.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FFDCA; 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 the petition.

A. Residue Chemistry

Because an exemption from the requirement of a tolerance is requested, no field residue studies are required.

	1. Plant metabolism. "NA-Remove"

	2. Analytical method. "NA-Remove"
 
	3. Magnitude of residues. "NA-Remove"
 
B. Toxicological Profile

	1. Acute toxicity.  This substance was tested in an acute oral toxicity study according to the fixed dose method (OECD 420). Following a preliminary test in which there were no deaths at a dose level of 5000 mg/kg, an additional four fasted Sprague-Dawley DC strain rats received a dose of 5000 mg of the undiluted test material per kg body weight by gavage. There were no signs of toxicity, all animals showed normal gains in body weight, and there were no abnormalities on necropsy. The acute oral LD50 was therefore >5000 mg/kg.  In a dermal irritation study with rabbits (OECD 404), this substance was non-irritating at all time points of 24, 48 and 72 hours following application.  In an eye irritation study with rabbits (OECD 405), this substance was non-irritating at all time points of 24, 48 and 72 hours following application.  In a skin sensitization study in guinea pig (OECD 406), this substance was found not sensitizing to the test animals skin.

	2. Genotoxicty. This substance has been tested in a bacterial mutagenicity study (OECD 471) using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and Escherichia coli WP2 uvrA.. The test material was dissolved in tetrahydrofuran at concentrations up to 5000 ug/plate. Appropriate solvent and positive controls were included and gave expected results. No toxicity to bacterial cells was observed. No significant increase in the number of revertants was observed at any concentration with and without metabolic activation in any of the strains tested. The results were confirmed in a repeat experiment; both experiments used the direct plate incorporation method.

An in vitro micronucleus study has been conducted (OECD draft guideline 487). No increase in the incidence of micronuclei was observed in duplicate cultures of human lymphocytes at any concentration in either the initial experiment (4 hour exposure, 16 hour expression, with and without metabolic activation) or the repeat experiment (20 hour exposure without metabolic activation; 4 hour exposure, 16 hour expression, with metabolic activation). No test material induced toxicity was observed.

Further evidence of the lack of effects on chromosomes in vitro was obtained when tested according to OECD 473. No statistically significant increase in the frequency of cells with chromosome aberrations was observed in either the initial or the repeat experiment when tested with and without metabolic activation up to a dose level that was limited by the onset of precipitate. Appropriate solvent and positive controls were included and gave expected results.

	3. Reproductive and developmental toxicity. 
 
In a two-generation reproductive toxicity study, this substance [0 (vehicle), 50, 250, or 1000 mg/kg/day)] was given orally to F0 and F1 parental male and female rats for at least 70 days prior to mating and throughout the 14-day mating, post mating holding (for males), and gestation and lactation (for females) periods. There was a test item-related, non-adverse decrease in anogenital distance in F1 females born from dams given 250 and 1000 mg/kg/day. Test item-related histopathological lesions were identified in the lungs (chronic interstitial/alveolus inflammation) of both males and females of the F0 and F1 generations with corresponding macroscopic findings and/or increased lung weights and the kidneys (renal tubule hyaline droplets likely representing α2μ-globulin) of the F1 males only. The lung lesions were most likely secondary to aspiration of the test material and therefore not relevant for human risk assessment. The renal effects are a well-known male rat specific effect which is induced by hydrocarbons and has no relevance for humans. An equivocal, non-adverse slight decrease in F2 pup brain weights was noted. Based on the absence of adverse, test item-related findings on the integrity and performance of the male and female reproductive systems, the absence of adverse findings directly attributable to the test item in non-reproductive tissues, and the absence of adverse effects on in-life parameters (such as body weight, feed consumption, and clinical observations), the dosage level of 1000 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive and systemic toxicity.

Administration of this substance in a two- generation reproductive toxicity study in male and female rats at dosages up to 1000 mg/kg/day had no effect on reproductive performance or gestation length and parturition of both the F0 and F1 parental generations.  Andrology parameters for F0 and F1 males were unaffected by test item administration. In addition, there were no test item-related effects on F1 and F2 litter parameters, postnatal survival, physical condition/mortality, and pup body weights. Vaginal patency of F1 females and balanopreputial separation in F1 males were also unaffected by test item administration. Based on the absence of adverse test item related findings, the top dose of 1000 mg/kg/day was considered to be a NOAEL for developmental toxicity.

	4. Subchronic toxicity. The oral administration of this substance to rats for a period of ninety consecutive days at dose levels of 50, 200 and 1000 mg/kg/day in an OECD 408 study resulted in treatment-related effects in animals of either sex treated with 1000 and 200 mg/kg/day. The "no observed effect level" (NOEL) was considered to be 50 mg/kg/day. However the effects detected at 200 and 1000 mg/kg/day in the lungs and mesenteric lymph nodes were considered to be secondary to aspiration following the oral gavage and a normal response of the lymph nodes clearing the material, respectively, and were therefore not considered to be an adverse effect of treatment.  The "No Observed Adverse Effect Level" (NOAEL) was therefore considered to be 1000 mg/kg/day.

Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear are made up of linear, cyclic and branched alkanes.  Animal studies on a variety of linear, branched and cyclic alkanes have shown that these substances are not neurotoxic with the exception of n-hexane due to its metabolism to 2,5-hexadione.  However, distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear do not contain n-hexane and cannot be metabolized to its neurotoxic metabolites.  Furthermore, acute toxicity tests with very high doses (i.e. 5000 mg/kg body weight in the rat) of distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear did not produce any neurotoxicity.  Also neurotoxic effects were not observed in 28-day and 90-day studies.  

	5. Chronic toxicity. There is no evidence to suggest that linear, branched and cyclic alkanes present in this substance are direct-acting carcinogens. No evidence of hyperplasia or any other histopathological indications for effects related to carcinogenicity were seen in any of the available repeated-dose toxicity studies conducted for this substance and the available data indicates that this substance is not genotoxic.

	6. Animal metabolism. Due to their complex, multi-constituent nature, there are no substance-specific absorption, metabolism, distribution and excretion studies done specifically with distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear. However, studies with various complex mixtures of normal, branched and cyclic petroleum derived hydrocarbons show that absorption is inversely correlated with carbon chain length and independent of isomeric form, preparation process, or type of product. Constituents with carbon chain lengths up to approximately C30-C35 are absorbed through the gastro-intestinal tract for 2-20%.  However, when present as mineral oil hydrocarbons of higher molecular weight, corresponding to approximate chain lengths greater than C32-C35 are not absorbed to any significant extent.  For distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear, the majority of the constituents are of carbon chain lengths ranging from C27-C50 and are likely to be excreted, unabsorbed, in the feces.

	7. Metabolite toxicology. [No data is available]

	8. Endocrine disruption. Administration of this substance in a two- generation reproductive toxicity study in male and female rats at dosages up to 1000 mg/kg/day had no effect on the integrity and performance of reproductive systems or gestation length and parturition of both the F0 and F1 parental generations.  Andrology parameters for F0 and F1 males were unaffected by test item administration. In addition, there were no test item-related effects on F1 and F2 litter parameters, postnatal survival, physical condition/mortality, and pup body weights. Vaginal patency of F1 females and balanopreputial separation in F1 males were also unaffected by test item administration. Based on the absence of adverse test item related findings, the top dose of 1000 mg/kg/day was considered to be a NOAEL for reproductive and developmental toxicity. Therefore within the parameters of this study no harmful effects were observed on reproduction, development or overall health resulting from the interaction of distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear with the test animal hormone system.

C. Aggregate Exposure

	1. Dietary exposure. Dietary exposure has been assessed using the EPA I-DEEM model (Inert Dietary Exposure Evaluation Model). 

	i. Food. The I-Dietary Exposure Evaluation Model (DEEM) is a highly conservative model with the assumption that the residue level of the inert ingredient would be no higher than the highest tolerance for a given commodity.  Implicit in this assumption is that there would be similar rates of degradation between the active and inert ingredient (if any) and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentration of the active ingredient. The model assumes 100 percent crop treated (PCT) for all crops (every food eaten by a person each day has tolerance level residues.)

	ii. Drinking water. For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear, a conservative drinking water concentration value of 100 parts per billion (ppb) based on screening level modeling was used to assess the contribution to drinking water for the chronic dietary risk assessments for parent compound. These values were directly entered into the dietary exposure model.

	2. Non-dietary exposure. Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear are not currently used as inert ingredients in pesticide products that are registered for any use patterns that involve residential uses nor are there any other non-pesticidal residential uses for these inert ingredients, thus no residential exposures are expected. 

D. Cumulative Effects

	No information is available to indicate that Distillates (Fishcher-Tropsch), heavy, C18-C50 branched, cyclic and linear share a common mechanism of toxicity with any other substances and that it does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, it is assumed that Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear does not have a common mechanism of toxicity with other substances.

E. Safety Determination

In a 90-day repeated dose oral (gavage) toxicity study in the rat (OECD Guideline 408 and EPA 870.3100), animals were administered doses of the substance at 0, 50, 200, and 1000 mg/kg/day. Treatment-related effects in the lungs and mesenteric lymph nodes were seen at 200 and 1000 mg/kg/day dose levels, but the effects were considered to be adaptive and not to be an adverse effect of treatment. As such, the no observable effect level (NOEL) was considered to be 50 mg/kg/day, but the no observable adverse effect level (NOAEL) was considered to be 1000 mg/kg/day. 

In a 2-generation reproduction study in rats dosed by oral gavage at 0, 50, 250, and 1000 mg/kg/day, the systemic NOAEL was 1000 mg/kg/day.  Therefore, the overall NOAEL for repeat dose exposures to distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear is taken to be 1000 mg/kg/day.  Dividing the NOAEL by an uncertainty factor of 100 to account for inter- and intra-species variability, the chronic reference dose (cRfD) is therefore 10 mg/kg/day. 

Finally, the chronic population adjusted dose is calculated by dividing the cRfD by the FQPA factor, which is assumed to be 1X for Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear.  An additional FQPA factor (10X) is not required because effects do not tend to become more severe with higher doses and an adequate and reliable toxicity database is available.

The dietary exposures (food plus drinking water) for Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear are expressed as a percentage of the proposed aPAD and cPAD for the general U.S. population and children 1-2 years old, the most highly exposure subpopulation.  

	1. U.S. population. Based on I-DEEM screening level calculations, chronic dietary exposures are estimated to be 1.9% of the cPAD for the general U.S. population and acute dietary exposures are estimated to be 1.1% of the aPAD for the general U.S. population. These estimates demonstrate that the I-DEEM screening-level chronic and acute dietary exposure estimates (food plus drinking water) are below the cPAD and aPAD and are therefore below the level of concern for the general U.S. population. The screening-level exposure calculations reflect the default assumption of up to 50% inert ingredient in the pesticide product and, as such, reflect no concentration limit on distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear in formulated pesticide products.

	2. Infants and children. Based on I-DEEM screening level calculations, chronic dietary exposures are estimated to be 6.2% of the cPAD for children 1-2 years old and acute dietary exposures are estimated to be 3.3% of the aPAD for children 1-2 years old.  These estimates demonstrate that the I-DEEM screening-level chronic and acute dietary exposure estimates (food plus drinking water) are below the cPAD and aPAD and are therefore below the level of concern for infants and children. 

F. International Tolerances

	No international tolerances have been established for Distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic and linear.