

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

EPA Registration Division contact: P.V. Shah, 703-308-1846

BASF CORPORATION

PP IN-11023

	EPA has received a pesticide petition (IN-11023) from BASF Corporation, c/o Lewis & Harrison, LLC, 122 C Street NW, Suite 505, Washington DC 20001, 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 Poly(oxy-1,2-ethanediyl), α-(1-oxoalkyl)-ω-methoxy-, where the alkyl chain contains a minimum of 6 and a maximum of 18 carbons and the oxyethylene content is 3-13 moles (CASRN's 53100-65-5, 194289-64-0- 34398-00-0, 9006-27-3, 32761-35-6, 53467-81-5, 518299-31-5, 34397-99-4), under 40 CFR§180.910, when used as an stabilizer and solubilizing agent in pesticide formulations applied to growing crops or raw agricultural commodities after harvest.  This related group of compounds are collectively known as the Ethoxylated Fatty Acid Methyl Esters (EFAMEs).  BASF is proposing a limit of 25% EFAMEs in pesticide formulations applied to growing crops or raw agricultural commodities after harvest.  EPA has determined that the petition contains data or information regarding 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 the petition.

A. Residue Chemistry

Residue data, including an analytical method, is not pertinent or required for this petition since an exemption from the requirement of a tolerance is being requested.

B. Toxicological Profile

The safety data base for evaluating the potential human health effects for the EFAMEs is available.  The safety data base includes acute toxicity and genotoxicity studies that were conducted with the EFAMEs.  In addition, sub-chronic, chronic, developmental and reproductive toxicity, and metabolism studies have been performed with structurally similar compounds and can be bridged to the EFAMEs.  

 Acute toxicity

The EFAMEs exhibit low toxicity via the oral and inhalation routes. In addition, the EFAMES are not an eye irritant and slightly irritating to skin.  The skin sensitization data was equivocal. The results from the individual acute toxicity studies are described below.



 Acute oral toxicity
The acute oral LD50 of the EFAMEs is greater than 5,000 mg/kg-bw in the rat. 

 Acute inhalation toxicity.
In an acute inhalations study in the rat, the acute LC50 for the EFAMEs is greater than 15.7 mg/L.
 Acute eye irritation.
Based on results from both in vivo and in vitro studies, the EFAMEs are not considered to be an eye irritant.
 Acute skin irritation.
Based on the results of the skin irritation study, the EFAMEs can be considered a slight skin irritant.
 Skin sensitization
Since the test results for the EFAMEs were equivocal, it was concluded that no determination could be made regarding the dermal sensitization potential of these compounds.

 Genotoxicity

No mutagenic effects were observed for the EFAMEs and related compounds in the Ames test, in vivo micronucleus assay, and mouse lymphoma assay. Therefore, the EFAMEs are considered negative for genotoxicity.

  Repeat dose toxicity (subchronic and chronic)
Repeat-dose studies have not been conducted with the EFAMEs; however, several repeat dose studies have been conducted with fatty acid methyl/alkyl esters and alcohol ethoxylates and these studies can be bridged to the EFAMEs due to structurally similarities.

Fatty Acid Methyl/Alkyl Esters:
The fatty acid methyl/alkyl ester, methyl dodecanoate, (methyl laurate) was tested under OECD Guideline 422 (combined repeated dose and reproductive toxicity screening test).  In the study, 12 male and female Crj:CD (SD) rats, per dose level, were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal kill was on day 45 for males and on day 4 of lactation for females. The test substance showed no general toxicological effects in either sex. There were no clinical observations attributable to the administration of test substance and there was no mortality in any of the study groups. No effects were observed in terms of body weight, food consumption, hematology, blood chemistry, organ weight, necropsy or histopathological findings. Therefore, under the conditions of the study the oral NOAEL for methyl dodecanoate, after repeat dosing, is 1000 mg/kg/day in both sexes.

Fatty acid methyl/alkyl esters, methyl decanoate, methyl hexanoate, and methyl myristate (methyl tetradecanoate) were evaluated in an 84-day dietary study in rats that reported a NOEL of >300 mg/kg/day.



Another fatty acid methyl/alkyl ester, methyl hexanoate, was evaluated in a 17-week dietary study in rats exposed to 1,000, 2,500, or 10,000 ppm (~ 50, 125, or 500 mg/kg/day, respectively). The NOAEL was reported to be 10,000 ppm (~500 mg/kg/day).

C16-18 and C18 fatty acid methyl esters were evaluated in a one-year dermal study in mice.  A dose of 100 mg/kg was administered 3 times per day.  No signs of tumors were observed and the dermal NOAEL was reported to be 300 mg/kg/day.

Alcohol Ethoxylates
For the group of alcohol exthoxylates (AE), a NOAEL of 50 mg/kg/day is reported for C14-15AE in a 90-day dietary feeding study.  There are also studies with identical materials showing significantly higher NOAELs. A 90-day dietary feeding study with C14-15AE7 found a NOAEL of 785 mg/kg/day.  Most of the 90-day studies reported NOAELs ranging from 50-200 mg/kg/day.  None of the studies reported effects on the reproductive system. 

In a 104-week chronic oral feeding study  performed with the alcohol ethoxylates, C12-13AE6.5 or C14-15AE7, the NOAEL was 50 mg/kg/day. Effects observed at higher dose levels of 250 and 500 mg/kg/day were reduced food consumption and body weight gain.  At study termination, elevated organ-to-body weight ratios were noted for the liver, kidney and brain in females at the 250 and 500 mg/kg/day dose levels. These differences were not accompanied by histological changes in the organs examined. The NOAEL of 50 mg/kg/day is the lowest NOAEL observed in a chronic oral feeding study and is equal to the lowest NOAELs seen in subchronic feeding studies. 

 Reproductive and developmental toxicity.

Reproductive and developmental toxicity studies have not been conducted with the EFAMEs; however, several developmental toxicity and reproductive studies have been conducted with fatty acid methyl/alkyl esters and alcohol ethoxylates and these studies can be bridged to the EFAMEs.

The fatty acid methyl (alkyl) ester, methyl dodecanoate, (methyl laurate) (CAS 111-82-0) was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test.  12 male and female Crj:CD (SD) rats per dose were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal kill was on day 45 for males and on day 4 of lactation for females. There were no effects of the test substance on the estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, delivery index or parturition. The NOAELs for reproductive performance of males and females, as well as pup development are considered to be 1000 mg/kg/day in each case.





For the group of alcohol ethoxylates (AE), there are pertinent reproductive and developmental toxicity studies identified in the "HERA" study on household cleaning products.  None of the studies reported reproductive toxicity up to the highest dose tested, such as a feeding study for C14-15AE7 with a NOAEL for reproductive and developmental toxicity greater than 250mg/kg/day. The NOAEL for a reproductive/developmental toxicity feeding study with C12AE6 was greater than 250mg/kg/day. Based on these studies, it can reasonably be concluded that the alcohol ethoxylates do not cause reproductive toxicity and the NOAEL for reproductive toxicity is greater than 250 mg/kg/day. 

In the Agency's assessment of alkyl alcohol alkoxylates, there were two reproductive and developmental toxicity studies referenced on C14-15  alcohol ethoxylates.  In a study conducted in accordance with OECD Guideline 416, no treatment related effects were observed on reproduction or the offspring at a dose level of 250 mg/kg/day (HDT).  In the other reproductive/developmental toxicity study, the only significant effects observed in female rats were decreased body weight and body weight gain during premating at 400.8 mg/kg/day.  At this maternally toxic dose, offspring toxicity observed was decreased body weight on lactation day 21.  No treatment-related effects were observed on reproductive parameters.
         
 Carcinogenicity

No carcinogenicity studies have been conducted with the EFAMEs; however, no alerts were detected in a QSAR modeling study using a representative EFAME.  In addition, the mutagenicity studies conducted with the EFAMEs were negative.  Based on the lack of alerts in the QSAR study, the negative results in the genotoxicity studies and the lack of carcinogenicity in studies conducted with structurally similar compounds, it can be reasonably concluded that the EFAMEs do not exhibit any signals associated with carcinogenic potential.   

 Metabolism. 

No metabolism studies for the EFAMEs are available, but metabolism information can be transferred from fatty acid methyl esters and alcohol ethoxylates, as both contain comparable structure elements such as a long chain fatty acid or an ethoxylated hydroxy-group at a carbon function. 

Fatty acid methyl esters are hydrolyzed to the corresponding alcohol (methanol) and fatty acid by esterases, although it has been shown in-vitro that the hydrolysis rate of methyl oleate was lower when compared with the hydrolysis rate of the triglyceride, glycerol trioleate.  Depending on the route of exposure, esterase-catalyzed hydrolysis takes place at different places in the organism. The first cleavage products, fatty acids, are stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. The second cleavage product methanol, is slowly oxidized in the liver by the enzyme alcohol dehydrogenase  to formaldehyde, which itself is oxidized very rapidly by the enzyme aldehyde dehydrogenase to formic acid. Finally, formic acid is slowly metabolized to CO2 and H2O. 

Alcohol ethoxylates are readily absorbed in the gastrointestinal tract and rapidly excreted via the urine and feces depending on the chain length. The major degradation pathway of alcohol ethoxylates appears to be the degradation of the ether linkage and oxidation of the alkyl chain to form lower molecular weight polyethylene glycol-like materials and ultimately carbon dioxide and water. Studies with radio-labelled compounds showed that both the alkyl chain and the ethoxylate groups are sites of attack. 

Based on the above, it is assumed that the EFAMEs are also undergoing enzymatic hydrolysis which may form the fatty acid and the corresponding polyglycol ether. Both components are assumed to be degraded, with beta-oxidation forming carbon dioxide, water or water-soluble products, which were excreted via urine or feces  

 Metabolite toxicology. 

There are no metabolites of toxicological concern for the EFAMEs.

 Endocrine disruption. 
There is no information or evidence to indicate that the EFAMEs are an endocrine disruptor. None of the studies performed with the EFAMEs or related compounds have indicated any potential endocrine effects associated with the petitioned substance.

C. Aggregate Exposure

 Dietary exposure. 

Dietary (food and drinking water) exposures can occur from the use of the EFAMEs as an inert ingredient in pesticide formulations applied to growing crops. 

A quantitative dietary risk assessment for the EFAMEs was conducted using the NOEL of 50/kg-bw/day from the 104-week oral study conducted with the alcohol ethoxylates.  A Reference Dose (RfD) of 0.5mg/kg/day was calculated based by applying a 10x uncertainty factor for inter- and intra-species extrapolation to this NOEL.  The chronic Population Adjusted Dose (cPAD) is also 0.5 mg/kg/day. 

In the dietary exposure assessment, highly conservative dietary exposure estimates are derived using a dietary exposure model ("I-DEEM") developed by the Agency for food use inert ingredients. The model is based on the Agency's Dietary Exposure Evaluation Model (DEEM-FCID[(TM)], Version 3.16) for pesticide active ingredients.  I-DEEM assumes that food use inert ingredients can potentially be used, unless limitations are proposed, on all food crops.   I-DEEM uses, as a surrogate, residue data on 57 high-use agricultural pesticides.  The model generates upper bound dietary exposure estimates for a subject inert based on the highest tolerance for a given commodity from the universe of the 57 high-use agricultural pesticides.  I-DEEM assumes an inert concentration of 50%.   Since the petitioner is proposing a limitation at 25% for the EFAMEs in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest an adjustment factor of 0.5 is utilized in the dietary assessment.  
For drinking water exposure estimates, I-DEEM assumes a "worst-case" concentration of 100 parts per billion (ppb) of a food-use inert in drinking water.

Only a chronic dietary exposure estimate has been conducted for the EFAMEs since no adverse effects attributed to an acute or single exposure of the EFAMEs were apparent in the safety data base.  Therefore, an acute dietary exposure risk assessment is not necessary.

The table below shows the dietary exposure and dietary risks derived for the EFAMEs using the I-DEEM model.  The % cPAD (percent of population adjusted dose) was calculated by dividing the dietary exposure by the RfD or PAD of 0.5 mg/kg/day for the EFAMEs.  It should be noted that the dietary exposure and risk estimates are significantly overstated since I-DEEM assumes that 100% of all foods are treated with the EFAMEs and that the highest tolerance level for an active ingredient would be achieved.
  
             Summary of Dietary (Food and Drinking Water) Exposure
               and Risk for Ethoxylated Fatty Acid Methyl Esters
                                  Population
                                   Subgroup
                                 Acute Dietary
                                   Exposure
                                  (mg/kg/day)
                                     %aPAD
              Chronic Dietary Exposure (Food and drinking water)
                                  (mg/kg/day)
                                     %cPAD
                            General U.S. Population
                          No acute endpoint selected
                                     0.094
                                     18.8%
                                  All Infants
                                       
                                     0.197
                                     39.4%
                                 Children 1-2
                                       
                                     0.353
                                     70.6%
                                 Children 3-5
                                       
                                     0.242
                                     48.4%
                                 Children 6-12
                                       
                                     0.125
                                     25.0%
                                  Youth 13-19
                                       
                                     0.067
                                     13.4%
                                 Adults 20-49
                                       
                                     0.072
                                     14.4%
                                  Adults 50+
                                       
                                     0.075
                                     15.0%
                                 Females 13-49
                                       
                                     0.073
                                     14.6%

For each population subgroup, the percentage of the cPAD is less than 100.  Generally, a dietary risk estimate that is less than 100% of the cPAD does not exceed the Agency's risk concerns.  Therefore, there is a reasonable certainty that no harm will result to the U.S. population from dietary exposure to the EFAMEs.

 Food. 

As noted above, dietary exposures are well below 100% of the cPAD, and, therefore, are below EPA's established level of concern for all U.S. subpopulations. 

 Drinking water. 

Drinking water exposure has been incorporated in the food exposure estimate for the EFAMEs.  It is assumed that the "worst-case" concentration of EFAMEs in drinking water is 100 parts-per-billion (ppb).  This value yields  risk estimates that are not of concern.



D. Cumulative Effects

Cumulative effects are not expected from the use of the EFAMEs.

E. Safety Determination

 U.S. population. 

The % cPAD calculated for the general population (18.8%), is below the Agency's level of concern. Based on aforementioned conservative exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population from the aggregate exposure to the EFAMEs. 

 Infants and children.

The % cPAD calculated for infants and children (70.6%) is below the Agency's level of concern. Based on the aforementioned conservative exposure estimates, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to the EFAMEs.  The petitioner believes that the additional ten-fold safety factor noted in Section 408 of the FFDCA is not applicable for the EFAMEs since the toxicity data base is adequate and there is no evidence to suggest that the EFAMEs will cause developmental effects or have an adverse effect on reproductive organs.  Furthermore, the EFAMEs do not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. None of the studies performed with the EFAMEs or related compounds have been associated with any endocrine effects.

F. International Tolerances

There are no CODEX MRLs established for the EFAMEs.




