


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]

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:

[United Phosphorus, Inc.]

[IN-10626]

	EPA has received a pesticide petition (IN-10626) from [United Phosphorus, Inc.], [630 Freedom Business Center, Suite 402 King of Prussia, PA  19406] 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 1,1'-iminodiproan-2-ol (diisopropanolamine; DIPA; CAS No. 110-97-4) under 40 CFR 180.910 when used as an inert ingredient (neutralizer or stabilizer) in a pesticide formulation at no more than 10% by weight of the formulation.  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

	1. Plant metabolism.  [NA-Remove based on the fact that this information
is generally not required for the establishment of a tolerance exemption.]

	2. Analytical method. [The petition proposes to establish exemptions from the requirement of a tolerance and no analytical method is generally required for establishment of a tolerance exemption.]

	3. Magnitude of residues. [NA-Remove based on the fact that this information
is generally not required for the establishment of a tolerance exemption.]


B. Toxicological Profile

DIPA is widely used as an emulsifier, stabilizer, neutralizer, surfactant, and chemical intermediate.  The major uses of DIPA are as a scavenger for carbon dioxide and hydrogen sulfide in the purification of natural gas, and as a pH adjuster or as an emulsifier or viscosity modifier in personal care products (cosmetics, tanning solutions, soaps, detergents).  DIPA belongs to the general class of alkanolamines which typically exhibit low acute oral and dermal toxicity, but also display eye and skin irritancy.  EPA has already reviewed and granted 40 CFR 180.910 and 40 CFR 180.920 tolerance exemptions for other similar alkanolamines.  DIPA is approved for use in non-food use pesticide formulations without limitations. 

Some toxicity data for DIPA has been considered by EPA previously when establishing the exemption from requirement of a tolerance for TIPA (triisopropanolamine; 40 CFR 180.910).  TIPA and Monoisopropanolamine (MIPA) data were considered in some cases as surrogate data for DIPA.

	1. Acute toxicity.  [DIPA and its surrogate TIPA have low acute oral and dermal toxicity.  The oral and dermal LD50s for DIPA are >2000 mg/kg and >8000 mg/kg, respectively.  The oral and dermal LD50s for TIPA are both >5000 mg/kg. Both are dermal and eye irritants.  Neither DIPA nor TIPA are dermal sensitizers in the guinea pig.  Based on the acute LD50 values, no acute reference dose is needed for risk assessment. ]

	2. Genotoxicty. [Multiple genotoxicity studies have been conducted on DIPA and its surrogates MIPA and TIPA.  Four in vitro genotoxicity studies are available on DIPA:  a gene mutation test in CHO cells, two Ames Salmonella assays and a chromosomal aberration test using rat hepatocytes.  All four studies were negative.  MIPA was tested in two Ames Salmonella studies.  It was clearly negative in one of the studies, but positive in TA1535 in the second study.  The positive finding in TA1535 was not reproducible in two out of four assays.  An Ames Salmonella assay, in vitro chromosomal aberration using rat hepatocytes, a HGPRT gene mutation assay using Chinese hamster ovary cells and a micronucleus test in the mouse were conducted on TIPA.  TIPA was negative in all four assays.  DIPA, MIPA and TIPA have no or very little genotoxicity potential.]

	3. Reproductive and developmental toxicity. [A reproduction study was not available on DIPA.  In a one-generation rat reproduction study, TIPA administered up to a dose of 609 mg/kg/day in males and 700 mg/kg/day in females did not results in any parental, reproductive or offspring toxicity.  TIPA was not a reproductive toxicant under the conditions of this study.

A developmental toxicity study was conducted on DIPA in the rat at dose levels of 0, 100, 300 or 1000 mg/kg.  The NOAEL was 1000 mg/kg for both maternal and developmental toxicity.   A developmental toxicity study was also conducted on the surrogate TIPA in the rat.  The NOAEL for maternal toxicity was 400 mg/kg based on decreased body weight gain and food consumption.  The NOAEL for developmental toxicity was 1000 mg/kg, the highest dose tested.  Neither DIPA nor TIPA are developmental toxicants.

Given the low developmental toxicity and the lack of developmental effects, an FQPA Safety Factor of 1X is proposed for DIPA.]

	4. Subchronic toxicity. [Subchronic toxicity studies have been conducted on DIPA and its surrogates MIPA and TIPA.  Fourteen-day and 90-day repeated dose toxicity studies have been conducted on DIPA in rats.  The NOAEL in the 14-day study was 600 mg/kg/day based on slightly reduced food and water consumption, decreased body weight gain in males and increased kidney weights observed at 1200 mg/kg/day.  Based on effects on clinical chemistry parameters at 500 and 1000 mg/kg/day, the NOAEL in the 90-day study for males is 100 mg/kg/day.  The NOAEL for females was 500 mg/kg/day based on higher urine specific gravity observed at 1000 mg/kg/day.  The NAOEL of 100 mg/kg/day from the 90-day repeat dose study is used to propose the chronic reference dose for risk assessment.

Fourteen-day (rat) and 90-day (rat and dog) repeated dose toxicity studies have been conducted on TIPA.  The NOAEL in the 14-day study was 100 mg/kg/day based mild effects on glucose levels and effects on kidney weights, which were not accompanied by any microscopic findings in the kidney, observed at 300 mg/kg/day in males.  The NOAEL in the 90-day rat study was 609/700 mg/kg/day, the highest dose tested.  There were no treatment-related effects observed in the 90-day dog study.  The NOEL was the highest dose tested, 7500 ppm equivalent to 272 mg/kg/day for male dogs and 288 mg/kg/day for female dogs

In a 28-day dermal toxicity study in the rat, DIPA was tested at dose levels of 0, 100, 500 or 750 mg/kg/day.  The NOAEL for systemic effects was the highest dose tested or 750 mg/kg/day.  The NOAEL for dermal effects was 100 mg/kg/day based on very slight to slight erythema observed at the test site at 500 mg/kg/day.  In a 28-day dermal toxicity study in the rat, the systemic NOAEL was the highest dose of TIPA tested, 3000 mg/kg/day which higher than the limit dose for studies of this type.  Neither DIPA nor TIPA was not dermally toxic systemically after repeated dosing.

A two-week inhalation study was conducted on MIPA in rats and mice.  No effects were observed up to a concentration of 75 ppm.]

	5. Chronic toxicity. [Limited carcinogenicity studies were conducted on DIPA and TIPA.  Only one dietary level (1%) of DIPA and TIPA (2%) was tested.  DIPA and TIPA did not increase the incidence of any tumor type under the conditions of these studies.  TIPA is not listed by ACGIH, IARC, NTP, or CA Prop 65.]

	6. Animal metabolism. [In the rat, DIPA was rapidly eliminated after i.v. administration and found primarily in the urine unchanged.  Dermally applied DIPA was slowly absorbed with a total absorption of 12% and was found unchanged in the urine, the primary route of excretion.  Orally administered TIPA was rapidly and extensively absorbed; a minimum of 83%.  Virtually all was rapidly excreted primarily as unchanged TIPA in the urine.]

	7. Endocrine disruption. [There is no information available that links DIPA or its surrogates MIPA and TIPA to direct effects on the endocrine system.  TIPA is not compatible with direct endocrine activity on the basis of structural activity relationships.  In addition, there is no histopathological or behavioral evidence of an endocrine function in any toxicity evaluations of TIPA or its close analogue (DIPA) conducted in laboratory animals.  The TIPA one-generation toxicity study conducted in rats included pre-mating, mating period, gestation, lactational and post-lactation dosing.]

C. Aggregate Exposure

	1. Dietary exposure. [Based on the low acute toxicity, no acute reference dose is established.  Based on the 90-day studies for DIPA the following is proposed: chronic oral cRfD (chronic reference dose) and chronic population-adjusted dose (cPAD) is 1 mg/kg/day based on the NOAEL of 100 mg/kg bw/day assuming a standard 100X uncertainty factor for inter- and intra-species variability and an FQPA safety factor of 1X.]

      i. Food. [An assessment based on the EPA Inert's Branch dietary exposure model I-DEEM could be conducted.  I-DEEM uses a screening level dietary assessment of 57 of the most "significant" active ingredients as surrogates for inerts within the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 2.14).  Exposure from food, animal commodities and drinking water are included.  It is expected that based on the proposed cRfD, exposure to DIPA from food, animal commodities and drinking water would be well below the proposed cPAD for the general US population and all subpopulations.]

      ii. Drinking water. [Drinking water estimates have been included in the I-DEEM model.]

      2. Non-dietary exposure. [No exposure to DIPA is expected through residential pesticidal products.  Some exposure to DIPA from non-pesticide uses may occur via coatings of paper, personal care products, lubricants, pigments, or plastics.]

D. Cumulative Effects

	[For the purposes of this tolerance action, it is not assumed that DIPA has a common mechanism of toxicity with other substances.]

E. Safety Determination

      1. U.S. population. [For the general population, the estimated exposure is expected to be well below the cRfD.]

      2. Infants and children. [No increased sensitivity is noted for the young; an FQPA Safety Factor of 1X is proposed based on reproductive and developmental toxicity results for DIPA and the related compounds TIPA and MIPA as well as registration decisions for TIPA-herbicide salts which indicate no developmental or reproduction concerns.  Estimated exposure for children is expected to be well below the proposed cPAD.]

F. International Tolerances

	[There are no known CODEX or international tolerances or tolerance exemptions established for DIPA.]

