1

EPA REGISTRATION DIVISION

– COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
EPA Registration Division Contact: P.V. Shah, Ph.D., 703

- 308

- 1846

Cognis Corporation PP: 7E7893
EPA has received a pesticide petition ( 1E7 893 from Cognis Corporation, c/o Lewis & Harrison LLC, 122 C Street NW, Suite 740, Washington DC 20001, proposing pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA ), 21 USC 346 a (d), to amend 40 CFR § 180.9 10 and 180.930 to se t a maximum use

- level of 2

- ethylhexanol (CAS No. 104

- 76

- 7) of 20% in pesticide formulation s as an inert ingredient

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; howev er, 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 this petition is a requ est for an exemption from the requirement of a tolerance , no residue data is being submitted and an analytical method for plant residues is not required.

B. Toxicological Profile

1. Acute toxicity. 2

- ethylhexanol is of low acute toxicity by the oral and de rmal routes . Studies in rats and mice have LD 50 s ranging from 2000 to 6400 mg/kg body weight. 2

- ethylhexanol is moderately irritating to the skin and severely irritating to the eye.

2. Genotoxicity . Numerous genotoxicity studies have been conducted with 2

- ethylhexanol , including five (5) Ames tests, an in vitro cell transformation assay, an 8

- a zaguanine resistance assay, a mouse micronucleus test, a mouse lymphoma assay, a Rec

- assay, a CHO mutation assay, an unscheduled DNA synthesis assay, an in vivo do minant lethal assay and an in vivo chromosomal aberration assay. The results of all in vitro assays except the 8

- a zaguinine resistance assay were negative and all in vivo studies were negative as well

. The genotoxicity data clearly indicate that 2

- ethylh exanol is not mutagenic

.

3. Reproductive and developmental toxicity

. Several reproductive and developmental toxicity studies have been performed with 2

- ethylhexanol

.2 Cognis Corp. concluded that n one of the studies showed any developmental or reproductive toxicity associated with 2

- ethylhexanol , even at high dose levels.

. By the oral route, four studies have been identified. In the first study, p regnant mice were gavaged with 2

- ethylhexanol in corn oil at 1525 mg/kg/da y over gestation days (GD) 6 through 13. Control mice were gavaged with corn oil, and dams were allowed to litter. Administration of 2

- ethylhexanol caused statistically significant decreased maternal body weight gain, decreased number of viable litters, decreased liveborn per litter, decreased percentage survival of pups and decreased birth weight and weight gain for pups.

In the second oral study, pregnant rats were gavaged with 2

- ethylhexanol at approximately 800 and 1600 mg/kg bw (6.25 or 12.5 mmol/kg bw) on GD 12. On GD 20 the rats were killed. Following cesarean section implantation sites were determined in situ and the number of dead or resorbed fetuses was determined. Live fetuses were removed and examined; internal and external soft tissue and skeletal malformations were recorded. At the high dose, statistically significant effects were seen in the live fetuses. These effects include hydronephrosis (8%), tail defects (5%), and limb de fects (10%). No maternal effects associated with the test compound were reported.

The third study was conducted using m icroencapsulated 2

- ethylhexanol provided to mice on GD 0 to 17 at 0, 90, 300 or 900 ppm in feed. These doses are equivalent to 0, 13.5 , 45.0, or 135 mg/kg/day. At sacrifice (GD 17) the number of ovarian corpora lutea and uterine implantation sites, including resorptions, and dead or live fetuses, were recorded. Live fetuses were sexed and examined for external, visceral and skeletal ma lformations and variations. There were no treatment

- related changes in the incidence of individual, external, visceral, skeletal or total malformations or variations. Therefore , the study showed that 2

- ethylhexanol did not cause any developmental toxic effects throughout gestation at a co ncentration up to 135 mg/kg/day.

The fourth study was the results of a surrogate chemical for assessing the reproductive toxicity of 2

- ethylhexanol. The study was referenced in a submission to USEPA in 2003

. Diethylh exyl adipate (DEHA; the diester of adipic acid with 2

- ethylhexanol) is known to be well absorbed by rodents and primates and rapidly converted (both in the gut and after systemic absorption) to 2

- ethylhexanol and adipic acid so DEHA is an appropriate

surro gate for 2

- ethylhexanol.3 In a one

- generation reproduction study, groups of Wistar

- derived rats (15 males/dose; 30 females/dose) were administered DEHA in their diets at a level of 0, 28, 170 or 1080 mg/kg/day. After 10 weeks on the diet, the animals wer e mated to produce one

- generation of offspring that was reared to day 36 post partum. Test substance was administered continuously throughout the study (approximately 1

- 19 weeks of exposure). No effects were seen on male or female fertility. At the high est dose, however, there was a reduction in the body weight gain of the dams during gestation; an increase in liver weight in both male and female parents; and reductions in offspring weight gain, total litter weight and litter size. The NOAEL and LOAEL f or this study were also 170 and 1080 mg/kg/day DEHA (about 120 and 760 mg/kg/day 2

- ethylhexanol ), respectively. The results of the study show that DEHA administration to male and female rats did not interfere with fertility, even at parentally toxic doses

.

4. Subchronic toxicity . Eleven (11) s ubacute and subchronic studies have been performed with 2

- ethylhexanol . All the studies show that repeated exposure to 2

- ethylhexanol has low potential for toxicity. The major target organ for 2

- ethylhexanol is the liver with peroxisome proliferation as the major hepatic endpoint. The subchronic studies are summarized below.

Mice were fed 2

- ethylhexanol in their diet at a dose of approximately 1500 mg/kg for four days. Increases in hepatic peroxisomes were obs erved.

Rats (strain unspecified) were fed 0
, 100
, 500
, 2500 or 12,500 ppm 2

- ethylhexanol for 13 weeks. The highest dose is about 650 mg/kg/day. There were no significant effects on mortality, body weights, food consumption or kidney weights. Histopathological lesions included cortical degeneration in the kidneys of the high dose male rats, focal liver congestion or swelling in the high dose female rats. No effects were observed in the 2500 ppm group.

M ice were gavaged with 0
, 143
, 351
, 702
, 1053 or 1755 mg/kg of 2

- ethylhexanol for 14 days. A significant increase in liver weight and number of hepatic peroxisomes were observed at 702 mg/kg and higher.

F344 rats were gavaged with 0
, 25
, 125
, 250 or 500 mg/kg 2

- ethylhexanol 5 days/week for 13 weeks. Body weights were decreased in the high

- dose group of both sexes. Relative liver, kidney, and stomach weights were increased at 250 and 500 mg/kg. Gross pathological examination revealed forestomach lesions in the 500 mg/kg animals and peroxisome proliferation in the liver.4 B6C 3F1 mice were gavaged with 0
, 25
, 125
, 250 or 500 mg/kg/day for 13 weeks. At 500 mg/kg/day the only effects seen in the mouse were increased relative stomach weights in males and a low incidence of gross and microscopic findings in the forestomach and liv er.
Rats gavaged with 1,350 mg/kg of 2

- ethylhexanol for seven days showed increased liver weights and liver peroxisomes.

Rats fed 2.0% 2

- ethylhexanol (approx. 1,000 mg/kg) in their diet for 14 days showed no significant effects on peroxisome enzymes. However, in another dietary study where rats were also fed 2.0% 2

- ethylhexanol in their diet (approx. 1000 mg/kg) but for 21 days, a number of effects were noted including: decreased serum lipids, increased liver weights, and an increase in liver peroxis omes.
Rats were gavaged with 2

- ethylhexanol at a dose of 130 mg/kg/day for 14 days. No significant effects were seen on the testes, serum lipids, and various liver endpoints, including peroxisome proliferation.

Rats were gavaged with 100
, 320 or 950 mg/kg of 2

- ethylhexanol for five days/week for 28 days. Liver weights and liver peroxisomes were significantly i ncreased at 320 and 950 mg/kg.

Rats were gavaged with 0
, 143
, 352
, 702 or 1053 mg/kg of 2

- ethylhexanol for 14 days. A significant increase in liver weight and number of hepatic peroxisomes were observed at 702 mg/kg and h igher.

5. Chronic toxicity

. C arcinogenicity studies in both rat s and mice were conducted

. In the mouse study
, male and female mice were gavaged with 2

- ethylhexanol at dose s of 0, 50, 200 or 750 mg/kg/day for eighteen (18) months. No substance

- related changes were seen at 50 or 200 mg/kg/day. At 750 mg/kg/day, reduced body weight gain related to decreased food consumption and increased mortality was noted. Treatment

- relat ed hematological changes were seen, and slight but not statistically significant increases were noted in focal hyperplasia of the epithelium of the forestomach. No statistically significant increases in tumor incidence were noted In the rat s tudy
, male and female rats were gavaged five days/week for 24 months at 0, 50, 150 or 500 mg/kg/day. Dose

- related reduced body weight gain was noted at 150 mg/kg/day and higher. Clinical findings included poor general condition, labored breathing, and piloere ction. Increased mortality occurred in females at 500 mg/kg/day. No increa se in5 tumor incidence was noted. Based on the results of the rat and mice studies it can be reasonably concluded that 2

- ethylhexanol is not carcinogenic.

6. Animal metabolism . The metabolic fate of 2

- ethylhexanol has been studied in rats and rabbits. It is readily converted to 2

- ethylhexanoic acid, which can be oxidized to a hydroxyl acid and a diacid. Within 28 hours following a single oral dose of [ 14 C]ethylhexanol to rats, abou t 81% of the radioactivity was recovered in the urine, about 6% was recovered in the air as CO 2 , and about 8% was in the feces. The chief metabolites in the urine were 2

- ethylhexanoic acid, 2

- ethylhexanoic acid glucuronide, 2

- ethyl

- 1,6

- hexanedioic acid an d 2

- ethyl

- 5

- hydroxyhexanoic acid. In the rabbit given an oral dose of 2

- ethylhexanol , the major urinary metabolite was 2

- ethylhexanoyl glucuronide; 2

- ethyl

- 2,3

- dihydroxyhexanoic acid and a trace of unmetabolized 2

- ethylhexanol were also present.

7. Metabolite toxicology . There are no metabolites of concern.

8. Endocrine disruption

. Based on the existing safety data base t here is no evidence that 2

- ethylhexanol causes endocrine disruption.

C. Aggregate Exposure

1. Dietary Exposure : The proposed increase in the maximum concentration of 2

- ethylhexanol from 2.5% to 7.0%
, when used in pesticide products applied pre
- and post

- harvest and to animals
, should only minimally raise dietary exposure since 2

- ethylhexanol

can currently be used in herbicides, with out a concentration limit of 20% , on all food crops. In addition, 2

- ethylhexanol is found naturally in the environment and has been identified as a plant volatile in a number of fruits including cassava, apricots plums, apples and nectarines.

2. Non

- Dietary Exposure : The Agency previously determined that the aggregate exposure (dietary and non

- dietary) to 2

- ethylhexanol was acceptable. Since this petition does not involve any increase in non

- dietary exposure to 2

- ethylhexanol there is no need to assess this exposure , as pertains to this petition.

D. Cumulative E

ffects

There is no evidence that 2

- ethylhexanol shares a common mechanism of toxicity with any other pesticide active and/or inert ingredient.6

E. Safety Determination

1. U.S. Population

- The available safety data clearly establish that: (i) 2

- ethylhexanol is of low acute toxicity by the oral and dermal routes ; (ii) in subchronic repeat dose studies, hepatic effects were observed only at high dose levels; (iii) based on long

- term bioassays in the mouse and rat
, 2

- ethylhexanol is not carcinogenic ; (iv) there is no evidence that 2

- ethylhexanol is neurotoxic or immunotoxic; (v) 2

- ethylhexanol is not mutagenic in the standard battery of in vitro and in vivo tests ; (vi) 2

- ethylhex anol is not a developmental or reproductive toxin. Cognis Corp. concluded that there is a reasonable certainty that no harm will result to the general population from the proposed increase in concentration of 2

- ethylhexanol in pesticide products applied pre
- and post

- harvest and to animals

.

2. Infants and Children

– Based on an extensive safety data base for 2

- ethylhexanol there is no evidence that 2

- ethylhexanol presents any increased or unique risks to infants and children. Cognis Corp. concluded that there is a reasonable certainty that no harm will result to infants and children from the proposed increase in concentration of 2

- ethylhexanol in pesticide products applied pre
- and post

- harvest and to animals

.

F. International Tolerances

Th ere are no Codex MRLs established for 2

- ethylhexanol.