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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 ( 1E7893 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 346a(d), to amend 40 CFR §180.910 and 180.930 to set a maximum use-level of 

2-ethylhexanol (CAS No. 104-76-7) of 20% in pesticide formulations 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; 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 this petition is a request 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 dermal 

routes. Studies in rats and mice have LD50s 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-azaguanine 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 dominant lethal assay and an in vivo chromosomal 

aberration assay. The results of all in vitro assays except the 8-azaguinine 

resistance assay were negative and all in vivo studies were negative as well. 

The genotoxicity data clearly indicate that 2-ethylhexanol is not mutagenic.

3. Reproductive and developmental toxicity. Several reproductive and 

developmental toxicity studies have been performed with 2-ethylhexanol. 
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Cognis Corp. concluded that none 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, 

pregnant mice were gavaged with 2-ethylhexanol in corn oil at 1525 

mg/kg/day 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 defects 

(10%). No maternal effects associated with the test compound were 

reported.

The third study was conducted using microencapsulated 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 malformations 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 concentration 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. Diethylhexyl 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 

surrogate for 2-ethylhexanol.
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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 were 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 highest 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 for 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) subacute 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 

observed.

 

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. 

Mice 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. 
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B6C3F1 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 liver.

 

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 peroxisomes. 

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 increased 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 

higher. 

5. Chronic toxicity. Carcinogenicity studies in both rats and mice were 

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

ethylhexanol at doses 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-related 

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 study, 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 piloerection. 

Increased mortality occurred in females at 500 mg/kg/day. No increase in 
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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 [14C]ethylhexanol to rats, about 81% of the radioactivity was 

recovered in the urine, about 6% was recovered in the air as CO2, 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 and 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 there 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, without 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 Effects

There is no evidence that 2-ethylhexanol shares a common mechanism of 

toxicity with any other pesticide active and/or inert ingredient. 
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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-

ethylhexanol 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

There are no Codex MRLs established for 2-ethylhexanol.