1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803 

Type of Review: Toxicology (Registration Review)

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 

MEMORANDUM

DATE: August 16, 2012

SUBJECT: Toxicology Scoping Document for the Registration Review of 1,4-Dimethylnaphthalene and 2,6-

Diisopropylnaphthalene.

Registration Review Case #: 6029

PC Code: 055802 and 055803

CAS #: 571-58-4 and 24157-81-1

Chemical Class: Biochemicals

FROM: Angela L. Gonzales, Biologist

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P)

TO: Leonard Cole, Senior Regulatory Specialist

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P)

ACTION REQUESTED

The following scoping document contains the human health assessment for the biopesticides 1,4-

dimethylnaphthalene (1,4-DMN) and 2,6-diisopropylnaphthalene (2,6-DIPN) in support of the

development of the Registration Review Work Plan. 

Executive Summary

Based on the available data and information, the Agency does not foresee the need for new data or for new risk 

assessments for 1,4-DMN and 2,6-DIPN. Hazard and exposure information as well as Agency risk assessments 

on these chemicals were evaluated against current safety standards established by the Agency’s scientific 

policies and regulations and it was determined that there is no need to conduct additional risk assessments. The 

active ingredients are either naturally occurring or functionally identical to naturally occurring plant growth 

regulators, have a non-toxic mode of action, and are of low toxicity. There is reasonable certainty of no harm to 

the general population from exposure to these chemicals in pesticide products when they are used according to 

label instructions. 

I. Background
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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1,4-Dimethylnaphthalene

As a pesticide, 1,4-DMN is used to prolong the storage-life of potatoes. The active ingredient is a plant growth 

regulator which works via suppression of sprout formation and is applied to potatoes during storage and 

shipping. 1,4-DMN naturally occurs in potatoes at high enough concentrations to prevent sprouting; however, 

under suitable conditions there is a decrease of the chemical in potatoes and sprouting occurs. (1,4-

Dimethylnaphthalene Fact Sheet, 2001)

The chemical was first registered by the Agency in 1994. There are currently four registered products 

containing the active ingredient. One of these products is a manufacturing-use product (MP); the remaining 

three are end-use products (EPs). 1,4-DMN is the sole active ingredient in these products. There are no 

currently approved uses for this chemical as an inert ingredient in pesticide products.

2,6-Diisopropylnaphthalene

As a pesticide, 2,6-DIPN is used to prolong the storage-life of potatoes. The active ingredient is a plant growth 

regulator which works via suppression of sprout formation and is applied to potatoes during storage. The active 

ingredient is not naturally-occurring, but is functionally identical to plant growth regulators found naturally (1-

isopropyl-4,6-dimethylnaphthalene, 1-methyl-7-isopropylnaphthalene, and 4-isopropyl-1,6-

dimethylnaphthalene) in potatoes. (2,6-Diisopropylnaphthalene BRAD, 2003) 

The chemical was first registered by the Agency in 1995. There are currently two registered end-use products 

containing the active ingredient. 2,6-DIPN is the sole active ingredient in these products. There are no currently 

approved uses for this chemical as an inert ingredient in pesticide products.

II. Tolerances

40 CFR § 180.1142: 1,4-Dimethylnaphthalene; exemption from the requirement of a tolerance.

An exemption from the requirement of a tolerance is established for residues of the plant growth regulator 1,4-

dimethylnaphthalene when applied post harvest to potatoes in accordance with good agricultural practices. [60 

FR 7457, Feb. 8, 1995]

40 CFR § 180.590: 2, 6-Diisopropylnaphthalene (2, 6-DIPN); tolerances for residues.

(a) General. Tolerances are established for residues of the growth inhibitor 2,6-DIPN, including its metabolites 

and degradates, in or on the commodities in the following table. Compliance with the tolerance levels specified 

in the following table is to be determined by measuring only 2,6-Diisopropylnaphthalene.

Commodity Parts per million

Cattle, fat 0.2

Cattle, meat 0.02

Cattle, meat byproducts, except fat 0.02
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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Goat, fat 0.2

Goat, meat 0.02

Goat, meat byproducts, except fat 0.02

Horse, fat 0.2

Horse, meat 0.02

Horse, meat byproducts, except fat 0.02

Milk, fat 0.02

Potato, granules/flakes 5.5

Potato, wet peel 6.0

Potato, whole 2.0

Sheep, fat 0.2

Sheep, meat 0.02

Sheep, meat byproducts, except fat 0.02

(b) Section 18 emergency exemptions . [Reserved]

(c) Tolerances with regional registrations . [Reserved]

(d) Indirect or inadvertent residues . [Reserved]

[71 FR 52011, Sept. 1, 2006, as amended at 74 FR 66579, Dec. 16, 2009; 77 FR 32406, June 1, 2012]

III. Incidents

According to the Incident Data System, there have been no reports of incidents resulting from the use of 

pesticide products containing 1,4-DMN or 2,6-DIPN as active ingredients.

IV. Toxicity Profile

1,4-Dimethylnaphthalene

Sufficient data have been provided to fulfill the biochemical pesticide data requirements under 40 CFR 

158.2050 for the current use patterns for 1,4-DMN. The data available to the Agency are summarized in Table 

1 below.
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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Table 1. Human Health Assessment Data Requirements for 1, 4-DMN (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity 

Category/Description MRID

Acute oral toxicity (rat)

(870.1100) LD50 = 2,730 mg/kg for males and females III 43082510

Acute dermal toxicity (rabbit)

(870.1200) LD50 > 2,000 g/kg for males and females IV 43082511

Acute inhalation toxicity (rat)

(870.1300) LC50 > 4.16 mg/L for males and females IV 43082512

Primary eye irritation (rabbit)

(870.2400)

Moderately irritating. Moderate ocular irritation was 

observed in all rabbits at 24 hours post-treatment with 

clearance by day 21.

II 43082513

Primary dermal irritation (rabbit)

(870.2500)

Slightly irritating. After treatment, very slight to slight 

erythema was observed in all males and females 

through 72 hours with persistence in females until day 

7. Well-defined to moderate edema was observed in all 

males and females within 24 hours post-treatment. At 

72 hours, slight edema was observed in one male and 

one female.

IV143082514

Dermal sensitization (Buehler-guinea pig)

(870.2600) Not a sensitizer 43082515

Dermal sensitization (LLNA)

(870.2600) Not a sensitizer 48590903

90-Day oral toxicity

(870.3100)

Rats were administered 1,4-DMN in the diet at doses 

of 0, 50, 250 and 1,000 mg/kg/day for 90 days. The 

LOAEL was 250 mg/kg-day which was based on 

kidney effects which were more prevalent in males 

than females. The NOAEL was 50 mg/kg/day.

46316806

90-Day dermal toxicity

(870.3250)

Waived. Prolonged dermal exposure is not expected 

based on the use pattern and appropriate PPE 

requirements and reentry restrictions on labels of enduse products. Products are applied as aerosols in indoor 

potato storage facilities and applicators/handlers must 

vacate premises during treatment. Premises are 

ventilated prior to reentry. Applicators/handlers must 

wear long sleeved shirts, long pants, socks, shoes, 

protective eyewear and chemical-resistant gloves. 

Should reentry occur after application and prior to 

ventilation, applicators must also wear coveralls, 

respirators and face-sealing goggles (unless a full-face 

respirator is used).

90-Day inhalation toxicity

(870.3465)

Waived. Significant repeated inhalation exposure as a 

gas, vapor or aerosol is not expected based on the use 

pattern and appropriate PPE requirements and reentry 

restrictions on labels of end-use products. Products are 

applied as aerosols in indoor potato storage facilities 

and applicators/handlers must vacate premises during 

treatment. Premises are ventilated prior to reentry. 

Should reentry occur after application and prior to 

ventilation, applicators must wear respirators to 

prevent inhalation exposure. 

Mutagenicity

(Bacterial reverse mutation test; 870.5100)

Not mutagenic under the conditions of the study. 

Mutagenicity was not observed with or without 

metabolic activation in any of the 5 strains of 

Salmonella typhimurium tested. 

43082516
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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Table 1. Human Health Assessment Data Requirements for 1, 4-DMN (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity 

Category/Description MRID

Mutagenicity

(Unscheduled DNA synthesis in 

mammalian cells; 870.5550)

(In vitro) Not genotoxic under the conditions of the 

study. No induction of nuclear grain counts in 

hepatocytes was observed at the tested concentration 

range of 0.25 μg/ml to 10 μg/ml. 

43082517

(In vivo) Not genotoxic under the conditions of the 

study. No induction of nuclear grain counts in

hepatocytes was observed when rats were given a 

single dose of up to 1,000 mg/kg 1,4-DMN.

48590901

Mutagenicity

(In vivo mammalian erythrocyte 

micronucleus test; 870.5395)

Not mutagenic under the conditions of the study. There 

was no increase in the number of micronuclei per 

1,000 polychromatic erythrocytes in the bone marrow 

of mice at doses of 225 mg/kg, 450 mg/kg and 900 

mg/kg 1,4-DMN. A decrease in the polychromatic 

erythrocyte (PCE) and normochromatic erythrocyte 

(NCE) ratio was observed with increased doses of the 

chemical.

43082518

Mutagenicity

(In vitro mammalian cell gene mutation 

test; 870.5300)

Not mutagenic without metabolic activation in mouse 

lymphoma cells under the conditions of the study. 

Dose-dependent mutagenicity was observed however, 

with metabolic activation.2

46577001

Developmental toxicity (rabbits)

(870.3700)

Developmental toxicity was not observed at the highest 

dose tested; therefore, the no-observed-adverse-effectlevel (NOAEL) was 250 mg/kg/day. 

There were indications of maternal toxicity at 250 

mg/kg-day; reduced food consumption and reduced 

body weight gain were observed. The lowest-observedadverse-effect-level (LOAEL) was 250 mg/kg/day and 

the NOAEL was 80 mg/kg/day for maternal toxicity.

48590904

Reproduction and fertility effects3(rats)

(870.3800)

Reproductive toxicity was not observed at the highest 

dose tested; therefore the NOAEL was 7,500 ppm. 

There were indications of developmental toxicity at 

7,500 ppm; delayed vaginal patency and preputial 

separation were observed, although these effects were 

considered secondary to body weight effects that were 

attributed to a reduction in food consumption. The 

LOAEL was 7,500 ppm and the NOAEL was 2,000 

ppm for developmental toxicity.

Based on a single histological change in the kidney 

observed in one rat at the 7,500 ppm dose, the LOAEL 

was 7,500 ppm and the NOAEL was 2,000 ppm for 

systemic toxicity.

48590905

Carcinogenicity3

(rats)

(870.4300)

Not carcinogenic under the conditions of the study. No 

carcinogenicity was observed when 1,4-DMN was 

administered daily in the diet of rats for 52 or 104 

weeks at doses of 0, 10, 33 and 250 mg/kg/day. 

48590906

Dermal absorption3

(870.7600)

The mean total percutaneous absorption of 1,4-DMN 

when applied in vitro to human skin was 2.5% of the 

dose applied.

48590902

1Originally classified as Toxicity Category III; however, the results of the study and the information provided under 40 CFR § 156.62 

indicate that the chemical should be classified into Toxicity Category IV.
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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2

Although mutagenicity was observed with metabolic activation in this in vitro study, 1,4-DMN is considered to not likely be 

mutagenic. This conclusion is based on the negative results observed in all of the four other mutagenicity studies, two of which were 

in vivo studies.

3This study was not required by the Agency but was submitted nonetheless.

2,6-Diisopropylnaphthalene

Sufficient data have been provided to fulfill the biochemical pesticide data requirements under 40 CFR 

158.2050 for the current use patterns for 2,6-DIPN. The data available to the Agency are summarized in Table 

2 below.
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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Table 2. Human Health Assessment Data Requirements for 2, 6-DIPN (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity 

Category/Description MRID

Acute oral toxicity (rat)

(870.1100) LD50 > 5,000 mg/kg for males and females IV 44641404

Acute dermal toxicity (rabbit)

(870.1200) LD50 > 5,000 g/kg for males and females IV 44614105

Acute inhalation toxicity (rat)

(870.1300) LC50 > 2.60 mg/L for males and females IV 44614106

Primary eye irritation (rabbit)

(870.2400)

Practically non-irritating (24-hour MMTS score of 

0.7)1. No corneal opacity or iritis was noted during the 

study. One hour after test substance instillation, all 

animals exhibited conjunctivitis with clearance by 48 

hours.

III144614107

Primary dermal irritation (rabbit)

(870.2500)

Slightly irritating. After treatment, very slight 

erythema was observed in 4 animals, 2 of which 

exhibited very slight edema. All animals were clear of 

irritation by 48 hours.

IV 44614108

Dermal sensitization (Buehler-guinea pig)

(870.2600) Not a sensitizer 44614109

90-Day oral toxicity

(870.3100)

Rats were administered 2,6-DIPN in the diet at doses 

of 0, 53.9, 104 or 208 mg/kg/day in males and 0, 61.8, 

121 or 245 mg/kg/day in females for 90 days. The 

LOAEL was 208 mg/kg-day for males and 245 

mg/kg/day for females which was based on decreased 

body weight gains and food consumption, and adrenal

and kidney effects. The NOAEL was 104 mg/kg/day 

for males and 121 mg/kg/day for females. 

45049301

90-Day dermal toxicity

(870.3250)

Waived. Prolonged dermal exposure is not expected 

based on the use pattern and appropriate PPE 

requirements and reentry restrictions on labels of enduse products. Products are applied as aerosols in indoor 

potato storage facilities and applicators/handlers must 

vacate premises during treatment. Premises are 

ventilated prior to reentry. Applicators/handlers must 

wear a respirator, long sleeved shirts, long pants, 

socks, shoes, and chemical-resistant gloves. 

90-Day inhalation toxicity

(870.3465)

Waived. Significant repeated inhalation exposure as a 

gas, vapor or aerosol is not expected based on the use 

pattern and appropriate PPE requirements and reentry 

restrictions on labels of end-use products. Products are 

applied as aerosols in indoor potato storage facilities 

and applicators/handlers must vacate premises during 

treatment. Premises are ventilated prior to reentry. 

Applicators/handlers must wear respirators to prevent 

inhalation exposure. 

Mutagenicity

(Bacterial reverse mutation test; 870.5100)

Not mutagenic under the conditions of the study.

Mutagenicity was not observed with or without 

metabolic activation in any of the 5 strains of 

Salmonella typhimurium tested. 

44614111

Mutagenicity

(Unscheduled DNA synthesis in 

mammalian cells; 870.5550)

Not genotoxic under the conditions of the study. No 

induction of nuclear grain counts in hepatocytes was 

observed when rats were given single doses of up to 

2,000 mg/kg 2,6-DIPN.

44614110
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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Table 2. Human Health Assessment Data Requirements for 2, 6-DIPN (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity 

Category/Description MRID

Mutagenicity

(In vivo mammalian erythrocyte 

micronucleus test; 870.5395)

Not mutagenic under the conditions of the study. There 

was no increase in the number of micronuclei per 

approximately 2,000 polychromatic erythrocytes in the 

bone marrow of mice at doses of 100, 200, 500, 800, 

1,500 or 2,000 mg/kg 2,6-DIPN. A decrease in the 

polychromatic erythrocyte (PCE) and normochromatic 

erythrocyte (NCE) ratio was observed at the highest 

dose.

44614112

Mutagenicity

(In vitro mammalian cell gene mutation 

test; 870.5300)

Under the conditions of the study, the test substance 

was mutagenic without metabolic activation in mouse 

lymphoma cells. With metabolic activation, results 

were equivocal.2

45438801

Developmental toxicity (rabbits)

(870.3700)

For developmental toxicity, the LOAEL was 500

mg/kg/day based on reduced fetal body weights and a 

slightly increased incidence of skeletal malformations. 

The NOAEL was 150 mg/kg/day.

For maternal toxicity, the LOAEL was 150 mg/kg/day 

based on reduced body weight gain and reduced food 

consumption. The NOAEL is 50 mg/kg/day.

45000101

Metabolism

Supplemental metabolism data were submitted from 

the open scientific literatures on 2,6-DIPN in rats. In 

the first study, when rats were given a single dose of 

100 mg/kg of the chemical, residues were detectable in 

all tissues 2 hours after dosing. With the exception of 

body and subcutaneous fat, no residues were detected 

after 48 hours. Similar results were observed in rats 

given daily doses of 100 mg/kg of the chemical for 30 

days. The estimated half-life of 2,6-DIPN in fat was 

approximately 7 days. The second study suggested that 

the chemical is metabolized in rats primarily by way of 

an oxidative pathway involving the isopropyl groups. 

45163201

1

In the study, the severity of irritation score at 24-hours (Maximum Mean Total Score [MMTS]) after dosing was calculated to be 0.7. 

Based on the interpretation of the score using this method, the test substance was classified as practically non-irritating. The EPA, 

which uses a different method to classify a substance into a Toxicity Category, has classified the test substance into Toxicity Category 

III because the minimal effects observed in the study did not clear in less than 24 hours.

2

Although mutagenicity was observed in this in vitro study, 2,6-DIPN is considered not likely to be mutagenic. This conclusion is 

based on the negative results observed in all of the three other mutagenicity studies, two of which were in vivo studies. 

VI. References

U.S. EPA Biopesticides Registration Action Document (BRAD) for 2,6-DIPN. Issued October, 2003.

<http://www.epa.gov/pesticides/biopesticides/ingredients/factsheets/factsheet_055803.htm >

U.S. EPA Biochemical Fact Sheet for 1,4-DMN. Issued January, 2001. 

<http://www.epa.gov/pesticides/biopesticides/ingredients/factsheets/factsheet_055802.htm>

cc: A. L. Gonzales, L. Cole, BPPD Science Review File, IHAD/ARS

 A. L. Gonzales, FT, PY-S: 08/16/12
1,4

-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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