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: February 20, 2013

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 /s/

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P)

TO: Colin Walsh, Regulatory Action Leader

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P)

ACTION REQUESTED

The following document contains a review of the mammalian toxicology data submitted as supplemental data 

for the biopesticide 1,4-dimethylnaphthalene (1,4-DMN) in support of the development of the Registration

Review Final Work Plan. The document also contains revised data tables for both 1,4-DMN and 2,6-DIPN 

which supersede the data tables in the preliminary work plan scoping document.

Executive Summary

In the previous scoping document for 1,4-DMN, a 90-day oral toxicity study was identified that was submitted 

as supplemental data for which an Agency review could not be found. The Agency has since conducted a review 

of these data and determined that the data are acceptable; however, due to the toxic endpoints (kidney effects) 

identified in the study, the current risk assessment regarding the exemption from the requirement of a tolerance 

may need to be refined. Revised data tables for both 1,4-DMN and 2,6-DIPN have been included in this 
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

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document which supersede the data tables in the preliminary work plan scoping document.

I. Data Summary

A 90-day oral toxicity study was conducted on 1,4-DMN and submitted in MRID 46316806. The study was 

conducted according to OCSPP Guideline 870.3100, “90-day Oral Toxicity in Rodents”

1,4-dimethylnaphthalene was administered to groups of 10 female and 10 male Sprague-Dawley rats in the diet 

at target doses of of 0, 50, 250 or 1,000 mg/kg/day (equivalent to 0, 500, 2,500 and 10,000 ppm, respectively) 

for 90 days. Target doses were based on consumption of 25 g of food-day by a 250 g rat. Twenty additional rats 

(10/sex) were included in the high-dose and control group and were kept for 28 days after 90 days to determine 

the recovery potential from treatment-induced effects. The following evaluations were conducted: mortality, 

food consumption and 1,4-DMN intake, body weight, functional observational battery and motor activity, 

clinical chemistry, hematology, organ weight, gross pathology and histopathology. No treatment-related 

mortality was observed. Discolored inguinal fur was observed in 12/20 high-dose males, 2/10 mid-dose males 

and in one high-dose female. Treatment-related effects on food consumption were observed in a dose-response 

manner throughout the study. A significant decrease in food consumption in the high dose group was observed, 

which resulted in reduced body weight gain compared to controls. A decrease in consumption was observed in 

mid-dose males for 7 weeks. Effects in the low-dose group were minimal. No difference in food consumption 

was observed between the high-dose and vehicle control groups during the recovery period. During the recovery 

period, high-dose animal body weights remained significantly lower than controls although total body weight 

gain was significantly higher in the high-dose animals than in controls. Daily intakes of 1,4-DMN ranged from 

23-65, 119-315 and 367-1121 mg/kg/day for the target doses of 50, 250 and 1,000 mg/kg/day, respectively. 

Daily food consumption remained steady while body weight increased (due to growth) which resulted in lower 

actual doses than targeted during the last few weeks, particularly in males. No significant differences in the 

functional observational battery or motor activity parameters were noted except for decreased forelimb strength 

in high-dose males. This effect was most likely due to the decreased body weight in that group. Statistically 

significant differences between the treatment and control groups were observed with regard to clinical 

chemistry. Cholesterol levels were increased in the high- and mid-dose males. BUN levels were decreased in the 

high- and mid-dose females. Except for the differences in cholesterol and BUN levels, all other differences 

observed were considered unrelated to treatment because the values were considered within the normal range, 

were sporadic in nature and of low magnitude. Random differences in hematology were also noted which were 

minor in nature and considered to be the result of biological variability rather than treatment-related. Several 

statistically significant organ weight ratio differences were noted in the high-dose group. In high- and mid-dose 

males, significantly increased kidney-to-body weight ratios were noted. In high- and mid-dose females, the 

absolute liver, liver-to-body and liver to-brain weight ratios were increased. No treatment-related 

histopathological findings were noted in any of the organs (except for the kidneys) that correlated with the 

statistically significant differences noted above. Gross necropsy findings were considered unrelated to treatment 

as they were sporadic, singular in occurrence and observed in all groups including controls. Histopathology 
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

Type of Review: Toxicology (Registration Review) 

 

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findings indicate that the kidney was the target organ of 1,4-DMN. An increase in incidence and severity of 

chronic progressive nephropathy (CPN), a kidney anomaly that spontaneously occurs in aging rats, basophilic 

tubules and infiltration of mononuclear cells was observed in 5/10 high-dose males and in 1/10 animals in each 

of the other groups including controls. After the recovery period, minimal CPN was observed in 6/10 high-dose 

males and 1/10 control males. After the recovery period, CPN was noted in 3/10 high-dose females. Effects 

were more severe in males. Basophilic tubules were also noted in 6/10 mid-dose males and 2/10 low-dose and 

control males; these observations were considered to be treatment related. Infiltration of mononuclear cells was 

observed in 3/10 mid-dose males and 1/10 in each of the other groups. After the recovery period, there was no 

clear difference in the incidence of the changes between the high-dose and control groups. All other 

histopathology findings were not considered to be related to treatment because they occurred sporadically, were 

low in severity and were observed in all groups including controls. Based on the findings in the study, the 

lowest-observed-adverse-effect-level (LOAEL) is 250 mg/kg/day based on higher incidences of basophilic 

tubules and mononuclear cell infiltration in males. The no-observed-adverse-effect-level (NOAEL) is 50 

mg/kg/day. 

II. 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. The LD50 value for the acute dermal toxicity data requirement has been revised subsequent to the 

review in the preliminary work plan.
1,4-DMN and 2,6-DIPN PC Code: 055802 and 055803

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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 mg/kg for males and females III 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.

IV1 43082514

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)

LOAEL = 250 mg/kg/day based on kidney effects 

(higher incidences of basophilic tubules and 

mononuclear cell infiltration) in male rats. 

NOAEL = 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. 
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

(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

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
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

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

1

Originally 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.

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. 3

This 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. The LD50 value for the acute dermal toxicity data requirement has been revised subsequent to the 

review in the preliminary work plan.
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 mg/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.

III1 44614107

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 chemicalresistant 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
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

(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

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. 

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

 A. L. Gonzales, FT, PY-S: 02/20/13
1,4

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

Type of Review: Toxicology (Registration Review) 

 

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