Document ID: EPA-HQ-OPP-2012-0670-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-09-26T04:00Z

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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-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
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.

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.
                                     IV[1]
                                   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)
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 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 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
                                 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 ug/ml to 10 ug/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-effect-level (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-observed-adverse-effect-level (LOAEL) was 250 mg/kg/day and the NOAEL was 80 mg/kg/day for maternal toxicity.
                                       
                                   48590904
                                       
                 Reproduction and fertility effects[3] (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
                                       
                              Carcinogenicity[3]
                                    (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 absorption[3]
                                  (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. 
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.
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.
                                    III[1]
                                   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 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 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
                                 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