2

Table of Contents

EXECUTIVE SUMMARY..................................................................................................................................3

I. BACKGROUND ..................................................................................................................................................... 7

II. INERT INGREDIENT PROFILE ........................................................................................................................... 7

III. HUMAN HEALTH ASSESSMENT................................................................................................................... 9

A. Summary of Toxicity Data.....................................................................................................................9

B. Toxicity Endpoint Selection ................................................................................................................19

C. Special Considerations for Infants and Children ...................................................................................21

IV. EXPOSURE ASSESSMENT................................................................................................................................... 22

A. Dietary Exposure: ...............................................................................................................................22

i. Acute exposure....................................................................................................................................22

ii. Chronic exposure................................................................................................................................22

iii. Cancer exposure ................................................................................................................................24

B. Residential Exposure ..........................................................................................................................24

V. AGGREGATE RISK AND DETERMINATION OF SAFETY .............................................................................. 25

A. Acute Dietary Risk ..................................................................................................................................26

B. Chronic Dietary Risk. ..............................................................................................................................26

C. Aggregate Cancer Risk for U.S. Population ............................................................................................26

D. Short-Term Aggregate Risk ....................................................................................................................26

E. Intermediate-Term Aggregate Risk ........................................................................................................27

F. Determination of Safety .........................................................................................................................28

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY ....................................................................................... 28

A. Occupational Handler Risk .................................................................................................................28

B. Occupational Post-Application Risk....................................................................................................30

VII. CUMULATIVE EXPSOURE........................................................................................................................... 30

IX. ENVIRONMENTAL JUSTICE STATEMENT ............................................................................................... 30

X. ENVIRONMENTAL FATE CONSIDERATIONS .............................................................................................. 31

XI. ECOTOXICITY................................................................................................................................................ 32

XII. RISK CHARACTERIZATION......................................................................................................................... 32

REFERENCES............................................................................................................................................................... 37

APPENDIX .................................................................................................................................................................... 39
3

EXECUTIVE SUMMARY

Technology Sciences Group Inc. (1150 18th Street, N.W. Suite 1000, Washington, D.C. 20036) 

submitted a petition (PP 2E8031) on behalf of Wellmark International (1501 E. Woodfield Road, 

Suite 200 West, Schaumburg, IL 60173), requesting an exemption from the requirement of a 

tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Act with respect 

to diisopropyl adipate (DIPA) as an inert ingredient applied to growing crops only (40 CFR 

180.920) as a solvent at no more than 40% of formulation. It is intended to be used primarily in 

pesticides formulations for control of mosquitos. EPA published the Notice of Filing for this 

petition in the Federal Register on August 22, 2012 (77 FR 50665). No substantial comments were 

received in response to this notice. 

Based upon review of the data supporting the petition, the proposed use patterns may results in 

applications of pesticides post-harvest. Therefore EPA believes a more appropriate exemption 

would be under 40 CFR 180.910. EPA has modified the exemption requested to include an 

exemption from the requirement of a tolerance for residues of diisopropyl adipate (CAS Reg. No. 

6938-94-9) under 40 CFR 180.910 when used as an inert ingredient in pesticide formulations 

applied to growing crops or to raw agricultural commodities after harvest at no more than 40% in 

formulated products intended for mosquito control.

The acute oral toxicity of diisopropyl adipate in rodents, as expressed as an LD50, ranges from 

1,500 mg/kg to 8,800 mg/kg. In the guinea pig, the acute oral toxicity of diisopropyl adipate is 

about 6,600 mg/kg and in the rabbit, 5,000 mg/kg. In the dog, the acute oral LD50 of diisopropyl 

adipate is greater than 8,000 mg/kg. Diisopropyl adipate is minimally irritating to the eyes and skin 

of rabbits. 

The potential for toxicity following repeat dose exposure to diisopropyl adipate was evaluated 

based on toxicity studies with diisopropyl adipate as well as toxicity data on the two primary 

metabolites of diisopropyl adipate, adipic acid (CAS Reg. No. 124-04-9) and isopropyl alcohol 

(CAS Reg. No. 67-63-0). Isopropyl alcohol was previously assessed in the U.S. EPA inert 

reassessment document titled, Inert Reassessment –n-Propanol; CAS# 71-23-8, dated August 24, 

2005 and no end points of concern were identified. In addition, toxicity data from two structural 

analogues of diisopropyl adipate, dipropyl adipate and diisobutyl adipate, were also considered. 

These substances would be expected to have toxicological properties similar to diisopropyl adipate 

and can be used to supplement the available toxicity data on diisopropyl adipate. The studies 

summarized below were either performed with diisopropyl adipate, adipic acid, dipropyl adipate or 

diisobutyl adipate. 

In a 5 week study, guinea pigs that were administered adipic acid orally showed no adverse 

effects up to doses of 1000 mg/kg/day. In a 90 day oral toxicity study, male rats were given 0, 0.1, 

1 or 5% adipic acid and female rats were given 0 or 1% adipic acid. The NOAEL was 1% (1000 

mg/kg/day) and a LOAEL of 5% (5000 mg/kg/day) based on growth retardation in males. In a 19 

week oral toxicity study in rats, each rat was given 0, 50, 100, 200 or 400 mg adipic acid/rat/day. 

The NOAEL was 200 mg adipic acid/rat/day (equivalent to 1700 mg/kg/day) and the LOAEL was 

400 mg adipic acid/rat/day (equivalent to 3,400 mg/kg/day) was based on slight effects on liver 

and irritation of the intestine. In a 33 week subchronic oral toxicity study on groups of 13-15 male 
4

and female rats at doses of 0, 400, 800 mg/rat/day or approximately 0, 1600 and 3200 mg/kg 

bw/day adipic acid produced a LOAEL of 400mg/rat/day (equivalent to 1600 mg/kg bw/day) 

based on slight liver effects and inflammation of the intestine and no NOAEL was observed. In a 

3 week inhalation toxicity study, rats were exposed to 0.126 mg/L adipic acid for 6 hr periods daily 

for five days a week for a total of 15 exposures. No signs of toxicity were seen, blood tests gave 

normal values and autopsy results revealed all organs to be normal. 

The mutagenic potential of adipic acid was evaluated in a Host-Mediated Assay, in an in vivo

cytogenetics test, and a dominant lethal assay. These tests were negative. 

An OECD SIDS Initial Assessment Report on Adipic Acid (2004) concluded that adipic acid 

was not carcinogenic in a limited two-year feeding study where groups of twenty male rats were 

dosed with food containing 0, 0.1, 1, 3 and 5% (equivalent to 0, 75, 750, 2250 or 3750 mg/kg/day) 

adipic acid, and female rats were dosed with 0% (n=10) and 1% (n=19) adipic acid, respectively. 

The incidences of tumors observed in the adipic acid treated groups were observed at the same 

levels as in the control groups.

Developmental studies (FDRL 1972) via oral gavage using adipic acid on mice, rats, hamsters 

and rabbits showed no maternal or developmental toxicity. The NOAELs for mice, rats and 

hamsters were 263, 288 and 205 mg/kg/day, respectively. These studies were not conducted at the 

limit dose. However, the concern for developmental toxicity of diisopropyl adipate is low because 

no systemic toxicity was seen in chronic studies at doses near the limit dose. In addition, the 

developmental toxicity studies conducted with two analogue substances (dipropyl adipate and 

diisobutyl adipate) via intraperitoneal route showed no developmental toxicity at doses around 700 

mg/kg/day. 

An immunotoxicity study from the OECD SIDS 2004 IUCLID Data Set stated that the 

lymphocyte mitogenesis test was used to test for immunotoxicity in vitro. In this test lymphocytes 

were stimulated by a polyclonal mitogen specific for either B or T cells. Neither B nor T 

lymphocyte mitogenesis was inhibited by adipic acid at concentrations up to 0.3%.

There were no neurotoxicity studies available in the database. However, there were no clinical 

signs of neurotoxicity observed in the available studies.

There are no published metabolism studies on diisopropyl adipate specifically, but the 

metabolic pathways of diisopropyl adipate are proposed based on the characteristic molecular 

structure of diisopropyl adipate and the known metabolic pathways for structurally similar 

compounds. Diisopropyl adipate is a linear fatty acid diester that has an isopropyl group bound to 

the oxygen atom on each end of the molecule. Given these structural groups, diisopropyl adipate 

metabolism is almost certainly catalyzed by carboxylesterase enzymes that are ubiquitous 

throughout the body to produce adipic acid plus two molecules of isopropyl alcohol.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 
5

Acute dietary risk assessment was not conducted because no endpoint of concern following a 

single or few exposures identified in the available studies. A chronic dietary exposure assessment 

was completed and performed using the Dietary Exposure Evaluation Model DEEM-FCIDTM, 

Version 3.16. The chronic RfD (cRfD) of 7.5 mg/kg/day was determined on the basis of the 

carcinogenicity study in rats. The LOAEL of 3% adipic acid (equivalent to 2250 mg/kg/day) is 

based on decreased in body weight gains seen in males. This study provided the lowest NOAEL 

(750 mg/kg/day for adipic acid in male and female rats) in the database (most sensitive endpoint) 

and will also provide the most protective limits for human effects. An UF of 100X (10-fold for 

interspecies extrapolation and 10-fold for intra species variability) was applied to the NOAEL of 

750 mg/kg/day to derive the cRfD. The FQPA safety factor of 1X is applicable for chronic dietary 

risk assessment. Therefore, the chronic population-adjusted dose (cPAD) is 7.5 mg/kg/day. This 

endpoint of concern was used for all dermal and inhalation exposure scenarios. Dermal and 

inhalation absorption is assumed 100%. 

Registration Division’s (RD’s) level of concern (LOC) for diisopropyl adipate occupational and 

residential dermal and inhalation exposures is 100 [i.e., a margin of exposure (MOE) greater than 

100 is not of concern to RD]. The LOC is based on a 10X uncertainty factor (UF) to account for 

interspecies extrapolation to humans from the animal test species and 10X UF to account for intraspecies sensitivity.

Short-term aggregate exposure takes into account short-term residential exposure plus chronic 

exposure to food and water (considered to be a background exposure level). Diisopropyl adipate is 

used as inert ingredients in pesticide products that are currently registered for uses that could result 

in short-term residential exposure and the Agency has determined that it is appropriate to 

aggregate chronic exposure through food and water with short-term residential exposures to 

diisopropyl adipate. EPA has concluded that the combined short-term aggregated food, water, and 

residential exposure result in aggregate MOEs of 14,400 for both adult males and females 

respectively. Adult residential exposure consists of high end post application dermal exposure 

from contact with treated lawns. As the level of concern is for MOEs that are lower than 100, this 

MOE is not of concern. EPA has concluded that the combined short-term aggregated food, water 

and residential exposure results in an aggregate MOE of 4,400 for children. Children’s residential 

exposure includes total exposures associated with contact with treated surfaces (dermal and handto-mouth exposures). As the level of concern is for MOEs that are lower than 100, these MOEs are 

not of concern. 

Intermediate-term aggregate exposure takes into account intermediate-term residential exposure 

plus chronic exposure to food and water (considered to be a background exposure level). 

Diisopropyl adipate is currently registered for uses that could result in intermediate-term 

residential exposure and the Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with intermediate-term residential exposures to diisopropyl 

adipate. EPA has concluded that the combined intermediate-term aggregated food, water and 

residential exposures results in aggregate MOEs of 16,600 for adult makes and females. Adult 

residential exposure consists of contact with treated lawns. EPA has concluded the combined 

intermediate-term aggregated food, water and residential exposure results in an aggregate MOE of 

4,800 for children. Children’s residential exposure includes total exposures associated with contact 

with treated surfaces (dermal and hand-to-mouth exposures). As the level of concern is for MOEs 
6

that are lower than 100, this MOE is not of concern. Dietary cancer risk was not calculated because 

the Agency has no identified any concerns for carcinogenicity relating to diisopropyl adipate. 

Occupational handler risks are not of concern for all scenarios. RD notes that the occupational 

handler assessment assumes that mixer/loader/applicators wear protective gloves when using open 

pour in support of aerial and groundboom application. The estimated MOEs are greater than 100 

based on 100% dermal absorption. Therefore, the estimated MOEs do not exceed the Agency’s 

level of concern. This assessment is considered to be a screening level estimate, demonstrating that 

there are minimal potential risks to workers re-entering fields treated with pesticides containing 

diisopropyl adipate as inert ingredients. Therefore an occupational post application risk assessment 

was not performed.

Based on the ready biodegradability of DIPA and the generally low modeled partitioning of 

DIPA into surface waters, effects of concern to nontarget aquatic species resulting from the use of 

DIPA as an inert ingredient are not anticipated. Acute toxicity studies performed with adipic acid 

on fish, invertebrates and algae showed that the compound was slight to practically nontoxic. Open 

literature studies utilizing adipic acid on terrestrial plants showed low toxicity as well. Diisopropyl 

adipate is not expected to pose an environmental fate concern due to its biodegradability. Adipic 

acid is expected to partition mainly to the water however based on the acute aquatic toxicity 

studies which showed low toxicity to aquatic organisms, this is not expected to be of concern.

Taking into consideration all available information on diisopropyl adipate, EPA concludes that 

there is a reasonable certainty that no harm to any population subgroup will result from aggregate 

exposure to diisopropyl adipate when considering occupational, dietary exposure and all other 

nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, 

the establishment of an exemption from tolerance under 40 CFR 180.910 for residues of 

diisopropyl adipate (CAS Reg. No. 6938-94-9) when used as a pesticide inert ingredient for preand post-harvest food use as a solvent intended to be used primarily for control of mosquitos at no 

more than 40% in formulated products, can be considered assessed as safe under section 408(q) of 

the FFDCA.
7

I. BACKGROUND

Technology Sciences Group Inc. (1150 18th Street, N.W. Suite 1000, Washington, D.C. 

20036) submitted a petition (PP 2E8031) on behalf of Wellmark International (1501 E. Woodfield 

Road, Suite 200 West, Schaumburg, IL 60173), requesting an exemption from the requirement of a 

tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Act with respect 

to diisopropyl adipate (DIPA) as an inert ingredient applied to growing crops only (40 CFR 

180.920) as a solvent at no more than 40% of formulation. It is intended to be used primarily in 

pesticides formulations for control of mosquitos. Wellmark has registered two subject products for 

use by federal, state, tribal, or local officials to treat areas for large mosquito populations.

Diisopropyl adipate is used as a solvent to help keep the active ingredient dissolved in the 

formulation. Diisopropyl adipate is used as a solvent in several types of pesticide formulations, 

currently used for non-food use purposes. This tolerance exemption petition covers pre-harvest 

usage on growing crops though the proposed use of the inert is indirect application as a result of 

mosquito eradication/control in areas near crops. Use of diisopropyl adipate is proposed to be 

limited to no more than 40% in formulated products intended for mosquito control. These 

mosquito control products are proposed for application to areas in close proximity to growing 

crops, and this use would require an exemption from the requirement of a tolerance for pre-harvest 

application (40 CFR 180.920). The inert use would be limited to crop application only indirectly 

when treating to control mosquitoes in and near cropland.

Based upon review of the data supporting the petition, the proposed use patterns may 

results in applications of pesticides post-harvest. Therefore EPA believes a more appropriate 

exemption would be under 40 CFR 180.910. EPA has modified the exemption requested to include 

an exemption from the requirement of a tolerance for residues of diisopropyl adipate (CAS Reg. 

No. 6938-94-9) under 40 CFR 180.910 when used as an inert ingredient in pesticide formulations 

applied to growing crops or to raw agricultural commodities after harvest at no more than 40% of 

formulated products intended for mosquito control.

II. INERT INGREDIENT PROFILE

A. Summary of Uses

Diisopropyl adipate is used as a solvent in several types of pesticide formulations, currently 

used for non-food use purposes. Diisopropyl adipate and related adipate compounds are 

ingredients that have been used for many years in personal care products including skin 

cleansers, perfumes and colognes, bath oils, skin fresheners and hair grooming aids. 

Diisopropyl adipate functions as a solvent and emollient in cream-type skin preparations 

and is used to modify the flow properties of emollient blends in cosmetic products and is 

typically included in personal care products at concentrations from 0.1 to 25% (CIR 1984).

B. Physical Chemical Properties

Some of the physical and chemical characteristics of diisopropyl adipate, along with its 

structure and nomenclature, are found in Table 1. Some of the physical and chemical 
8

characteristics of adipic acid, along with its structure and nomenclature, are found in table 

2.

Table 1. Physical and Chemical Properties of Diisopropyl Adipate (DIPA)

Parameter Value Source

Structure ChemIDplus

CAS # 6938-94-9 ChemIDplus

Molecular Weight (g/mol) 230.3

Common Names DIPA

Physical State Liquid Sigma-Aldrich MSDS

Melting Point (°C) -1.10 ChemIDplus

Boiling Point (°C) @ 19 hPa 136 Sigma-Aldrich MSDS

Density (g/cm3 @ 20°C) 0.966 Sigma-Aldrich MSDS

Vapor Pressure (mmHg @ 25°C) 0.0446 EPI Suite 4.0 (registrant)

Partition Coefficient (Log P) 2.762 Sigma-Aldrich MSDS

Water Solubility (mg/L) 55.61(WSKOW result)

187.42 (Fragment result) EPI Suite 4.0 (registrant)

Henry's Law Constant 3.03x10-6 EPI Suite 4.0 (registrant)
9

Table 2. Physical and Chemical Properties of Adipic Acid

Parameter Value Source

Structure

CAS # 124-04-9 OECD SIDS 2004

Molecular Weight (g/mol) 146.14 OECD SIDS 2004

Common Names

Hexanedioic Acid; 1,4-

Butanedicarboxylic acid; 1,6-

Hexanedioic acid; Adipinic acid

OECD SIDS 2004

Physical State White, odorless, crystalline solid Kennedy 2002

Melting Point (°C) 152 Merck 2001

Boiling Point (°C) @ 1013 hPa 337.5 Davis 1985; Merck 2001

Density (g/cm3 @ 25°C) 1.36 Beilstein 2003

Vapor Pressure (Pa @ 18.50°C) 9.7 Kirk-Othmer 1991

Partition Coefficient (Log Kow @ 

25°C) 0.093 BASF 1988a

Water Solubility (g/L @ 25°C) 23 MITI 1992

Flash point (Closed cup in °C) 196 David 1985

Auto Flammability (Ignition 

temperature in °C) 420 Davis 1951

Ionization Constants (@ 25°C) pKa1 = 4.34

pKa2 = 5.44 Davis 1985

pH value (@ 25°C) 2.7 (saturated solution) 

3.2 (0.1% solution) Davis 1985

III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data 

The potential for toxicity following repeat dose exposure to diisopropyl adipate was 

evaluated based on data using diisopropyl adipate as the inert ingredient. However, when 

data are not available, then the toxicity data on the two following metabolites are used, 

adipic acid (CAS Reg. No. 124-04-9) and isopropyl alcohol (CAS Reg. No. 67-63-0). Data 

from compounds with similar structural and functional groups were also used on occasion. 

Isopropyl alcohol was previously assessed in the U.S. EPA inert reassessment document 

titled, Inert Reassessment –n-Propanol; CAS# 71-23-8, dated August 24, 2005 and no end 

points of concern were identified. Therefore all the studies summarized below were either 

performed with diisopropyl adipate (DIPA), adipic acid or a similar surrogate compound. 
10

Acute Oral Toxicity

The acute toxicity of diisopropyl adipate and structurally similar compounds has been 

studied over the past decades (CIR, 1984). The toxicity of diisopropyl adipate has been 

evaluated often as a component of cosmetic products. The acute oral toxicity of diisopropyl 

adipate was examined by dosing rats by gavage with product formulations that contain high 

percentages of diisopropyl adipate. For example a single dose formulation of 5,000 mg/kg 

bw was administered to five albino rats that was 5% diisopropyl adipate (approx. 250 

mg/kg bw). No abnormal behavior or deaths were reported during the seven day 

observation period (CIR, 1984). A second acute oral toxicity study was conducted in rats 

that received by gavage a dose formulation of 15,000 mg/kg that was in a product 

composed of 20.75% diisopropyl adipate (approx. 3,100 mg/kg bw). Again, no deaths or 

abnormal behavior was observed during the seven day observation period (CIR, 1984). 

(MRID 48827401)

In rats, an LD50 value of 5,560 mg/kg bw was established in a study similar to OECD TG 

401 performed with single gavage doses up to 10,000 mg/kg bw of adipic acid (99.8%) 

administered as 50% suspension in carboxymethyl cellulose vehicle. Mortality was seen 

during the first 48 hours. Lethal doses caused acute dilation of the heart and acute 

congestive hyperaemia, ulceration of glandular stomach (bleeding-corrosive gastritis), pale 

liver, intestinal atony and reddening of intestinal mucosa (BASF 1978c). Animals that 

survived to termination at 14 days showed no gross pathological changes. The doses used

in this test were in excess of the currently accepted limit dose. (OECD SIDS 2004)

No signs of toxicity were observed following administration of a single dose of 5,000 

mg/kg bw of adipic acid (suspended in saline) to ten male rats (Litton Bionetics Inc. 1974). 

(OECD SIDS 2004)

In mice, an LD50 value of 1,900 mg/kg bw was established after the oral administration of 

adipic acid (6% solution in 0.5% methyl cellulose) to groups of 13 male animals. Autopsy 

of animals that died during the experiment showed distention of the stomach and irritation 

and hemorrhage of the intestines as well as spastic contraction of the caecum. Initial 

mortality developed overnight and deaths continued throughout the first week, survivors 

appeared normal (Horn et al. 1957). (OECD SIDS 2004)

Dermal Toxicity

Dermal toxicity and potential irritation of diisopropyl adipate were evaluated in guinea pigs 

that were exposed for three consecutive days via whole-body immersion test, and the 

results were summarized by the Cosmetic Ingredient Review (CIR, 1984). The abdominal 

fur was clipped from six albino guinea pigs and the ventral body surface was immersed in a 

0.1% solution of diisopropyl adipate for four hours per day for three days. The solution was 

composed of diluted formulated product that was originally 20.75% diisopropyl adipate. 

Clinical signs of toxicity were monitored and recorded and dermal irritation was scored. 

There were no signs of systemic toxicity, and two of the six guinea pigs exhibited slight 

dermal irritation.
11

No lethality was reported in rabbits following occlusive dermal administration of 5,010 

(n=1) and 7,940 mg/kg bw (n=2) of 40% adipic acid in corn oil for 24 hours. Animals 

showed reduced appetite and activity and the viscera were normal at necropsy after 14 days

observations (Solutia Inc. 1975). (OECD SIDS 2004)

Inhalation Toxicity

In a study similar to OECD TG 403, neither mortality, toxic symptoms or macroscopic 

pathological changes were observed in 20 rats exposed for 4 hours (nose only) to the 

maximal attainable concentration of 7,700 mg/m3 (7.7 mg/L) of adipic acid (99.8%) dust. 

Fifty percent of the particles had a MMAD below 3.5 μm (BASF 1981). (OECD SIDS 

2004)

Primary Eye Irritation

Eye irritation was evaluated in albino rabbits using two different batches of diisopropyl 

adipate and the results were summarized by CIR (CIR, 1984). For each batch of DIPA, 0.1 

ml of undiluted test article was instilled in one eye of six rabbits, and the untreated eye 

served as a control. Rabbits were observed until all eyes were negative for irritation, up to 

seven days. The first batch of diisopropyl adipate caused negligible irritation on day 1 that 

resolved by day 2. No irritation was reported in rabbit eyes following exposure to the 

second batch of diisopropyl adipate. The reason for the slight eye irritation elicited from 

one batch and not the other was undetermined. The purity of the test article batches was not 

provided, and test article purity could impact the study result.

Primary Skin Irritation

A primary skin irritation study was performed on three lots of diisopropyl adipate (CIR 

1984). The studies were evaluated using the Draize method. In each experiment, 0.1 ml of 

the undiluted product was applied under occlusion to the clipped back skin of nine albino 

rabbits. After 24 hrs of contact the dressing was removed and the site scored. The first lot 

had a PII of 1.6 and the second, 1.3. These scores indicated that the material was a mild 

irritant. The third lot caused no irritation in eight rabbits and only barely perceptible 

erythema in one. The PII score of 0.06 indicated that this compound was minimally 

irritating. 

Dermal Sensitization

On a safety assessment of Stearamide DIBA-Stearate, diisopropyl adipate was assessed 

briefly. The study stated that diisopropyl adipate had low acute oral and percutaneous 

toxicity, and was only a very mild ocular irritant. In skin irritation studies using rabbits, 

5.0% to 100% diisopropyl adipate caused minimal to mild irritation; these results were also 

seen in clinical testing with only moderate cumulative irritation, and no sensitization or 

photosensitization. (Lanigan 2001) 

The results of the available acute toxicity studies are summarized in Table 3.
12

Acute Toxicity

Table 3. Acute Toxicity Profile of Diisopropyl Adipate /Adipic Acid (metabolite)

Study Type Results

Toxicity 

Category MRIDs # /Reference

Acute Oral - rat LD50 > 250 mg/kg bw calculated from 5,000 

mg/kg bw *0.05 for test composition 

(diisopropyl adipate)

II 48827401; CIR 1984

Acute Oral - rat LD50 > 3,100 mg/kg bw calculated from 

15,000 mg/kg bw * 0.2075 for test 

composition (diisopropyl adipate)

III 48827401; CIR 1984

Acute Oral - rat LD50 = 5,560 mg/kg bw (adipic acid) IV BASF 1978c; OECD SIDS 

2004 Adipic Acid

Acute Oral - rat LD50 > 5,000 mg/kg bw (adipic acid) IV Litton Bionetics Inc. 1974; 

OECD SIDS 2004 Adipic 

Acid

Acute Oral - mice LD50 = 1,900 mg/kg bw (adipic acid) III Horn et al. 1957; OECD 

SIDS 2004 Adipic Acid

Acute Dermal -

guinea pigs

LD50 > 0.10% (diisopropyl adipate) using 

whole body submersion. 

N/A 48827401 (CIR, 1984)

Acute Dermal -

rabbit

LD50 > 4,764 mg/kg bw calculated from 

7940 mg/kg * 0.6 for test composition (adipic 

acid) 

IV Solutia Inc. 1975; OECD 

SIDS 2004 Adipic Acid

Acute Inhalation -

rat

LD50 > 7.7 mg/L (adipic acid) 

No mortality, toxic symptoms or macroscopic 

pathological changes

IV BASF 1981; OECD SIDS 

2004 Adipic Acid

Primary Eye 

Irritation - rabbit

Minimal effects clearing in less than 24 hours 

(diisopropyl adipate)

IV 48827401 (CIR, 1984)

Primary Skin 

Irritation - guinea 

pigs

Slight irritation (diisopropyl adipate) IV 48827401 (CIR, 1984)

Primary Skin 

Irritation - rabbit

Minimal to mild irritation (diisopropyl 

adipate)

IV 48827401 (CIR, 1984)

Primary Skin 

Irritation

Minimal to mild irritation (diisopropyl 

adipate)

IV Open Lit. Lanigan (2001)

Dermal 

Sensitization

Negative (diisopropyl adipate) Neg. Open Lit. Lanigan (2001)

Subchronic Oral Toxicity - Guinea Pig

Guinea pigs fed 400 to 600 mg/kg adipic acid for five weeks showed no adverse effects 

(MRID 48827401; Kennedy 2002). 
13

Subchronic Oral Toxicity – Rat

In a 90-day feeding study with adipic acid (Hazleton Laboratories 1950; Kennedy 2002), 

groups of 10 male rats were given a basal diet supplemented with 0, 0.1, 1, or 5% adipic 

acid; similar groups of females were given 0 or 1% adipic acid. The males receiving 5% 

adipic acid exhibited a marked retardation of growth during the entire feeding period. No 

histological examination of tissues was done and no effects were seen at 1%. 

In a study summarized in the OECD SIDS Initial Assessment Report on Adipic Acid 

(2004), groups of 8 to 10 male rats received sodium adipate (0, 50, 100, 200 and 400 mg 

per rat daily; equivalent to 0, 420, 840, 1700 and 3400 mg/kg bw/day) in a protein deficient 

diet for 19 weeks. After 7 weeks and at the end of experiment, rats were killed and 

examined grossly. Weight gain and general behavior were recorded and histopathology of 

liver, kidneys and intestine was performed. Rats fed with 400 mg/rat/day showed reduced 

weight gain and lower weight after 19 weeks. No obvious symptoms were observed. 

Several unexplained intercurrent deaths in control and dose groups occurred, and only 5-7 

animals in each group survived 19 weeks. Only at 400 mg/rat/day slight effects were seen 

on liver and irritation of intestine. The NOAEL is 200 mg/rat/day (equivalent to1700

mg/kg bw. The LOAEL is 400 mg (equivalent to 3400 mg/kg bw). The study is very 

limited in its reliability because no details are provided on the distribution of intercurrent 

deaths amongst the treatment/control groups, only kidneys, liver and intestine have been 

examined histopathologically. 

In a second study summarized in the OECD SIDS Initial Assessment Report on Adipic 

Acid (2004), groups of 13-15 male and female rats received adipic acid (neutralized with 

NaOH) in a standard diet (0, 400, 800 mg per rat/day, equivalent to 0, 1600 and 3200 

mg/kg bw/day) for 33 weeks. Weight gain and general behavior were recorded. After 8, 

23 and 25 weeks, rats were killed and histopathology of liver, kidneys and intestine was 

performed. The administration of 400 mg/rat/day of adipic acid had no effect on weight 

gain and general behavior of the animals. Ten out of 14 rats fed with 800 mg/rat/day died 

during the first 4 weeks. The surviving animals showed retarded weight gain, appeared 

unkempt and apathetic and suffered from heavy diarrhea during the first three weeks. They 

recovered by the fifth week, and after 33 weeks, the weights of the high-dose rats were the 

same as that of the 400 mg/rat/day group. The authors did not record the body weight of 

control animals at the end of the experiment, i.e. at 33 weeks. Histopathology: slight effects 

were seen on liver and inflammation of intestine at 400 mg/rat/day. The LOAEL was 400 

mg/rat/day (equivalent to 1600 mg/kg/day). No NOAEL was obtained in this study (Lang 

and Bartsch 1953). The study is very limited in its reliability because only kidneys, liver 

and intestine have been examined histopathologically.

Chronic Oral Toxicity - Rat

According to the OECD SIDS Initial Assessment Report on Adipic Acid (2004), a twoyear study consisting of 20 male rats were given 0, 0.1, 1, 3 and 5% of adipic acid in the 

diet (equivalent to doses of 0, 75, 750, 2250 and 3750 mg/kg bw/day). Group of 10 or 19 

female rats received food containing 0 or 1% adipic acid (equivalent to 0 and 750 mg/kg 

bw/day, respectively). Bodyweights, food consumption and general appearance were 

recorded weekly throughout the experimental period. After 2 years, surviving rats were 
14

weighed, killed, and examined grossly. The percent survival for each test group was higher 

than for the control group. There were no bodyweight differences during the test period in 

female and male rats treated with 0, 0.1 and 1% adipic acid. The weight gains of the male 

rats receiving 3 and 5% adipic acid were significantly less than the control groups. At 

necropsy there was no treatment related effects observed. Results of microscopic 

examination of the organs revealed no compound related effect. The NOAEL was 1% for 

male and female rats (equivalent to750 mg/kg bw/day) and the LOAEL was 3% (equivalent 

to 2250 mg/kg/day) based on decreased body weights (Horn et al. 1957). It is important to 

note that at the study does not fully comply with current guidelines for chronic studies due 

to the age of the study. 

Subchronic Inhalation Toxicity - Rat

Two male and two female rats were exposed to adipic acid dust at a concentration of 126 

μg/L (0.126 mg/L) for 6-hour periods daily, five days a week for a total of 15 exposures. 

No signs of toxicity were seen; blood tests gave normal values, and autopsy results 

revealed all organs to be normal (Gage 1970). (MRID 48827401; Kennedy 2002)

Carcinogenicity

OECD SIDS Initial Assessment Report on Adipic Acid (2004) concluded that adipic acid 

was not carcinogenic in a limited two-years feeding study where groups of twenty male rats 

were dosed with food containing 0, 0.1, 1, 3 and 5% adipic acid (approx 0, 75, 750, 2250, 

3750 mg/kg bw/day), and female rats were dosed with 0% (n=10) and 1% (n=19) adipic 

acid (approx. 0, 750 mg/kg bw/day), respectively. Animals that died during the study and 

survivors were analyzed for incidences of tumor growth and lung pathology. The 

incidences of tumors observed in the adipic acid treated groups were as frequent as in the 

control groups (Horn et al. 1957). The study does present many deficiencies such as the 

number of animals used was low, microscopic examination of only tissues was done only 

on a representative number of animals for each group and only one concentration was 

tested for females. The maximum tolerated dose for females was not reached and the purity 

of adipic acid was not indicated.

Developmental Toxicity - Rats and Mice

In a developmental toxicity study using adipic acid (Food and Drug Research Laboratories, 

Inc., or FDRL 1972), rats and mice were gavaged from day 6 through day 15 of gestation. 

The mice received 0, 2.6, 12, 56, or 263 mg/kg/day of adipic acid and the rats received 0, 

2.9, 13, 62, or 288 mg/kg/day adipic acid. All animals were observed daily for appearance 

and behavior, and on day 17 (mice) or 20 (rats), dams were subjected to Caesarean section 

under anesthesia and the numbers of implantation sites, resorption sites and live and dead 

fetuses were recorded. The body weights of the live pups were also recorded. All fetuses 

were examined for the presence of gross external abnormalities and one-third of the fetuses 

in each liter were examined for visceral abnormalities. The remaining fetuses were cleared 

and stained for examination of skeletal defects. No teratogenic effects or any adverse 

effect on maternal or fetal survival were reported. No significant increase in any adverse 

effect was identified in rats or mice exposed to the highest dose of adipic acid tested. The 

maternal and developmental NOAEL in mice and rats was 263 and 288 mg/kg/day, 

respectively, the highest doses tested.
15

In another developmental toxicity study (Singh et al. 1973), a variety of adipic acid esters 

were intraperitoneal injected in Sprague-Dawley rats. Among the compounds tested were 

dipropyl adipate and diisobutyl adipate. In the study, rats received the intraperitoneal 

injects of the test articles on days 5, 10 and 15 of pregnancy. Resorptions, live and dead 

fetuses, and fetus weights were recorded, as were skeletal and visceral abnormalities. The 

NOAEL for dipropyl adipate was approximately 727 mg/kg/day (assuming a specific 

gravity of 0.96 g/ml) based on an increase in resorptions compared to controls, and a slight 

but significant increase in gross abnormalities compared to controls at the LOAEL dose of 

1,211 mg/kg/day. The NOAEL for diisobutyl adipate was 1,130 mg/kg/day based on a 

small but significant increase in gross abnormalities compared to controls at the 1,884 

mg/kg dose. 

Developmental Toxicity - Rabbits

Groups of 10 to 14 Dutch-belted female rabbits were gavaged from gestation day 6-18 

(doses of 2.5, 12, 54 and 250 mg/kg bw/day of adipic acid) with no signs of maternal or 

fetal toxicity observed at the highest doses tested. The number of abnormalities seen in 

either soft or skeletal tissue of the test groups did not differ from the number occurring 

spontaneously in the controls. No difference between treatment and control groups were 

found for corpora lutea, implantations, total no. of resorptions, total no. of fetuses, total no. 

of live litters and fetal weights. (FDRL 1972 & 1974)

Developmental Toxicity - Hamster

Hamsters were given oral doses of 0, 2, 9.5, 44 or 205 mg/kg/day adipic acid for five 

consecutive days during gestation (day 6-10). There were 21-24 animals per group. Body 

weights were recorded on days 0, 8, 10 and 14 days of gestation, and all animals were 

observed daily for appearance and behavior. Detailed examination of all dams and fetuses 

revealed no clearly discernible effects on nidation or on maternal or fetal survival. The 

number of abnormalities seen in either soft or skeletal tissues of the test groups did not 

differ from the controls. An increase of resorption/implant sites from 3.5 to 7.7% in the 

highest dose group. Consequently the average number of live fetuses was reduced form 

12.6 to 11.4 a reduction as high as caused by the positive control substance aspirin. (FDRL 

1972 & 1974)

Reproductive Toxicity

No reproductive toxicity study was available in the database, however, OECD SIDS Initial 

Assessment Report on Adipic Acid (2004) concluded that a two-years feeding study in rats 

histopathological examination of testes, ovaries and uterus revealed no evidence of an 

adverse effect on the reproductive organs up to the highest doses tested (males approx. 

3750 mg/kg/day, females approx. 750 mg/kg/day). In addition, oral developmental toxicity 

studies in mice, rats, and rabbits with adipic acid at doses up to 288, 263 and 250 

mg/kg/day did not alter any reproductive indices and they were neither embryotoxic or 

teratogenic. In view of the low systemic toxicity of the compound, however, this endpoint 

seems to be adequately covered despite the lack of reproductive studies. 
16

Immunotoxicity

OECD SIDS 2004 IUCLID Data Set stated that the lymphocyte mitogenesis test was used 

to test for Immunotoxicity in vitro. In this test lymphocytes were stimulated by a polyclonal 

mitogen specific for either B or T cells. Neither B nor T lymphocyte mitogenesis was 

inhibited by adipic acid at concentrations up to 0.3%.

Neurotoxicity

No studies were available in the database. However, there was no evidence of neurotoxicity 

in the available studies.

Mutagenicity and Genotoxicity

U.S. FDA contracted a series of studies to evaluate the potential genotoxicity of adipic 

acid, and all tests were negative for genotoxicity (Litton Bionetics 1974). 

The Host-Mediated Assay is a combination of the bacterial reverse mutation assay without 

metabolic activation conducted in vitro (the Ames Assay) and an in vivo phase where the 

exposure of the bacteria to the test article is in the peritoneal cavity of a mouse. The three 

indicator species used in this test were: Salmonella typhimurium strains TA-1530, and G46, and Saccharomyces cerevisiae strain D-3 (a diploid strain). The in vivo micronucleus 

assay was performed once, exposing mice to one of three low dose levels of: 3.75, 37.5 or 

375 mg/kg adipic acid, and the assay was performed a second time exposing mice to a 

single dose of 5,000 mg/kg adipic acid or to repeated doses of 2,500 mg/kg. The results 

from the first in vivo test at lower doses suggested increased frequencies and weak 

mutagenicity, but were not confirmed at higher doses. The in vitro tests with the three 

indicator species were negative.

The in vivo cytogenetics test was conducted in male rats exposed to either a single high 

dose of adipic acid or to five doses of 2,500 mg/kg adipic acid. (Litton Bionetics 1974). 

Colcemid was administered to the rats four hours after the last compound dosing and two 

hours prior to sacrifice to arrest the bone marrow cells in C-mitosis. Diplod cells were 

analyzed for chromatid gaps and breaks, chromosome gaps, breaks and reunions, 

polyploidy, and other chromosome aberrations. Adipic acid was considered non-mutagenic 

as measured by the cytogenic test in vivo. 

The dominant lethal assay was conducted by exposing 10 male rats to either a single high 

dose of adipic acid or to five doses of 2,500 mg/kg adipic acid (Litton Bionetics 1974). 

Each treated male rat was mated with two virgin female rats each week for eight weeks (the 

acute group) or seven weeks (repeated dose group). Two weeks after mating the female rats 

were scarified and evaluated for fertility index, pre-implantation loss and lethal effects on 

the embryos. The fertility index, pre-implantation loss, and lethal effects on the embryos in 

the adipic acid-treated rats did not differ from saline-treated controls, while the positive 

controls caused significant pre-implantation loss and embryo resorption during the first five 

weeks. It was concluded that adipic acid does not induce lethal mutations. 

OECD SIDS Initial Assessment Report on Adipic Acid (2004) concluded that a variety of 

mutagenicity tests in vitro and in vivo have failed to demonstrate that adipic acid possesses 
17

genotoxic potential. A number of good quality Ames tests in Salmonella typhimurium

similar to OECD TG 471 and an examination of chromosome damage in human lung cells 

in culture produced negative results. In gavage studies in male rats it did not induce 

chromosome damage in the bone marrow or dominant lethal mutations in dose-response or 

time-trend pattern. 

Metabolism and Pharmacokinetics

There are no published metabolism studies on diisopropyl adipate specifically, but the 

metabolic pathways of diisopropyl adipate are proposed based on the characteristic 

molecular structure of diisopropyl adipate and the known metabolic pathways for 

structurally similar compounds. diisopropyl adipate metabolism can be deduced based on 

the common structural groups that make up diisopropyl adipate, the known enzymes that 

interact with these structural groups, and the metabolites that result from these interactions. 

In addition, the metabolism of a number of compounds that are structurally similar to 

diisopropyl adipate has been characterized, and this supports the proposed metabolic 

pathway for diisopropyl adipate. diisopropyl adipate is a linear fatty acid diester that has an 

isopropyl group bound to the oxygen atom on each end of the molecule. Given these 

structural groups, diisopropyl adipate metabolism is almost certainly catalyzed by 

carboxylesterase enzymes that are ubiquitous throughout the body, to produce an alcohol 

plus a carboxylate (Parkinson & Ogilvie 2008). In humans, carboxylesterase enzymes are 

present in a wide variety of tissues, including the liver, small intestine, colon, kidney, 

trachea and lung (Parkinson & Ogilvie 2008). Hydrolysis of ester-containing compounds in 

the plasma is catalyzed by butyrylcholinesterases and paraoxonases in humans (Parkinson 

& Ogilvie 2008). Carboxylase enzymes catalyze the reaction between water and the 

carboxylic esters to produce adipic acid plus two molecules of isopropyl alcohol. The 

identical reaction is depicted in a diagram y Parkinson & Ogilvie for the dimetyl ester of 

succinic acid. The initial step in diisopropyl adipate metabolism produces monoisopropyl 

adipic alcohol. Evidence suggests that MIPA is a short-lived molecule and this second step 

proceeds rapidly as detailed below (Keith et al. 1992). 

The assumption that diisopropyl adipate is metabolized to form adipic acid and the 

corresponding isopropyl alcohol based on the chemical structure of diisopropyl adipate and 

the known distribution and function of carboxylase and other enzymes is reinforce by the 

known metabolic pathway of another adipic acid ester, diethylhexyl adipate (DEHA). 

DEHA is metabolized by carboxylase enzymes to form one molecule of adipic acid for 

each two molecules of the corresponding alcohol, ethylhexyl alcohol (EHA; Keith et al., 

1992). The hydrolysis of DEHA to adipic acid and EHA is said to be rapid and complete, 

such that the monoester is not metabolically produced (Keith et al. 1992). EHA and the 

downstream metabolite 2-ethylhexanoic acid are considered the toxic metabolites of DEHA 

(Keith et al. 1992). In contrast, the primary metabolite of diisopropyl adipate in addition to 

adipic acid is isopropyl alcohol, which is low in toxicity compared to EHA (Faber et al. 

2008). 

The metabolism of adipic acid has been characterized, and proceeds by beta oxidation 

(Rusoff, et al. 1960). Urinary metabolites of adipic acid following administration of the 

radiolabeled compound included: urea, glutamic acid, lactic acid, beta-ketoadipic acid and 
18

citric acid as well as unmetabolized adipic acid (Rusoff et al. 1960). Studies were 

conducted to confirm that intermediaries I beta oxidation were formed from adipic acid, 

including identification of radiolabeled acetyl-γ-phenyl-α-aminobutryric acid after 

administration of γ-phenyl-α-aminobutyric acid and C14-labeled adipic acid to rats. This 

provided very strong evidence that acetate is a metabolite of adipic acid. In addition, 

radioactive glycogen was detected following administration of glucose and radiolabeled 

adipic acid to rats (Rusoff et al. 1960).

Adipic acid is a direct food substance affirmed as generally recognized as safe (GRAS) by 

the U.S. Food and Drug Administration (U.S. FDA) (21 CFR 184.1009), and it meets the 

specifications of the Food Chemicals Codex, 3rd Edition. Adipic acid may be used in a 

variety of foods as a flavoring agent, and may be included in condiments at levels up to 

5%, in gelatin and puddings up to 0.55% and in snack foods up to 1.3% (21 CFR 

184.1009).

There is strong evidence to support the metabolism of diisopropyl adipate to form adipic 

acid and isopropyl alcohol, in a molar ratio of 1:2. Isopropanol is metabolized by alcohol 

dehydrogenase to form acetone, and further metabolized to acetate and formate, which is 

ultimately converted to carbondioxide (IPCS, 1990). Adipic acid is metabolized by beta 

oxidation that provides energy to support cellular function and forms carbondioxide that 

may be exhaled or enter the carbon pool of the body (Rusoff et al. 1960).

Table 4. Toxicology Profile for Diisopropyl Adipate and Adipic Acid

Guideline No./ Study 

Type

Doses Levels MRID No. 

(year)/References

Results

5 weeks Oral Toxicity 

Study 

(guinea pigs)

400 to 600 mg/kg 

(approximately 700-1000 

mg/kg/day for 5 wks (adipic 

acid)

MRID 48827401 

Kennedy 2002 cited 

DuPont 1943

NOAEL = 1000 mg/kg/day.

90 Days Oral Toxicity 

Study (rats)

Male: 0, 0.1, 1 or 5 % 

(approximately 0, 100, 

1000 or 5000 mg/kg/day)

Female: 0 or 1 % 

(approximately 0 or 1000 

mg/kg/day) (adipic acid)

MRID 48827401 

Kennedy 2002 cited 

Hazleton 

Laboratories 1950

NOAEL = 1% (approximately 

1000 mg/kg/day)

LOAEL = 5% (approximately 

5000 mg/kg/day) based on growth 

retardation in males. 

19 weeks Oral Toxicity 

Study (rats)

0, 50, 100, 200 or 400 mg/ 

rat (approximately 0, 420, 

840, 1700 and 3400 mg/kg 

bw/day) (adipic acid)

Lang and Bartsch 

1953

NOAEL = 200 mg (approximately 

1700 mg/kg/day)

LOAEL = 400 mg (approximately 

3,400 mg/kg/day) based on 

reduced weight gain and lower 

weight after 19 weeks. Limited 

reliability due to random deaths. 

33 weeks Oral Toxicity 

Study (rats)

0, 400 or 800 mg/rat/day 

(approx 0, 1600 and 3200 

mg/kg bw/day) (adipic 

acid)

OECD SIDS 2004 

cited Lang and 

Bartsch 1953

NOAEL = N/A

Slight effects were seen on liver 

and inflammation of intestine at 

400 mg/rat/day (approximately 

1600 mg/kg/day). 

3 Weeks- Inhalation 

Toxicity Study (rats)

0.126 mg/L (adipic acid) MRID 48827401 

Kennedy 2002 cited 

Gage 1970

NOAEL = 0.126 mg/L
19

Table 4. Toxicology Profile for Diisopropyl Adipate and Adipic Acid

Guideline No./ Study 

Type

Doses Levels MRID No. 

(year)/References

Results

Developmental Toxicity

Sprague-Dawley 

[Crl:CD(SD)]

Intraperitoneal Injected

0.1, 0.4, 0.8 or 1.3 ml/kg 

(dipropyl adipate)

0.2, 0.6, 1.2 or 2.0 ml/kg

(diisobutyl adipate)

MRID 48827401 

Singh et al. 1973

NOAEL (dipropyl adipate) = 727 

mg/kg/day

LOAEL (dipropyl adipate) = 1,211 

mg/kg/day based on increase 

resorptions and slight but 

significant increase in gross 

abnormalities.

NOAEL (diisobutyl adipate) = 

1,130 mg/kg/day

LOAEL (diisobutyl adipate) = 

1,884 mg/kg/day based on small 

but significant increase in gross

abnormalities.

Developmental Toxicity 

Study-Rats

0, 2.9, 13, 62, or 288 

mg/kg/day(adipic acid)

MRID 48827401

FDRL 1972

Maternal and Developmental 

NOAEL = 288 mg/kg/day

Developmental Toxicity 

Study-Mice

0, 2.6, 12, 56 or 263 

mg/kg/day(adipic acid)

MRID 48827401

FDRL 1972

Maternal and Developmental 

NOAEL = 263 mg/kg/day

Developmental Toxicity 

Study-Rabbit screening 

test

2.5, 12, 54, or 250 

mg/kg/day (adipic acid)

MRID 48827401

FDRL 1972

Maternal and Developmental 

NOAEL = 250 mg/kg/day

Developmental Toxicity 

Study-Hamster

0, 2, 9.5, 44, 205 mg/kg 

bw/day(adipic acid)

MRID 48827401

FDRL 1972

Maternal and Developmental 

NOAEL = 205 mg/kg/day

2 Year Oral Toxicity 

Study (rats;)

Chronic Toxicity/

Carcinogenicity in rats

male: 0, 0.1, 1, 3 or 5 % (0, 

approx. 75, 750, 2250 and 

3750 mg/kg/day; female: 0, 

750 mg/kg/day) (adipic 

acid)

OECD SIDS 2004 

cited Horn et al. 1957

NOAEL = 1% (approx. 750 

mg/kg/day)

LOAEL = 3% (approx. 2250 

mg/kg/day) based on body weight 

retardation in males. 

Evidence of carcinogenicity was 

not observed.

Host-Mediated Assay

(Salmonella typhimurium

strains TA-1530, and G46, and Saccharomyces 

cerevisiae strain D-3 (a 

diploid strain)

3.75, 37.5 or 375mg/kg 

Lower Dose Test; 

single dose 5000 mg/kg or 

repeated doses of 2500 

mg/kg Higher Dose Test 

(adipic acid)

MRID 48827401

Litton Bionetics 1974

Results from the lower doses 

suggested increased frequencies 

and weak mutagenicity, but were 

not confirmed at the higher doses. 

The in vitro tests with the three 

indicator species were negative.

Cytogenetics Assay

(male rats)

single high dose or five 

doses of 2500 mg/kg 

(adipic acid)

MRID 48827401

Litton Bionetics 1974

Considered non-mutagenic as 

measured by the cytogenic test in 

vivo.

Dominant Lethal Assay

(rats)

single high dose of adipic 

acid or five doses of 2500 

mg/kg (adipic acid)

MRID 48827401

Litton Bionetics 1974

Adipic acid does not induce lethal 

mutations.

B. Toxicity Endpoint Selection

The chronic toxicity/carcinogenicity study in rats was selected for all exposure scenarios 

and durations for this risk assessment. The NOAEL in this study was 750 mg/kg/day. The 

LOAEL was 2,250 mg/kg/day based on body weight retardation. The rationale for 
20

selecting this study is as follows. The lowest NOAEL (205 mg/kg/day) in the database was 

observed in a developmental study in hamsters. In this study 205 mg/kg/day was the 

highest dose tested. This study was not selected because maternal and developmental 

toxicity were not observed at doses as high as 263 and 288 mg/kg/day in mice and rats, 

respectively. Also, in a developmental toxicity study where rats were treated via 

intraperitoneal injection of adipic acid esters, maternal and developmental toxicity were not 

observed at doses at high as 727 mg/kg/day. The developmental LOAEL was 1,211 

mg/kg/day based on increased resorptions and a slight but significant increase in gross 

abnormalities. However, these studies are not useful for endpoint selection because they 

were conducted via intraperitoneal route which is not relevant for the dietary, dermal or 

inhalation risk assessment. Also, the 19 and 33 weeks and 2 years oral toxicity studies 

showed no evidence of toxicity at doses as high as 750 mg/kg/day. Therefore, the chronic 

toxicity study in rats with the NOAEL of 750 mg/kg/day provided a good basis for 

establishing the chronic reference dose (cRfD). The NOAEL is considered extremely 

conservative because the extrapolation from adipic acid to diisopropyl adipate was not 

performed in order to keep the toxicity endpoint selection more conservative. Diisopropyl 

adipate is a large molecular weight compound compared to adipic acid. Converting adipic 

acid to diisopropyl adipate in a 1 to 1 molar ratio (one molecule of diisopropyl adipate 

contains 1 molecule of adipic acid) would mean the NOAEL and LOAEL values would be 

increased proportionately to the molecular weight ratios, 230 g/mol for diisopropyl adipate 

and 146 g/mol for adipic acid (eg. The NOAEL of 750 mg/kg/day for adipic acid would 

become 1,181 mg/kg/day if converted to diisopropyl adipate). The uncertainty factor of 

100x was used for 10x intraspecies variability and 10x for interspecies extrapolation.

Table 5. Summary of Toxicological Doses and Endpoints for Diisopropyl Adipate for Use in Human Health 

Risk Assessment

Exposure/Scenario Point of Departure and 

Uncertainty/Safety Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Acute dietary 

(General population 

including infants and 

children)

An acute effect was not found in the database therefore an acute dietary assessment is not 

necessary.

Chronic dietary 

(All populations)

NOAEL= 750 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

Chronic RfD = 

750 mg/kg/day

cPAD = 7.5

mg/kg/day

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Incidental oral short-term 

(1 to 30 days)

NOAEL= 750 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE = 

100

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Incidental oral 

intermediate-term 

(1 to 6 months)

NOAEL= 750 mg/kg/day

UFA= 10 x

UFH= 10 x

FQPA SF = 1 x

LOC for MOE = 

100

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Dermal short-term 

(1 to 30 days)

Dermal (or oral) study NOAEL = 

750 mg/kg/day (dermal 

LOC for MOE = 

100

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 
21

absorption rate = 100 %

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

2250 mg/kg/day based on based 

on body weight retardation.

Dermal intermediateterm

(1 to 6 months)

Dermal (or oral) study NOAEL = 

750 mg/kg/day (dermal 

absorption rate = 100 %

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE = 

100

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Inhalation short-term 

(1 to 30 days)

Inhalation (or oral) study 

NOAEL= 750 mg/kg/day 

(inhalation absorption rate = 

100%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE = 

100 

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Inhalation 

(1 to 6 months)

Inhalation (or oral) study 

NOAEL = 750 mg/kg/day 

(inhalation absorption rate = 

100%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE = 

100 

[Chronic Toxicity/

Carcinogenicity-rat] LOAEL = 

2250 mg/kg/day based on based 

on body weight retardation.

Cancer (Oral, dermal, 

inhalation)

Based on the lack of tumor formation in a chronic/carcinogenicity study and the lack 

of mutagenicity, diisopropyl adipate is considered not likely to be carcinogenic.

UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of 

the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study 

for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA SF = Food 

Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. 

MOE = margin of exposure. LOC = level of concern.

C. Special Considerations for Infants and Children

Section 408 of the FFDCA provides that EPA shall apply an additional margin of safety for 

infants and children in the case of threshold effects to account for prenatal and post natal 

toxicity and the completeness of the database on toxicity and exposure unless EPA 

determines that a different margin of safety will be safe for infants and children. EPA 

concludes that the FQPA safety factor could be reduced to 1X for diisopropyl adipate for 

the following reasons:

i. The toxicity database for diisopropyl adipate includes several subchronic and 

chronic studies, several developmental toxicity studies, a chronic/carcinogenicity study, a 

mutagenicity study, and an immunotoxicity study. In addition, the metabolism of 

structurally similar compounds has been characterized, and that data supports the proposed 

metabolic pathways of diisopropyl adipate.

ii. Fetal susceptibility was not observed in rats, mice, rabbits or hamsters in any of the 

developmental studies with adipic acid, a metabolite of diisopropyl adipate. Maternal and 

developmental toxicity was not observed at doses as high as 288 mg/kg/day. Also, in a 
22

developmental toxicity study in rats treated with dipropyl adipate or diisobutyl adipate, 

analogues of diisopropyl adipate, maternal and developmental toxicity was not observed at 

> 1, 130 mg/kg/day. A 2-generation reproduction toxicity study in rodents is not available 

in the database. However, the concern for the lack of this study is low because maternal 

and offspring toxicity was not observed at or above the limit dose (at levels up to 1,211 

mg/kg/day) in rats and the lack of any effects on reproductive indices in mice, rats and 

rabbits. In addition, there was no evidence of histopathological changes in reproductive 

organs in chronic toxicity studies.

iii. There is no indication that diisopropyl adipate is a neurotoxic chemical. Although 

no neurotoxicity studies are available in the database, no clinical signs of neurotoxicity 

were observed in the available subchronic and chronic studies. Therefore, there is no need 

for a developmental neurotoxicity study or additional UFs to account for neurotoxicity. 

iv. An immunotoxicity study in rats was available for review. Neither B nor T 

lymphocyte mitogenesis was inhibited by adipic acid at concentrations up to 0.3% 

(approximately 225 mg/kg/day).

v. The dietary food exposure assessment utilizes proposed tolerance level or higher 

residues and 100% CT information for all commodities. By using these screening-level 

assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X 

FQPA safety factor can be reduced to 1X.

IV. EXPOSURE ASSESSMENT

Based on its postulated metabolism, there are two residues of concern, adipic acid and 

isopropyl alcohol. Isopropyl alcohol was previously assessed in the U.S. EPA inert reassessment 

document titled, Inert Reassessment –n-Propanol; CAS# 71-23-8, dated August 24, 2005 and no 

end points of concern were identified. Therefore diisopropyl adipate and adipic acid are used in 

this risk assessment.

A. Dietary Exposure:

 i. Acute exposure. No adverse effects attributable to a single exposure of diisopropyl 

adipate were seen in the toxicity databases. Therefore, acute dietary risk assessment for 

diisopropyl adipate is not required.

 ii. Chronic exposure. In conducting the chronic dietary exposure assessment using the

Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16, EPA used food 

consumption information from the U.S. Department of Agriculture’s National Health and 

Nutrition Examination Survey, What we eat in America, (NHANES/WWEIA). This dietary 

survey was conducted from 2003 to 2008. As to residue levels in food, no residue data 

were submitted for diisopropyl adipate. In the absence of specific residue data, EPA has 
23

developed an approach which uses surrogate information to derive upper bound exposure 

estimates for the subject inert ingredient. Upper bound exposure estimates are based on the 

highest tolerance for a given commodity from a list of high-use insecticides, herbicides, 

and fungicides. A complete description of the general approach taken to assess inert 

ingredient risks in the absence of residue data is contained in the memorandum entitled 

“Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and 

Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. 

Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPAHQ-OPP-2008-0738.

In the dietary exposure assessment, the Agency assumed that the residue level of the inert 

ingredient would be no higher than the highest tolerance for a given commodity. Implicit 

in this assumption is that there would be similar rates of degradation (if any) between the 

active and inert ingredient and that the concentration of inert ingredient in the scenarios 

leading to these highest of tolerances would be no higher than the concentration of the 

active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an 

extremely conservative assessment of dietary risk due to a series of compounded 

conservatisms. First, assuming that the level of residue for an inert ingredient is equal to 

the level of residue for the active ingredient will overstate exposure. The concentration of 

active ingredients in agricultural products is generally at least 50 percent of the product and 

often can be much higher. Further, pesticide products rarely have a single inert ingredient; 

rather there is generally a combination of different inert ingredients used which 

additionally reduces the concentration of any single inert ingredient in the pesticide product 

in relation to that of the active ingredient. In the case of diisopropyl adipate, EPA made a 

specific adjustment to the dietary exposure assessment to account for the use limitations of 

the amount of diisopropyl adipate that may be in formulations (no more than 40% by 

weight in pesticide and assumed that the diisopropyl adipate is present at the maximum 

limitations rather than at equal quantities with the active ingredient. 

Second, the conservatism of this methodology is compounded by EPA’s decision to assume 

that, for each commodity, the active ingredient which will serve as a guide to the potential 

level of inert ingredient residues is the active ingredient with the highest tolerance level. 

This assumption overstates residue values because it would be highly unlikely, given the 

high number of inert ingredients, that a single inert ingredient or class of ingredients would 

be present at the level of the active ingredient in the highest tolerance for every commodity. 

Finally, a third compounding conservatism is EPA’s assumption that all foods contain the

inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of 

all foods are treated with the inert ingredient at the rate and manner necessary to produce 

the highest residue legally possible for an active ingredient. In summary, EPA chose a very 

conservative method for estimating what level of inert residue could be on food, and then 

use this methodology to choose the highest possible residue that could be found on food 

and assumed that all food contained this residue. No consideration was given to potential 

degradation between harvest and consumption even though monitoring data shows that 
24

tolerance level residues are typically one to two orders of magnitude higher than actual 

residues in food when distributed in commerce. 

Accordingly, although sufficient information to quantify actual residue levels in food is not 

available, the compounding of these conservative assumptions will lead to a significant 

exaggeration of actual exposures. EPA does not believe that this approach underestimates 

exposure in the absence of residue data.

Table 6. Summary of Chronic Dietary Exposure and Risk for Diisopropyl Adipate

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

7.5

0.037869 0.5%

All Infants (<1 year old) 0.078886 1.1%

Children 1-2 years old 0.141248 1.9%

Children 3-5 years old 0.097127 1.3%

Children 6-12 years old 0.050111 0.7%

Youth 13-19 years old 0.026960 0.4%

Adults 20-49 years old 0.028948 0.4%

Adults 50+ years old 0.030358 0.4%

Females 13-49 years old 0.029267 0.4%

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for diisopropyl adipate are 

significantly below the Agency’s level of concern for all supported commodities. The 

chronic dietary exposure estimate for the highest exposed population subgroup, children 1-

2 years old is 1.9% of the chronic population adjusted dose (cPAD). 

iii. Cancer exposure. OECD SIDS Initial Assessment Report on Adipic Acid (2004) also 

concluded that adipic acid was not carcinogenic. Diisopropyl adipate is not expected to be 

carcinogenic based on lack of mutagenicity and lack of carcinogenicity in rats with adipic 

acid. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer 

risk.

B. Residential Exposure

The term “residential exposure” is used in this document to refer to non-occupational, nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, 

and flea and tick control on pets). Diisopropyl adipate may be used in inert ingredients in 

pesticide products that are registered for specific uses that may result in outdoor residential 

exposures. Based on the proposed use pattern as a mosquito eradication/control agent in 

areas near crops, the major route of exposure is expected to be inhalation and dermal 

exposure as a result of off-target drift and oral exposure from inadvertent deposition on 

edible crops. A screening level residential exposure and risk assessment was completed for 

two sample product labels containing diisopropyl adipate as inert ingredients submitted by 

the registrant. The product label which contained a higher application rate of diisopropyl 

adipate (0.07 lb/acres) was used for screening level risk assessment purposes. The Agency 

conducted exposure assessments based on end-use product application methods and labeled 

application rates. The Agency has not conduct an assessment to represent worst-case 
25

residential exposure because neither of the products have been labeled for residential 

applicators. However the Agency conducted an assessment to represent worse-case 

residential exposure by assessing post-application exposures and risk from diisopropyl 

adipate in pesticide formulations. The assessment methodologies were taken from: 

Standard Operating Procedures for Residential Pesticide Exposure Assessment. 

EPA/OPP/Health Effects Division February 2012. The methodologies have been integrated 

into EPA software which was used to calculate the values in the table below. 

Table 7. Residential Post-application Short- and Intermediate-term Exposures and Risks for Diisopropyl 

Adipate Inerts

Exposure Scenario Application Rate1 Exposed Population 

& Exposure 

Duration2

Daily Dose 

(mg/kg/day)3

MOE4

Outdoor Products

Dermal Exposure to 

Treated Lawns

0.07 lb/day

Adult ST 0.0142 53,000

Adult IT 0.0072 100,000

Child ST 0.0272 28,000

Child IT 0.0136 55,000

Hand-to-Mouth from 

Treated Lawn

Child ST 0.0010 720,000

Child IT 0.0005 1,500,000

Object-to-Mouth 

from Treated Lawn

Child ST 0.0003 2,900,000 Child IT

Soil Ingestion Child ST 0.000004 210,000,000 Child IT

Total Lawn 

Combined 

Exposures*

Child ST 0.0283 27,000

Child IT 0.0141 53,000

1 Application rates for diisopropyl adipate are derived from one of two sample labels provided by the registrant. Application rates 

are based on label with the higher maximum inert application rates of products containing diisopropyl adipate inerts multiplied 2 ST and IT indicate short- or intermediate-term exposure durations 3 MOE = PoD (NOAEL of 750 mg/kg/day)/ Daily dose (mg/kg/day) 4 Combined exposures reflect the aggregation of dermal exposure to treated areas and HTM exposure from treated areas (for 

children). *Total Combined Exposures = (NOAEL of 750 mg/kg/day)/ [Daily dose dermal + Daily dose HTM (mg/kg/day)]

EPA has calculated the residential post-application exposures. The adult short-term MOE 

was calculated to be 53,000 from dermal exposure to treated lawns. The adult intermediateterm MOE was calculated to be 100,000 from dermal exposure to treated lawns. As the 

level of concern is for MOEs that are lower than 100, these MOEs are not of concern. The 

child total lawn combined short-term MOE was calculated to be 27,000 from treated lawns 

(dermal and hand-to-mouth exposures). The child total lawn combined intermediate-term 

MOE was calculated to be 53,000 from treated lawns (dermal and hand-to-mouth 

exposures). As the level of concern is for MOEs that are lower than 100, these MOEs are 

not of concern.

V. AGGREGATE RISK AND DETERMINATION OF SAFETY

EPA determines whether acute and chronic pesticide exposures are safe by comparing 

aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest 

safe exposures, taking into account all appropriate safety factors (SFs). EPA calculates the aPAD 
26

and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the 

probability of additional cancer cases given the estimated aggregate exposure. Short-, 

intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, 

water, and residential exposure to the POD to ensure that the MOE called for by the product of all 

applicable UFs is not exceeded. 

A. Acute Dietary Risk. An acute aggregate risk assessment takes into account exposure 

estimates from acute dietary consumption of food and drinking water using the exposure 

assumptions discussed in section IV for acute exposure. However there was no hazard 

attributable to a single exposure seen in the toxicity database for the diisopropyl adipate; 

therefore an acute aggregate risk assessment is not required. 

B. Chronic Dietary Risk. A chronic aggregate risk assessment takes into account exposure 

estimates from chronic dietary consumption of food and drinking water using the exposure 

assumptions discussed in section IV for chronic exposure. The chronic analysis was based on 

a chronic toxicity study in rats with a NOAEL of 750 mg/kg/day and LOAEL of 2250

mg/kg/day based on body weight retardation in males. A 100-fold uncertainty factor (UF) (10x 

for interspecies extrapolation and 10x for intraspecies variation) was incorporated. The 

chronic dietary exposure from food and water to diisopropyl adipate is 0.5% of the cPAD for 

the U.S. population and 1.9% of the cPAD for children 1-2 yrs old, the most highly exposed 

population subgroup.

C. Aggregate Cancer Risk for U.S. Population. The Agency has not identified any concerns 

for carcinogenicity relating to diisopropyl adipate; therefore, a cancer dietary exposure 

assessment was not performed and an aggregate risk assessment is not a concern.

D. Short-Term Aggregate Risk. Short-term aggregate exposure takes into account short-term 

residential exposure plus chronic exposure to food and water (considered to be a background 

exposure level). Diisopropyl adipate is used as an inert ingredient in pesticide products that are 

currently registered for uses that could result in short-term residential exposure and the Agency 

has determined that it is appropriate to aggregate chronic exposure through food and water 

with short-term residential exposures to the diisopropyl adipate. Using the exposure 

assumptions described in section IV, EPA has calculated the combined short-term aggregated 

food, water, and residential exposures. The adult aggregate MOE was calculated to be 14,400 

for both males and females. Adult aggregate MOE combines average food and water exposure 

from the chronic dietary exposure with high end post application dermal exposure form contact 

with treated lawns. As the level of concern is for MOEs that are lower than 100, this MOE is 

not of concern. EPA has concluded the combined short-term aggregated food, water, and 

residential exposures result in an aggregate MOE of 4,400 for children. Children’s residential 

exposure includes total exposures associated with contact with treated lawns (dermal and handto-mouth exposures). As the level of concern is for MOEs that are lower than 100, these MOEs 

are not of concern.
27

Table 8. Short-Term Aggregate Risk Calculations for Diisopropyl Adipate

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult Male 750 100 7.5 0.0379 0.0142 14,400

Adult 

Female

750

100

7.5

0.0379 0.0142 14,400

Child 750 100 7.5 0.1412 0.0283 4,400

1 The LOC (Level of Concern) is based on the standard inter- and intra-species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 6.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. 

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

E. Intermediate-Term Aggregate Risk. Intermediate-term aggregate exposure takes into account 

intermediate-term residential exposure plus chronic exposure to food and water (considered to 

be a background exposure level). Diisopropyl adipate is used as an inert ingredient in pesticide 

products that are currently registered for uses that could result in intermediate-term residential 

exposure and the Agency has determined that it is appropriate to aggregate chronic exposure 

through food and water with intermediate-term residential exposures to the diisopropyl adipate. 

Using the exposure assumptions described in section IV, EPA has calculated the combined 

intermediate-term aggregated food, water, and residential exposures. The adult aggregate MOE 

was calculated to be 16,600 for both males and females. Adult aggregate MOE combines 

average food and water exposure from the chronic dietary exposure with high end post 

application dermal exposure form contact with treated lawns. As the level of concern is for 

MOEs that are lower than 100, this MOE is not of concern. EPA has concluded the combined 

intermediate-term aggregated food, water, and residential exposures result in an aggregate 

MOE of 4,800 for children. Children’s residential exposure includes total exposures associated 

with contact with treated lawns (dermal and hand-to-mouth exposures). As the level of concern 

is for MOEs that are lower than 100, these MOEs are not of concern.

Table 9. Intermediate-Term Aggregate Risk Calculations for Diisopropyl Adipate

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult Male 750 100 7.5 0.0379 0.0072 16,600

Adult 

Female

750

100

7.5

0.0379 0.0072 16,600

Child 750 100 7.5 0.1412 0.0141 4,800

1 The LOC (Level of Concern) is based on the standard inter- and intra-species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 6.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. 

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].
28

F. Determination of Safety. Based on these risk assessments, EPA concludes that there is a 

reasonable certainty that no harm will result to the general population or to infants and children 

from aggregate exposure to residues of diisopropyl adipate.

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are evaluated 

based on likely maximum application rates for products which may contain the inert ingredient for 

the short-term exposure assessment, and average application rates for products likely to contain the 

inert ingredient for the intermediate- and long-term exposure durations. Active ingredient 

application rates are corrected for the maximum amount of inert ingredient likely to be in the final 

formulations to determine exposure and risk from exposure to the inert ingredient by 

fungicide/insecticide or herbicide. 

RD traditionally considers a level of concern (LOC) for these risk assessments to be an MOE 

of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors. 

A. Occupational Handler Risk

Exposure Scenarios

Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure 

Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The 

analystical techniques are those developed by the Science Policy Council on Exposure 

(ExpoSAC), Heath Effects Division, Office of Pesticide Programs, U.S. Environmental 

Protection Agency. The quantitative exposure/risk assessment developed for occupational 

handlers to support the requested exemption for the inert ingredient based on scenarios to 

represent the highest potential exposure. 

The algorithm used to estimate exposure is:

U.E. * AR * Units Treated/day * absorption factor ÷ body weight.

UE Unit Exposure in mg of material per lb of material handled. Unit Exposures 

are derived in the Pesticide Handlers Exposure Database (PHED) and are 

recently summarized in the “Occupation Pesticide Handler Unit Exposure 

Surrogate Reference Table” US EPA Office of Pesticide Programs, March 

2012 (unpublished)

AR Application Rate in lbs of material per unit (acres)

Units Treated/day - - In this case acres treated per day taken from the Health Effects 

Division Standard Operating Procedure 9.1 “Standard Values for Daily 

Acres Treated in Agriculture” Rev. 25 SEPT 2001 (unpublished) For aerial 

application 7500 A/day and for ground application 3000 A/day using ULV 

(ultra low volume) application technologies.
29

AF Absorption factor - - in this case assumed to be 100 % by the dermal and 

inhalation routes of exposure

BW Body Weight - - 80 kg for combined adults in the U.S. Taken from “Use of 

New Human Body Weight Data as Presented in the EPA’s Exposure Factors 

Handbook: 2011 Edition” HED “HotSheet” No. 31.

In this case occupational exposures are presented for aerial applicators, ground applicators 

and for mixer/loaders preparing and applying liquid formulations diluted for use in ULV 

applications. These are the occupational activities believed to be associated with the 

highest exposures relative to the proposed label use pattern(s). 

1. Unit Exposures are taken from “Occupational Pesticide handler Unit Exposure Surrogate Reference Table”, US EPA Office of 

Pesticide Programs, March 2012. 2. Application Rate = Calculated from registrant’s sample product labels. 3. Units Treated are taken from the Health Effects Division Standard Operating Procedure 9.1 “Standard Values for Daily Acres 

Treated in Agriculture: Rev. 25 SEPT 2001 (unpublished).

4. Average Daily Exposure = Unit Exposure * Application Rate * Units Treated ÷ 80 kg Body Weight 5. MOE = Margin of Exposure = NOAEL ÷ ADE. Short term NOAEL = 750 mg/kg bw/day 6. The PHED does not have unit exposures specific to applicators driving pickup trucks used for wide-area spraying. As a surrogate, 

the UE for Applicator, Open Cab Groundboom was used. The Agency believes that this is a conservative surrogate i.e., protective.

Both short- and intermediate-term dermal assessments, exposures assumed 100% dermal 

absorption due to absence of data. The inhalation toxicity and dermal toxicity was also 

assumed to be equivalent to oral toxicity. Risks were calculated using the Margin of 

Exposure (MOE) approach, which is a ratio of the exposure to the toxicological PoD. 

Occupational handler risks are not of concern. The Agency’s level of concern for 

Table 10. Summary of Exposure & Risk to Occupational Handlers From Diisopropyl Adipate

Unit Exposure1

mg inert/lb handled

Application 

Rate2

lb inert/unit

Units 

Treated3

Avg. Daily Exposure4

mg inert/kg bw/day

MOE5

Applicator, Open Cab Groundboom6

Dermal:

Single layer, no glove 

0.0786

Inhalation:

No respirator 

0.0012 

0.07

lb ai/A

3000 A/day Dermal:

Single layer, no glove 0.206

Inhalation:

No respirator 0.000893

3600

Applicator, Aerial, Fixed-Wing – Liquid

Dermal:

Enclosed cockpit 

0.005

Inhalation:

Enclosed cockpit 

0.068

0.07

lb ai/A

7500 A/day Dermal:

Enclosed cockpit 0.0328

Inhalation:

Enclosed cockpit 0.446

1600

Mixing / Loading Liquid

Dermal:

Single layer, no gloves 0.22

Single layer, gloves 

0.0376

Inhalation:

No respirator 

0.000219

0.07

lb ai/A

7500 A/day Dermal:

Single layer, no gloves 1.44

Single layer, gloves 

0.246

Inhalation:

No respirator 

0.00144

520 

(no gloves)

3036 

(Gloves)
30

inhalation and dermal exposure is for MOEs <100. In this case, the estimated MOEs are 

greater than 100 based on the assumption of 100% dermal absorption. Therefore, the 

estimated MOEs are not of concern. 

B. Occupational Post-Application Risk

Exposure Scenarios

RD uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to 

as re-entry exposure). Such exposures may occur when workers enter previously treated 

areas to perform job functions, including activities related to crop production, such as 

scouting for pests or harvesting. Post-application exposure levels vary over time and 

depend on such things as the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, and the chemical’s degradation properties. In 

addition, the timing of pesticide applications, relative to harvest activities, can greatly 

reduce the potential for post-application exposure. Inhalation exposures are not typically 

calculated for occupational post-application scenarios because inhalation exposures 

generally account for a negligible percentage of the overall body burden for most pesticide 

chemicals. 

This assessment is considered to be a screening level estimate, demonstrating that there are 

minimal potential risks to workers re-entering fields treated with pesticides containing 

diisopropyl adipate as inert ingredients. Therefore an occupational post application risk 

assessment was not performed.

VII. CUMULATIVE EXPSOURE 

Cumulative effects from substances with a common mechanism of toxicity, Section 

408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke 

a tolerance, the Agency consider “available information” concerning the cumulative effects of a 

particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found diisopropyl adipate to share a common mechanism of toxicity with any 

other substances, and diisopropyl adipate does not appear to produce a toxic metabolite produced 

by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that 

diisopropyl adipate does not have a common mechanism of toxicity with other substances. For 

information regarding EPA's efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at 

http://www.epa.gov/pesticides/cumulative.

IX. ENVIRONMENTAL JUSTICE STATEMENT 

Potential areas of environmental justice concerns, to the extent possible, were considered in 

this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 
31

Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, RD estimates risks 

to population subgroups from pesticide exposures that are based on patterns of that subgroup’s 

food and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Extensive data on food consumption patterns are compiled by the USDA under 

CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These 

data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized 

subgroups and exposure assessments are performed when conditions or circumstances warrant. 

Whenever appropriate, non-dietary exposures based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or playing on 

treated areas post-application are evaluated. Further considerations are currently in development 

as OPP has committed resources and expertise to the development of specialized software and 

models that consider exposure to bystanders and farm workers as well as lifestyle and traditional 

dietary patterns among specific subgroups

X. ENVIRONMENTAL FATE CONSIDERATIONS

Diisopropyl adipate is expected to have a minimal impact on the environment. The physical 

and chemical properties of diisopropyl adipate indicate it is readily biodegradable and will degrade 

rapidly in the environment. Diisopropyl adipate is expected to partition into both the water and the 

soil, based on the KOC and diisopropyl adipate in the water and soil will readily degrade. 

Diisopropyl adipate is not expected to bioconcentrate in aquatic organisms based on the low BCF. 

Diisopropyl adipate is not volatile, and is not expected to be released into the air. 

According to OECD SIDS Initial Assessment Report on Adipic Acid (2004), with regard to its 

chemical structure adipic acid is not expected to hydrolyze under environmental conditions. 

According to a Mackay calculation level I, the favorite target compartment of the substance 

(uncharged molecule) is water with 97%. It has to be considered, that at very low concentrations of 

adipic acid expected n the environment, the substance is mostly present as anion (i.e. 

deprotonated). As anions are neither subject to volatilization nor to adsorption, the hydrosphere is 

also the target compartment for the deprotonated molecule. The Henry’s law constant of 9.7 x 10-7

Pa m3 mol-1 (bond method) and of 8.8 x 10-2 Pa m3 mol-1 (ratio of vapor pressure versus solubility) 

at 25°C indicates that the compound has a low potential for volatilization from surface waters. The 

calculated half-life of adipic acid in air due to indirect photodegradation is t1/2 = 2.9 days. Adipic 

acid is readily biodegradable (MITI, comparable to OECD TG 301C: biodegradation 68-90% after 

14 days, OECD TG 301B: 91% after 28 days, closed bottle test OECD TG 301D: 83% after 30 

days). The bioconcentration factor BCF = 3 for adipic acid calculated from the octanol-water 

partition coefficient indicates that here is only a low potential for bioaccumulation of adipic acid in 

aquatic organisms. With a calculated Koc value of 22 adipic acid can be regarded as a substance 

without geoaccumulation potential.
32

XI. ECOTOXICITY

Based on the ready biodegradability of diisopropyl adipate and the generally low modeled 

partitioning of diisopropyl adipate into surface waters, effects of concern to nontarget aquatic 

species resulting from the use of diisopropyl adipate as an inert ingredient are not anticipated. 

Application rates of diisopropyl adipate as an inert ingredient will be low, limited to 40% of the 

formulation or less, which would not be expected to result in concentrations of concern for aquatic 

species. The ready biodegradability of diisopropyl adipate in the environment, and the low 

application rates of diisopropyl adipate indicate that chronic effects to aquatic species from 

diisopropyl adipate are particularly unlikely.

According to OECD SIDS Initial Assessment Report on Adipic Acid (2004), the toxicity of 

adipic acid to aquatic species are available with reliable experimental results of tests with fish, 

Daphnia and algae are available. The lowest valid effect data on acute fish toxicity was >1000 

mg/L (~1000 ppm) for Danio rerio (96 h-LC50) which is considered practically nontoxic. With 

Daphnia magna a 48 h-EC50-value of 85.6 mg/L (~86 ppm) was observed and considered slightly 

toxic. In an algae growth inhibition test with Desmodesmus subspicatus the 96 h-EC50 was 26.6 

mg/L. No tests are available on chronic toxicity of adipic acid.

Table 11. Test on acute toxicity of adipic acid to fish, Daphnia and algae

Species Test type Parameter Effects Reference IUCLID

Pimephales promelas Static 96 h-LC50 97 mg/l Mattson, Arthur and Walbridge 1976 4.1

Leuciscus idus Static 96 h-LC50

NOEC

230 mg/l

147 mg/l

BASF AG 1980 4.1

Danio rerio Static 96 h-LC50 >1000 mg/l BASF AG 1991 4.1

Daphnia magna Static 96 h-EC50 85.6 mg/l BASF AG 1988b 4.2

Desmodesmus subspicatus Static 96 h-EC50

72 h-EC50

26.6 mg/l

31.3 mg/l

BASF AG 1996 4.3

*Table was taken from OECD SIDS Initial Assessment Report on Adipic Acid 2004

OECD SIDS Initial Assessment Report on Adipic Acid (2004) states that several studies of 

toxicity of adipic acid towards terrestrial plants were found in the literature. Although none of 

these tests was performed according to guideline, the obtained effect values indicate that adipic 

acid is of low toxicity to terrestrial plants. 

Table 12. Effects of adipic acid on terrestrial plants

Plant Parameter Results Reference

Astragalus sinicus Root length EC0 = ca. 10 mg/l (measured) Pramanik et al. 2001

Raphanus sativus Seed germination EC0 = ca. 134 mg/l (measured) Kim et al. 2001

Triticum aestivum Primary root growth EC50 = ca. 170 mg/l (measured) Prill, Barton and Solt 1949

Lactuca sativa Seed germination EC50 = 6722 mg/l at pH 3.25 (measured) Reynolds 1975

*Table was taken from OECD SIDS Initial Assessment Report on Adipic Acid 2004

XII. RISK CHARACTERIZATION 

Technology Sciences Group Inc. (1150 18th Street, N.W. Suite 1000, Washington, D.C. 20036) 

submitted a petition (PP 2E8031) on behalf of Wellmark International (1501 E. Woodfield Road, 
33

Suite 200 West, Schaumburg, IL 60173), requesting an exemption from the requirement of a 

tolerance pursuant to section 408(d)(1) of the Federal Food, Drug, and Cosmetic Act with respect 

to diisopropyl adipate (DIPA) as an inert ingredient applied to growing crops only (40 CFR 

180.920) as a solvent at no more than 40% of formulation. It is intended to be used primarily in 

pesticides formulations for control of mosquitos. EPA published the Notice of Filing for this 

petition in the Federal Register on August 22, 2012 (77 FR 50665). No substantial comments were 

received in response to this notice. 

Based upon review of the data supporting the petition, the proposed use patterns may results in 

applications of pesticides post-harvest. Therefore EPA believes a more appropriate exemption 

would be under 40 CFR 180.910. EPA has modified the exemption requested to include an 

exemption from the requirement of a tolerance for residues of diisopropyl adipate (CAS Reg. No. 

6938-94-9) under 40 CFR 180.910 when used as an inert ingredient in pesticide formulations 

applied to growing crops or to raw agricultural commodities after harvest at no more than 40% of 

formulated products intended for mosquito control.

The acute oral toxicity of diisopropyl adipate in rodents, as expressed as an LD50, ranges from 

1,500 mg/kg to 8,800 mg/kg. In the guinea pig, the acute oral toxicity of diisopropyl adipate is 

about 6,600 mg/kg and in the rabbit, 5,000 mg/kg. In the dog, the acute oral LD50 of diisopropyl 

adipate is greater than 8,000 mg/kg. Diisopropyl adipate is minimally irritating to the eyes and skin 

of rabbits. 

The potential for toxicity following repeat dose exposure to diisopropyl adipate was evaluated 

based on toxicity studies with diisopropyl adipate as well as toxicity data on the two primary 

metabolites of diisopropyl adipate, adipic acid (CAS Reg. No. 124-04-9) and isopropyl alcohol 

(CAS Reg. No. 67-63-0). Isopropyl alcohol was previously assessed in the U.S. EPA inert 

reassessment document titled, Inert Reassessment –n-Propanol; CAS# 71-23-8, dated August 24, 

2005 and no end points of concern were identified. In addition, toxicity data from two structural 

analogues of diisopropyl adipate, dipropyl adipate and diisobutyl adipate, were also considered. 

These substances would be expected to have toxicological properties similar to diisopropyl adipate 

and can be used to supplement the available toxicity data on diisopropyl adipate. The studies 

summarized below were either performed with diisopropyl adipate, adipic acid, dipropyl adipate or 

diisobutyl adipate. 

In a 5 week study, guinea pigs that were administered adipic acid orally showed no adverse 

effects up to doses of 1000 mg/kg/day. In a 90 day oral toxicity study, male rats were given 0, 0.1, 

1 or 5% adipic acid and female rats were given 0 or 1% adipic acid. The NOAEL was 1% (1000 

mg/kg/day) and a LOAEL of 5% (5000 mg/kg/day) based on growth retardation in males. In a 19 

week oral toxicity study in rats, each rat was given 0, 50, 100, 200 or 400 mg adipic acid/rat/day. 

The NOAEL was 200 mg adipic acid/rat/day (equivalent to 1700 mg/kg/day) and the LOAEL was 

400 mg adipic acid/rat/day (equivalent to 3,400 mg/kg/day) was based on slight effects on liver 

and irritation of the intestine. In a 33 week subchronic oral toxicity study on groups of 13-15 male 

and female rats at doses of 0, 400, 800 mg/rat/day or approximately 0, 1600 and 3200 mg/kg 

bw/day adipic acid produced a LOAEL of 400mg/rat/day (equivalent to 1600 mg/kg bw/day) 

based on slight liver effects and inflammation of the intestine and no NOAEL was observed. In a 

3 week inhalation toxicity study, rats were exposed to 0.126 mg/L adipic acid for 6 hr periods daily 
34

for five days a week for a total of 15 exposures. No signs of toxicity were seen, blood tests gave 

normal values and autopsy results revealed all organs to be normal. 

The mutagenic potential of adipic acid was evaluated in a Host-Mediated Assay, in an in vivo

cytogenetics test, and a dominant lethal assay. These tests were negative. 

An OECD SIDS Initial Assessment Report on Adipic Acid (2004) concluded that adipic acid 

was not carcinogenic in a limited two-year feeding study where groups of twenty male rats were 

dosed with food containing 0, 0.1, 1, 3 and 5% (equivalent to 0, 75, 750, 2250 or 3750 mg/kg/day) 

adipic acid, and female rats were dosed with 0% (n=10) and 1% (n=19) adipic acid, respectively. 

The incidences of tumors observed in the adipic acid treated groups were observed at the same 

levels as in the control groups.

Developmental studies (FDRL 1972) via oral gavage using adipic acid on mice, rats, hamsters 

and rabbits showed no maternal or developmental toxicity. The NOAELs for mice, rats and 

hamsters were 263, 288 and 205 mg/kg/day, respectively. These studies were not conducted at the 

limit dose. However, the concern for developmental toxicity of diisopropyl adipate is low because 

no systemic toxicity was seen in chronic studies at doses near the limit dose. In addition, the 

developmental toxicity studies conducted with two analogue substances (dipropyl adipate and 

diisobutyl adipate) via intraperitoneal route showed no developmental toxicity at doses around 700 

mg/kg/day. 

An immunotoxicity study from the OECD SIDS 2004 IUCLID Data Set stated that the 

lymphocyte mitogenesis test was used to test for immunotoxicity in vitro. In this test lymphocytes 

were stimulated by a polyclonal mitogen specific for either B or T cells. Neither B nor T 

lymphocyte mitogenesis was inhibited by adipic acid at concentrations up to 0.3%.

There were no neurotoxicity studies available in the database. However, there were no clinical 

signs of neurotoxicity observed in the available studies.

There are no published metabolism studies on diisopropyl adipate specifically, but the 

metabolic pathways of diisopropyl adipate are proposed based on the characteristic molecular 

structure of diisopropyl adipate and the known metabolic pathways for structurally similar 

compounds. Diisopropyl adipate is a linear fatty acid diester that has an isopropyl group bound to 

the oxygen atom on each end of the molecule. Given these structural groups, diisopropyl adipate 

metabolism is almost certainly catalyzed by carboxylesterase enzymes that are ubiquitous 

throughout the body to produce adipic acid plus two molecules of isopropyl alcohol.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

Acute dietary risk assessment was not conducted because no endpoint of concern following a 

single or few exposures identified in the available studies. A chronic dietary exposure assessment 

was completed and performed using the Dietary Exposure Evaluation Model DEEM-FCIDTM, 

Version 3.16. The chronic RfD (cRfD) of 7.5 mg/kg/day was determined on the basis of the 

carcinogenicity study in rats. The LOAEL of 3% adipic acid (equivalent to 2250 mg/kg/day) is 
35

based on decreased in body weight gains seen in males. This study provided the lowest NOAEL 

(750 mg/kg/day for adipic acid in male and female rats) in the database (most sensitive endpoint) 

and will also provide the most protective limits for human effects. An UF of 100X (10-fold for 

interspecies extrapolation and 10-fold for intra species variability) was applied to the NOAEL of 

750 mg/kg/day to derive the cRfD. The FQPA safety factor of 1X is applicable for chronic dietary 

risk assessment. Therefore, the chronic population-adjusted dose (cPAD) is 7.5 mg/kg/day. This 

endpoint of concern was used for all dermal and inhalation exposure scenarios. Dermal and 

inhalation absorption is assumed 100%. 

Registration Division’s (RD’s) level of concern (LOC) for diisopropyl adipate occupational and 

residential dermal and inhalation exposures is 100 [i.e., a margin of exposure (MOE) greater than 

100 is not of concern to RD]. The LOC is based on a 10X uncertainty factor (UF) to account for 

interspecies extrapolation to humans from the animal test species and 10X UF to account for intraspecies sensitivity.

Short-term aggregate exposure takes into account short-term residential exposure plus chronic 

exposure to food and water (considered to be a background exposure level). Diisopropyl adipate is 

used as inert ingredients in pesticide products that are currently registered for uses that could result 

in short-term residential exposure and the Agency has determined that it is appropriate to 

aggregate chronic exposure through food and water with short-term residential exposures to 

diisopropyl adipate. EPA has concluded that the combined short-term aggregated food, water, and 

residential exposure result in aggregate MOEs of 14,400 for both adult males and females 

respectively. Adult residential exposure consists of high end post application dermal exposure 

from contact with treated lawns. As the level of concern is for MOEs that are lower than 100, this 

MOE is not of concern. EPA has concluded that the combined short-term aggregated food, water 

and residential exposure results in an aggregate MOE of 4,400 for children. Children’s residential 

exposure includes total exposures associated with contact with treated surfaces (dermal and handto-mouth exposures). As the level of concern is for MOEs that are lower than 100, these MOEs are 

not of concern. 

Intermediate-term aggregate exposure takes into account intermediate-term residential exposure 

plus chronic exposure to food and water (considered to be a background exposure level). 

Diisopropyl adipate is currently registered for uses that could result in intermediate-term 

residential exposure and the Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with intermediate-term residential exposures to diisopropyl 

adipate. EPA has concluded that the combined intermediate-term aggregated food, water and 

residential exposures results in aggregate MOEs of 16,600 for adult makes and females. Adult 

residential exposure consists of contact with treated lawns. EPA has concluded the combined 

intermediate-term aggregated food, water and residential exposure results in an aggregate MOE of 

4,800 for children. Children’s residential exposure includes total exposures associated with contact 

with treated surfaces (dermal and hand-to-mouth exposures). As the level of concern is for MOEs 

that are lower than 100, this MOE is not of concern. Dietary cancer risk was not calculated because 

the Agency has no identified any concerns for carcinogenicity relating to diisopropyl adipate. 

Occupational handler risks are not of concern for all scenarios. RD notes that the occupational 

handler assessment assumes that mixer/loader/applicators wear protective gloves when using open 
36

pour in support of aerial and groundboom application. The estimated MOEs are greater than 100 

based on 100% dermal absorption. Therefore, the estimated MOEs do not exceed the Agency’s 

level of concern. This assessment is considered to be a screening level estimate, demonstrating that 

there are minimal potential risks to workers re-entering fields treated with pesticides containing 

diisopropyl adipate as inert ingredients. Therefore an occupational post application risk assessment 

was not performed.

Based on the ready biodegradability of DIPA and the generally low modeled partitioning of 

DIPA into surface waters, effects of concern to nontarget aquatic species resulting from the use of 

DIPA as an inert ingredient are not anticipated. Acute toxicity studies performed with adipic acid 

on fish, invertebrates and algae showed that the compound was slight to practically nontoxic. Open 

literature studies utilizing adipic acid on terrestrial plants showed low toxicity as well. Diisopropyl 

adipate is not expected to pose an environmental fate concern due to its biodegradability. Adipic 

acid is expected to partition mainly to the water however based on the acute aquatic toxicity 

studies which showed low toxicity to aquatic organisms, this is not expected to be of concern.

Taking into consideration all available information on diisopropyl adipate, EPA concludes that 

there is a reasonable certainty that no harm to any population subgroup will result from aggregate 

exposure to diisopropyl adipate when considering occupational, dietary exposure and all other 

nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, 

the establishment of an exemption from tolerance under 40 CFR 180.910 for residues of 

diisopropyl adipate (CAS Reg. No. 6938-94-9) when used as a pesticide inert ingredient for preand post-harvest food use as a solvent intended to be used primarily for control of mosquitoes at no 

more than 40% in formulated products, can be considered assessed as safe under section 408(q) of 

the FFDCA.
37

REFERENCES

BASF AG (1978c). Unpublished data, Bericht ueber die Pruefung der akuten oralen Toxizitaet von 

Adipinsaeure an der Ratte, March 28, 1978c.

BASF AG (1981). Unpublished data, Akute Inhalationstoxizitaet LC50 an der Ratte, StaubAerosol-Versuch, July 31, 1981.

CIR, 1984. Final report on the safety assessment of dioctyl adipate and diisopropyl adipate. J. 

American College of Toxicology 3(3); 101-130.

DuPont Company, Haskell Laborartory, Unpublished Data, Toxicity of Adipic Acid, 1943.

Food and Drug Research laboratories, Inc. Teratologic evaluation of FDA 71-50 (adipic acid). 

Submitted to Food and Drug Administration (Contract FDA 71-26). February 26, 1974. National 

Technical Information Service, U.S. Department of Commerce. NTIS PB221802.

Gage, J.C. The Subacute Inhalation Toxicity of 109 Industrial Chemicals. Br. J. Ind. Med. 1970, 

27, 1-18.

Hazleton Laboratories, Unpublished Data, Acute Toxicity, 1950.

Horn HJ, Holland EG, and Hazleton LW (1957). Safety of adipic acid as compared with citric and 

tartaric acid. Agricult. Food Chem. 5, 759-762.

Kennedy GL Jr. 2002. Toxicity of adipic acid. Drug and Chemical Toxicology 25(2) 191-202.

Lang K and Bartsch A-R (1953). Ueber den Stoffwechsel und die Vertraeglichkeit der 

Adipinsaeue. Biochem. Z. 323, 462-468.

Lanigan RS. 2001. Final report on the safety assessment of Steearamide DIBA-Stearate. Int. J. 

Toxicol. 2001;20 Suppl 3:91-7. 

Litton Bionetics, Inc. (1974). Mutagenic Evaluation of Compound FDA 71-50, Adipic Acid, 

Report No. FDABF-GRAS-310. PB-245466, 1-138, December 9, 1974.

Litton Bionetics, 1974. Summary of Mutagenicity Screening Studies; Host-mediated assay, 

cytogenetics, dominant lethal assay. Contract FDA 71-268. Compound FDA 71-50, Adipic acid. 

Submitted to Food & Drug Administration Department of Helath Education and Welfare, 

Rockville, MD. Submitted by: Litton Bionetics, Inc. project No. 2446. December 9, 1974.

Parkinson A & Ogilvie BW, 2008. Biotransformation of xenobiotics; Carboxylesterases section. 

In: Casarett & Doull’s Toxicology The Basic Science of Poisons. Ed. Curtis Klassen. McGraw Hill 

Medical New York. Pages 177-178
38

Rusoff II, Baldwin RR, Domingues FJ, Monder C, Ohan WJ, Thiessen R, Jr. 1960. Intermediary 

metabolism of adipic acid. Toxicology and Applied Pharmacology 2:316-330.

Singh AR, Lawrence WH, Autian J, 1973. Embryonic-fetal toxicity and Teratogenic effects of 

adipic acid esters in rats. J. Pharmaceutical Sciences 62 (10); 1596-1600.

Solutia Inc. Data, YO-75-187 (1975). Cited in Robust Summary for dicarboxylic acid category

(prepared for US HPV Challenge program), Du Pont, July, 11, 2001.

US EPA. 2009. Estimation Programs Interface Suite for Microsoft Windows, v 4.00. United States 

Environmental Protection Agency, Washington, DC, USA.

US EPA. 2005. Inert Reassessment –n-Propanol; CAS # 71-23-8. United States Environmental 

Protection Agency. Washington, DC. USA.

US FDA, 1976. Select Committee on GRAS Substances Opinion: Adipic Acid. Database of Select 

Committee on GRAS Substances (SCOGS) Reviews.
39

APPENDIX

U.S. EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for INERTS-DIPA NHANES 2003-2008 2-day

Residue file name: E:\DEEM\DIPA.R08 Adjustment factor #2 used.

Analysis Date 01-31-2013/12:17:29 Residue file dated: 01-31-2013/10:34:11

Reference dose (RfD, Chronic) = 7.5 mg/kg bw/day

COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.037869 0.5%

Hispanic 0.041352 0.6%

Non-Hisp-White 0.037160 0.5%

Non-Hisp-Black 0.035190 0.5%

Non-Hisp-Other 0.044671 0.6%

Nursing Infants 0.049641 0.7%

Non-Nursing Infants 0.091947 1.2%

Female 13+ PREG 0.033048 0.4%

Children 1-6 0.109335 1.5%

Children 7-12 0.045482 0.6%

Male 13-19 0.026752 0.4%

Female 13-19/NP 0.027186 0.4%

Male 20+ 0.028199 0.4%

Female 20+/NP 0.030632 0.4%

Seniors 55+ 0.030537 0.4%

All Infants 0.078886 1.1%

Female 13-50 0.029281 0.4%

Children 1-2 0.141248 1.9%

Children 3-5 0.097127 1.3%

Children 6-12 0.050111 0.7%

Youth 13-19 0.026960 0.4%

Adults 20-49 0.028948 0.4%

Adults 50-99 0.030358 0.4%

Female 13-49 0.029267 0.4%

-------------------------------------------------------------------------------