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 ex posure

................................ ................................ ................................ ................................ 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. O ccupational 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

................................ ................................ ................................ ................................ ................................ .... 393 EXECUTIVE SUMMARY

Technology Sciences Group Inc. (1150 18 th 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

toleranc e 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.

B ased 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 reques ted 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 com modities 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 LD 50 , 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 LD 50 of diisopropyl adipate is greater than 8,000 mg/kg. D iisopropyl 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 u sed 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 ac id. 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 male4 and fe male 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 obs erved. 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 (2 004) 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 we re 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 develo pmental 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 ad ipate) 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 databas e. 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 charact eristic molecular

structure of diisopropyl adipate and the known metabolic pathways for structurally similar compounds. D iisopropyl adipate is a linear fatty acid diester that has an isopropyl group bound to the oxygen atom on each end of the molecule. Giv en 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 d ata 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 st udies. A chronic dietary exposure assessment was completed and performed using the Dietary Exposure Evaluation Model DEEM

- FCID TM

, 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)

a nd 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 intra

species sensitivity.

Short

- term aggregate exposure takes into account short

- term residential exposure plus chronic

exp osure 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 de termined 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 agg regate 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 hand

to

- 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 exposur e 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

e xposure 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 a nd 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 exposu re includes total exposures associated with contact with treated surfaces (dermal and hand

- to

- mouth exposures). As the level of concern is for MOEs6 that are lower than 100, this MOE is not of concern. Dietary cancer risk was not calculated because the Agen cy 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 estima ted 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 t o 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 model ed 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 showe d 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 diis opropyl 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 fr om tolerance under 40 CFR 180.91 0 for residues of diisopropyl adipate (CAS Reg. No. 6938

- 94

- 9) when used as a pesticide inert ingredient for pre

an d 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 18 th 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 pr imarily 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. D iisopropyl 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 c rops 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 l imited 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 reque sted 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 co mmodities 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

- foo d use purposes. D iisopropyl 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.

D iisopropyl a dipate 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 chemical8 characteristics of adipic acid, along with its struc ture 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/cm 3 @ 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/cm 3 @ 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) pKa 1 = 4.34 pKa 2 = 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 follow ing 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 Augus t 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 ab normal 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% diisop ropyl 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 LD 50 value of 5,560 mg/kg bw was established in a study similar to OECD TG 401 perf ormed 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 congestiv e 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 LD 50 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 d istention 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 Ingredien t 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 produ ct 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 let hality 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 attain able concentration of 7,700 mg/m 3 (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 batche s 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 w ere 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 irrita tion 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. A fter 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 perce ptible 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 w ith 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 In halation

-
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

G uinea 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 receiv ing 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 an d 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 to 1700 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

de aths 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 recei ved 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 histopatholo gy of liver, kidneys and intestine w as 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 survivin g 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 m g/ 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

Accord ing to the OECD SIDS Initial Assessment Report on Adipic Acid (2004), a two

year 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

f

emale 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 were14 w eighed, 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 gai ns of the male rats receiving 3 and 5% adipic acid were significantly less than the control groups. At necropsy there was no treatment related effect s observed. Results of microscopic examination of the organs revealed no compound related effect. The NOAEL was 1% for male and female rats ( equivalent to 750 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 du st 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 inci dences 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 lo w, 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 in dicated.

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, 1 2, 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 anesth esia 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 fet uses 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 inc rease 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 developmenta l 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 o f 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

g ravity 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 bas ed 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 see n 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 n o. 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. Cons equently 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 eviden ce 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 28 8, 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

meta bolic 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

- 1 530, and G

46, 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 e xposing 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 administ ered 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 adipi c 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 si gnificant 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 test s in vitro and in vivo have failed to demonstrate that adipic acid possesses17 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 pr oduced 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

struct urally 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 interac tions. 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 di ester 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 prod uce 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 es te r

- 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 o f 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 sh ort

- 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 diisopro pyl 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 a dipic 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 to xicity 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: ure a, glutamic acid, lactic acid, beta

- ketoadipic acid and18 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 wa s 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 18 4.1009), and it meets the specifications of the Food Chemicals Codex, 3 rd 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 fo ods 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 furthe r 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 carbo n 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 Toxici ty 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/L19 Table 4 . Toxicology Profile for Diisopropyl Adipate and Adipic Acid

Guideline No./ Study Type Doses Levels MRID No. (year)/ References Results

Developmen tal 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 ca rcinogenicity was

not observed.

Host

- Mediated Assay ( Salmonella typhimurium

strains TA

- 1530, and G

46, 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 wer e 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 f or20 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 developm ental 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 toxi city 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 selectio n 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/da y. 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 diisopr opyl 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 7 50 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

UF A = 10 x UF H = 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

UF A = 10 x UF H = 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

UF A = 10 x UF H = 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 %

UF A = 10 x UF H = 10 x FQPA SF = 1 x 2250 mg/kg/day based on based on body weight retardation.

Dermal intermediate

term (1 to 6 months) Dermal (or oral) study NOAEL =

750 mg/kg/day (dermal absorption rate = 100 %

UF A = 10 x UF H = 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%)

UF A = 10 x UF H = 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%)

UF A = 10 x UF H = 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.

UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivit y among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of data or other data deficiency. FQPA SF = Food Quali ty 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 differe nt 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 an d 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 toxici ty was not observed at doses as high as 288 mg/kg/day. Also, in a22 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 limi t 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 d iisopropyl 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 developmenta l 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

r esidues 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, t here 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 attributa ble 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

- FCID TM , Version 3.16 , EPA used food consumption information from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What we e at in America, (NHANES/WWEIA). This dietary

survey was conducted from 2003 to 2008 . As to residue levels in food, n o residue data

were submitted for diisopropyl adipate . In the absence of specific residue data, EPA has23 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 Aggregat e (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 EPA

HQ

- OPP

- 2008

- 0738.

In the dietar y 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 t he 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 ingredi ent 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 in gredients, 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 sum mary, 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 c onsideration was given to potential degradation between harvest and consumption even though monitoring data shows that24 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 approac h 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 commoditie s. 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

conc luded 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 ass ess cancer risk.

B. Residential Exposure

The term “residential exposure” is used in this document to refer to non

- occupational, non

dietary 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 cr ops, 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

tw o 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 purpos es. 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

- case25 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 w ere 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 Rate 1 Exposed Population & Exposure

Duration 2 Daily Dose (mg/kg/day) 3 MOE 4

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 intermediate

term MOE was calculated to be 100,000 from dermal exposure to treated lawns. As the

level of concern is for MO Es that are lower than 100, these MOE s 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. A GG REGATE 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 ca lculates the aPAD26 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 b y 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 R isk

. An acute aggregate risk assessment takes into account e xposure estimates from acute dietary consumption of food and drinking water using the exposure assumptions discussed in section IV for acute exposure

. However t here was no hazard attributable to a single exposure seen in the toxicity database for the diiso propyl adipate; therefore an acute aggreg ate risk assessment is not required.

B . Chronic Dietary R isk. A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary consumption of food and drinking water u sing 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

. T he 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. P opulation

. 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

- T erm Aggregate R isk

. Short

- term aggregate exposure takes into account short

- term residential exposure plus chronic exposure to food and water (considered to be a bac kground 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 14,4 00 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 aggre gate MOE of 4,400 for children. Children’s residential

ex posure 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, t hese MOEs

are not of concern.27 Table 8

. Short

- Term Aggregate Risk Calculations for Diisopropyl Adipate

Population PoD mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food &

Water Exposure 3
mg/kg/day Residential Exposure 4
mg/kg/day Aggregate

MOE (food and residential) 5

Adult Male 750 100 7.5 0.0379 0. 0142 14, 4 00

Adult

Female 750 100 7.5 0.0379 0. 0142 1 4,4 00

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

- T erm Aggregate R isk

. 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 i t 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 aggreg ated 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 derma l 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

M OE 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 LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food &

Water Exposure 3
mg/kg/day Residential Exposure 4
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 . Determi nation of S afety . Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will r esult to the general population or to infants and children from aggregate exposure to residues of diisopropyl adipate

.

VI. O CCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are evaluated based on likely maximum applicat ion 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 ingredie nt 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 o f 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 expo sure.

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 applicatio n 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 Presente d in the EPA’s Exposure Factors

H andbook: 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 li quid 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. Applic ation 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 Ex posure = Unit Exposure * Application Rate * Units Trea ted ÷ 8 0 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 Applic ator, Open Cab Grou n dboom 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 Occupatio nal Handle rs From Diisopropyl Adipate Unit Exposure 1
mg inert /lb handled Applic ation

Rate 2

lb inert /unit Units

Treated 3 Avg. Daily Exposure 4

mg inert /kg bw/day MOE 5

Applicator, Open Cab Groundboom 6

Dermal:

S ingle l ayer, n o g love

0.0786

Inhal ation : No r espirator

0.0012 0. 07

lb ai/A 3000 A/day Dermal:

S ingle l ayer, n o g love 0.206

Inhalation : No r espirator 0.000893 3600

Applicator, Aerial, Fixed

- Wing

– Liquid

Dermal:

E nclosed c ockpit

0.005

Inhal ation:

Enclosed c ockpit

0.068 0. 07

lb ai/A 7500 A/day Dermal:

E nclosed c ockpit 0.0328

Inhal ation:

E nclosed c ockpit 0.446 1600

Mixing / Loading Liquid

Dermal:

S ingle l ayer , no gloves 0.22 Single layer, gloves

0.0376

Inhal ation: No respirator

0.000219 0. 07

lb ai/A 7500 A/day Dermal: Single layer, no gloves 1.44 Single layer, gloves

0.24 6

Inhalation: No respirator

0.00 144 520 (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. Occup ational Post

- A pplication 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 acti vities, 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

.

VI I

. C UMULATIVE 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 n ot 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 h as 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. E NVIRONMENTAL JUSTICE STATEMENT

Potential areas of environmental justice concerns, to the extent possible, were consid ered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal31 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, R D 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. A dditionally, 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 develo pment 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. E NVIRONMENTAL 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 t he water and the soil, based on the K OC 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 exp ected 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 le vel 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 m 3 mol - 1 (bond method) and of 8.8 x 10 - 2 Pa m 3 mol - 1 (ratio of vapo r 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 t 1/2 = 2.9 days. Adipic acid is readily biodegr adable (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 parti tion coefficient indicates that here is only a low potential for bioaccumulation of adipic acid in aquatic organisms. With a calculated K

oc value of 22 adipic acid can be regarded as a substance without geoaccumulation potential.32 X I

. E COTOXICITY

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 a re 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 o f 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 acu te fish toxicity was >1000 mg/L (~1000 ppm) for Danio rerio (96 h

- LC 50 ) which is considered practically nontoxic. With Daphnia magna a 48 h

- EC 50 - value of 85.6 mg/L (~86 ppm) was observed and considered slightly toxic. In an algae growth inhibition test wit h Desmodesmus subspicatus the 96 h

- EC 50 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

- LC 50 97 mg/l Mattson, Arthur and Walbridge 1976 4.1

Leuciscus idus Static 96 h

- LC 50 NOEC 230 mg/l 147 mg/l BASF AG 1980 4.1

Danio rerio Static 96 h

- LC 50 >1000 mg/l BASF AG 1991 4.1 Daphnia magna Static 96 h

- EC 50 85.6 mg/l BASF AG 1988b 4.2 Desmodesmus subspicatus Static 96 h

- EC 50 72 h

- EC 50 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 EC 0 = ca. 10 mg/l (measured) Pramanik et al. 2001 Raphanus sativus Seed germination EC 0 = ca. 134 mg/l (measured) Kim et al. 2001

Triticum aestivum Primary root growth EC 50 = ca. 170 mg/l (measured) Prill, Barton and Solt 1949

Lactuca sativa Seed germination EC 50 = 6722 mg/l at pH 3.25 (measured) Reyno lds 1975 *Table was taken from OECD SIDS Initial Assessment Report on Adipic Acid 2004

XII. R ISK CHARACTERIZATION

Technology Sciences Group Inc. (1150 18 th 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 reque sted 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 co mmodities 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 LD 50 , ranges from 1,500 mg/kg to 8,800 mg/kg. In the guinea pig, the acute ora l toxicity of diisopropyl adipate is about 6,600 mg/kg and in the rabbit, 5,000 mg/kg. In the dog, the acute oral LD 50 of diisopropyl adipate is greater than 8,000 mg/kg. D iisopropyl adipate is minimally irritating to the eyes and skin

of rabbits.

The p otential 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 us ed 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 a dipic 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

40 0 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 approxi mately 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 wer e exposed to 0.126 mg/L adipic acid for 6 hr periods daily34 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, resp ectively. 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 n ot 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 w ith 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 mi togenesis 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 pa thways of diisopropyl adipate are proposed based on the characteristic molecular

structure of diisopropyl adipate and the known metabolic pathways for structurally similar compounds. D iisopropyl 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 mole cules 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

- FCID TM

, 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) is35 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 extrapolati on 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 a ccount for intra

species 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 exposur es 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 pos t 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 i n an aggregate MOE of 4,400 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, these MOEs a re 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 th at 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

intermedia te

- 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 l evel 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 open36 pour in support of aerial and groundboom application. The estima ted 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 t o 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 st udies 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 expec ted 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 o f 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 o ccupational, dietary exposure and all other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption fr om tolerance under 40 CFR 180.91 0 for residues of diisopropyl adipate (CAS Re g. No. 6938

- 94

- 9) when used as a pesticide inert ingredient for pre

and 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, Staub

Aerosol

- 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 Adipi c 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 Commer ce. 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,

R eport 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 F ood & 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

- 17838 Rusoff II, Baldwin RR, Domingues FJ, Monder C, Ohan WJ, Thiessen R, Jr. 1960. Intermediary metabolism of adipic acid. Toxicology an d 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 S ummary 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.

U S 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

- H isp

- 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%

-------------------------------------------------------------------------------