Document ID: EPA-HQ-OPP-2019-0569-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2022-01-04T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
			WASHINGTON, D.C.  20460

							OFFICE OF CHEMICAL SAFETY 								                     AND POLLUTION PREVENTION

MEMORANDUM  

DATE:		October 12, 2020

SUBJECT:      IN-11317; Adipic Acid: Human Health Risk and Ecological Effects Assessment 
      of a Food Use Pesticide Inert Ingredient 
 
            CAS Reg. No.: 124-04-9 
                  PC Code:  900282     
                  Decision:  551267

FROM:	Deirdre Sunderland, MHS 
      Industrial Hygienist
		Chemistry, Inerts & Toxicology Assessment Branch (CITAB)
		Registration Division (RD); 
	

TO:		Kerry B. Leifer 
      Branch Chief
		CITAB/RD 

 EXECUTIVE SUMMARY

In May 2019, Ecolab, Inc. submitted a petition (IN-11317) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting an exemption from the requirement of a tolerance for adipic acid (CAS Reg. No. 124-04-9) under 40 CFR § 180.940(a) when used as an inert ingredient in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils at a maximum of concentration of 100 parts per million (ppm). Adipic acid is currently approved for use as a nonfood use inert ingredient. 

Adipic acid is found naturally in select foods (e.g., beets and sugar cane) and is intentionally added to various other foods and beverages. It is also used in pharmaceuticals, cosmetics, and various industrial products. Adipic acid has been the subject of various peer-reviewed assessments (e.g., the Cosmetic Ingredient Review (CIR), the Organization for Economic Cooperation and Development (OECD) Screening Information Dataset (SIDS), and the Food and Agricultural Organization of the United Nations (FAO) and the World Health Organization (WHO) Joint Expert Committee on Food Additives (JECFA)) which are utilized in this risk assessment to aid in making a safety determination for adipic acid. 

Available acute studies on adipic acid include oral, dermal, and inhalation toxicity studies. In addition, various dermal and eye irritation studies, and a dermal sensitization study were available. Adipic acid has very low acute toxicity with an oral median lethal dose (LD50) in rats > 5000 mg/kg and 1900 mg/kg in mice. The dermal LD50 in rabbits was >7940 mg/kg as no mortality was seen. The inhalation LC50 in rats was > 7.7 mg/L as once again, no mortality was observed. Adipic acid produced slight/mild skin irritation and was not a skin sensitizer. Adipic acid is an eye irritant.  

Although quite often limited in scope and/or documentation, repeat dose oral toxicity testing in rats for adipic acid included a 4-week, 5-week, 19-week, 33-week, and a 2-year study. A 6-week oral guinea pig study was also carried out. All studies showed no/low toxicity and no reproductive/developmental toxicity was seen in any of the species tested. Adipic acid also tested negative for genotoxic effects in various in vitro and in vivo studies. In addition, there was no evidence of carcinogenicity or neuropathological changes or effects reported in any of the studies. The agency does not believe adipic acid will be carcinogenic or neurotoxic. The primary systemic health effect associated with adipic acid is irritation of the intestinal mucosa and decreased body weight at doses above the limit dose.  

A review of currently approved pesticide products containing adipic acid found that the majority of products were hard surface cleaners. Based on the current and proposed use pattern of adipic acid, dietary and residential exposure from pesticidal uses are expected. However, no endpoint of concern was identified in the database below the limit dose of 1000 mg/kg/day; therefore, a quantitative assessment of human exposure was not necessary. As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. 

Adipic acid does not present a hazard for the environment and was only slightly toxic to aquatic systems. Overall, the widespread use of adipic acid in foods, drugs, and cosmetics, in combination with the natural occurrence of adipic acid in certain foods, indicate that this compound does not pose a safety risk at doses proposed as an inert ingredient in pesticide formulations. 

Based upon the factors summarized above, the Agency is establishing an exemption from the requirement of a tolerance for adipic acid under 40 CFR § 180.940(a) as an inert ingredient in food use pesticide formulations at a maximum concentration of 100 part per million (ppm) in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils.

 BACKGROUND

In May 2019, Ecolab, Inc. submitted a petition (IN-11317) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting an exemption from the requirement of a tolerance for adipic acid (CAS Reg. No. 124-04-9) as an inert ingredient (acidulant) in pesticide formulations under 40 CFR § 180.940(a) at a maximum of concentration of 100 parts per million (ppm) when used in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils. Adipic acid is currently approved for use as a nonfood use inert ingredient and has widespread use in foods, cosmetics, pharmaceuticals, and in manufacturing. 

In foods, adipic acid occurs naturally in beets, sugar cane, ripe fruits of Morinda citrifolia (Indian Mulberry, Noni) and rice straw. (MRID 50847716) It is also intentionally added to various foods (e.g., as a flavoring agent, as a leavening agent in baked goods, as an acidulating agent for gelatin and jams, and as a neutralizing agent and buffer). Adipic acid is listed as a Generally Recognized as Safe (GRAS) food additive by the Food and Drug Administration (FDA) under 21 CFR 184.1009 which includes uses in baked goods, nonalcoholic beverages, condiments and relishes, dairy products, fats and oils, frozen dairy desserts, gelatins and puddings, gravies, and meat products, etc. According to Organization for Economic Cooperation and Development (OECD) Screening Information Dataset (SIDS), adipic acid is used in concentrations up to 10,000 mg/kg foodstuff. (MRID 50847716) 

In cosmetics, adipic acid acts as a pH adjuster or fragrance ingredient at concentrations up to 18%. (MRID 50847702) As a pharmacological agent, adipic acid is incorporated into controlled-release tablets to obtain pH-independent release. It is also used in some antacids to make them tart.

Adipic acid has various industrial uses including its use in the production of nylon, adhesives, plasticizers, gelatinizing agents, hydraulic fluids, lubricants, emollients, polyurethane foams, leather tanning, and urethane. (MRID 50847702, 50847707) It is also used as a "pH regulator in processes such as in the production of cleaning agents, pelletizing agent in disinfectant pills for drinking water, additive in flue gas sulfurization, in the coating of dishwashing machine tablets and as an additive in chemicals".(MRID 50847707)  "However, the bulk of the industrial production of adipic acid is driven by its usefulness in the manufacture of nylon-6,6 (in combination with 1,6- hexanediamine)." (MRID 50847702)

In 1977 and again in 1999, the Food and Agricultural Organization of the United Nations (FAO) and the World Health Organization (WHO) Joint Expert Committee on Food Additives (JECFA) concluded that the Acceptable Daily Intake (ADI) of adipic acid was 0-5 mg/kg body-weight. 

 PHYSICAL/CHEMICAL PROPERTIES 

Adipic acid is a dicarboxylic acid - an organic compound that contain two functional carboxylic acid ( - COOH) groups. Adipic acid is a white, crystalline solid with low water solubility. Table 1 lists the available physical and chemical properties for adipic acid. 

             Table 1: Physical/Chemical Properties of Adipic Acid
Characteristic
Value
Source (MRID)
Synonyms 
Hexanedioic acid; 
1,4-butanedicarboxylic acid;
1,6-Hexanedioic acid
50847711
50847706
50847716
Structure

Multiple
Structural Formula
COOH(CH2)4COOH
Multiple
Molecular Weight
146.14
50847702
Appearance
White monoclinic prisms
50847702
Density (g/cm[3])
 1.36 @ 25°C
50847702, 50847711, 50847716
Melting point
152°C
50847702, 50847711, 50847716
Boiling point 
265°C
330°C
337.5°C
50847702
50847711 
50847716
Vapor Pressure
0.07 mmHg @ 25°C 
9.7 Pa @ 18.5°C
50847702, 
50847716, 50847711
Water Solubility (g/L)
30 at 25°C
23 at 25°C
50847702
50847716
Log Kow
0.081
0.093 at 25°C
50847702, 50847711
50847716
pKa
4.34 and 5.44
50847716

 METABOLISM

After administration, adipic acid is primarily excreted in the urine or exhaled as carbon dioxide. Like many of the studies on adipic acid, the investigations into the metabolism of adipic acid are quite old and the full study reports were often not available to EPA. The various studies/reviews differ in the amount of excretion that is partitioned to urine versus expiration; however, they consistently show that primary routes of excretion are via urine or respiration. 

In general, dicarboxylic acids such as adipic acid are rapidly oxidized, resulting in very low cellular concentrations and practically non-detectable concentrations in the plasma. (MRID 50847702) Medium chain dicarboxylic acids (C8-C12) are metabolized via the beta-oxidation pathway in mitochondria and peroxisomes. (MRID 50847705) The beta-oxidation of dicarboxylic acids in the peroxisomes ceases when 6 C atoms remain (i.e. adipic acid). The adipic acid is then liberated from the peroxisomes to enter the cytosol, where it is taken up by mitochondria and activated to adipyl-CoA. Carboxylic acids chains with an even number of carbons, like adipic acid, are then completely oxidized and produce succinyl-CoA, a gluconeogenic substrate, as an intermediate metabolite. (MRID 50847702) 

According to the CIR (MRID 50847702):

      Adipic acid metabolism was studied using fasted male albino rats.[*] In 1 study, in which the rats were given a single oral dose, by gavage, with 50 mg radioactive adipic acid (labeled on C1 or C2), 70% of the radioactivity was exhaled as carbon dioxide in 24 hours. Adipic acid and the metabolites urea, glutamic acid, lactic acid, β-ketoadipic acid, and citric acid were recovered in the urine. Very little radioactivity was found in the tissues. Fasted male rats were also given a single dose of a solution containing 50 mg radioactive adipic acid (labeled on C1), by gavage, in conjunction with the intraperitoneal (ip) injection of 2 mL of 0.5 mol/L sodium malonate. After 24 hours, both radioactive adipic acid and succinic acid were found in the urine, which the researchers stated was an indication that adipic acid underwent β oxidation. In a study in which the rats were fed 25 mg radioactive adipic acid (labeled on C1) and 100 mg γ-phenyl-α-aminobutyric acid, followed by a 48-hour urine collection, it was determined that acetate is a metabolite of adipic acid. Finally, rats were given radioactive sodium bicarbonate with nonradioactive adipic acid. Radioactive citric acid was formed, which suggested that carbon dioxide interacted with a metabolite of adipic acid. (Details not specified.) 
      *Internal Citation: Organisation for Economic Co-Operation and Development. IUCLID data set for adipic acid. http://www.chem.unep.ch/irptc/sids/OECDSIDS/124049.pdf. Accessed July 29, 2010.

According to the OECD SIDS (MRID 50847716):

      When adipic acid or its sodium salt was administered to non fasted rats, rabbits and one dog 18  - 71 % of the doses were excreted in the urine. Breath was not analyzed in these studies (Mori 1918; Bernhard and Andreae 1937; Enders 1941). In an oral 28-day subacute study in rats excretion of adipic acid was similar from day 1 to 28, indicating that adipic acid did not accumulate during the treatment. Breath was not analyzed, (Enders 1941). It is unclear whether the methods of detection in these early studies were reliable.
      *Internal Citations: Mori Y (1918). The decomposition of muconic and adipic acids in the animal body. J. Biol. Chem. 35, 341-351. 
      Bernhard K and Andreae M (1937). Stoffwechselversuche mit Dicarbonsaeuren. Hoppe-Seylers Z.
      physiol. Chem. 245, 103-106.
      Enders A (1941). Vertraeglichkeit und Ausscheidungsverhaeltnisse von Dicarbonsaeuren. Arch Exp
      Pathol Pharmakol 197, 597-610.

And further, Kennedy (MRID 50847711) states that:
     
     The presence of beta-ketoadipic acid provided some evidence that the adipic acid is metabolized by beta-oxidation in a similar fashion as fatty acids. The presence of radioactive acetyl-gamma phenyl- alpha-aminobutyric acid after feeding gamma-phenyl-alpha-aminobutyric acid and radiolabeled adipic acid provided evidence that acetate is a metabolite of adipic acid...After repeated feedings of adipic acid to rats, the urinary excretion of adipic acid dropped to zero within 24 h after the last feeding (five days for rabbits). Whole-body analysis of rats sacrificed 24 or 72 h after the last adipic acid feeding showed no accumulation of adipic acid in body tissues.* However, another study found some slight accumulation of adipic acid in the liver and kidneys.
     *Internal Citation: Enders, A.A. Physiological Compatibility and Excretion of Dicarboxylic Acid.
     Arch. Exp. Pathol. Pharmakol. 1941, 197, 706 - 709.

  -  - TOXICOLOGY

Various studies have been conducted on adipic acid over the years; however, most of these studies were conducted in the 1950s and 1970s and only the study summaries are available to EPA. The summaries below, and in Table 2, were taken from various sources including peer reviewed documents such as the Cosmetic Ingredient Review, the Organization for Economic Cooperation and Development's SIDS, and the Food and Agricultural Organization of the United Nations and the World Health Organization (FAO/WHO) Joint Expert Committee on Food Additives. Based on the age of these studies there seems to be some discrepancy in reporting and so every attempt was made to validate and cross reference the studies. In many cases the studies were rated (3) or (4) by the OECD which indicates that the study is "invalid" or "not assignable", respectively. In many cases the studies were rated this way because of the lack of experimental detail and the study not being GLP (Good Laboratory Practices) compliant. GLP regulations were published in the United States on December 22, 1978 and became law on June 20, 1979, long after many of these studies were completed. In addition, documentation and testing standards were not the same as they are today and therefore, some these studies have been presented here for informational purposes because they help to illustrate the toxicity of adipic acid despite their limitations.  

 Acute Toxicity

Data on acute toxicity, as well as data on eye and skin irritation and skin sensitization, are discussed in this section. 

 Acute Oral Toxicity 
                                                                               
Various acute toxicity studies have been conducted on adipic acid in rats, mice, and rabbits. According to the SIDS document (MRID 50847716), following oral administration to rats, the LD50 of the test animals ranged from 940 to >11,000 mg/kg. Mice showed LD50 values of 1900 to 4200 mg/kg. No lethality was produced in rabbits given up to 11,000 mg/kg as a single oral dose whereas lethality was seen at 4860 mg/kg in another study. 
      
  Rat
                                                                               
Five Sprague Dawley rats (5/sex/dose) received gavage doses of 1470, 2150, 3160, 4540, 6810, or 10,000 mg/kg adipic acid in carboxymethyl-cellulose. (MRID 50847716) Mortality occurred within the first 48 hours. At lethal doses, signs of toxicity included acute dilatation of the heart and acute congestive hyperemia, ulceration of glandular stomach (bleeding-corrosive gastritis), intestinal atony, pale liver and reddening of intestinal mucosa. Surviving animals showed no gross pathological changes. The oral LD50 in rats was 5560 mg/kg. 

In another study male rats (5/dose) received 100, 200, 500, 1000, 2000 or 3000 mg/kg adipic acid and were observed for 10 days. A LD50 of 940 mg/kg was derived; however, in a follow up study, no mortality or signs of toxicity were observed in ten male rats following a gavage dose of 5000 mg/kg of adipic acid suspended in saline (MRID 50847716). As noted in the OECD SIDS review, the LD50 of 940 mg/kg was inconsistent with other acute oral toxicity results in rats for adipic acid. 

  Mice

In a 1957 study (MRID 50847706) performed by Horn et al., male albino mice (13/dose) were given an "oral" dose of 1500, 2000, or 2500 of a 6% suspension in 0.5% methyl cellulose and observed for 10 days. Animals that dies showed "distention of the stomach and small intestine, with a spastic concentration of the caecum". According to the study:

      Irritation and hemorrhage of the intestines were noted. Initial mortality developed overnight and deaths continued throughout the first week, after which survivors appeared normal. All animals were sacrificed after 10 days. 

The LD50 was reported as 1900 mg/kg.
                                                                               
  Rabbit 
        
No lethality was produced in a study with rabbits given up to 11,000 mg/kg as a single oral dose, whereas, lethality was seen at 4860 mg/kg in a different study as outlined in the Kennedy review. (MRID 50847711) Lethal doses produced signs of inactivity, stomach and intestinal distention, and irritation and hemorrhage of the intestines. 
 Acute Dermal Toxicity
An acute dermal toxicity study was carried out using New Zealand white rabbits (1-2/dose). Following occlusive dermal administration of 5010 or 7940 mg/kg of adipic acid for 24 hours, reduced appetite and activity were reported. No mortality or irritation of the skin was seen. The dermal LD50 was determined to be >7940 mg/kg. (MRID 50847716)

 Acute Inhalation Toxicity

In an acute inhalation test, the 4-hour lethal concentration for 50% of the animals (LC50) was determined to be >7.7 mg/L adipic acid. Male and female SD rats (10/sex/dose) were exposed head/nose-only in two independent experiments to 7.7 and 5.4 mg/L adipic acid dust. The former was the maximum attainable concentration. The mass median aerodynamic diameter (MMAD) was reported to be 3.5 microns and the geometric standard deviation (GSD) was 2.6. Animals were exposed for 4 hours and then observed for 14 days. No mortality, pathological changes, or clinical signs of toxicity were reported. (MRID 50847716)
 Skin Irritation 
Various dermal irritation studies carried out in rabbits and guinea pigs have been outlined in peer reviewed literature (e.g., the CIR (MRID 50847702) and OECD documents (MRID 50847716)). In some cases, the data is quite limited. The summaries are provided below but overall, adipic acid was a mild/slight skin irritant. 

A dermal irritation study was performed in which 500 mg of a 50% aqueous suspension of adipic acid was applied under an occlusive patch to a 5 cm x 5 cm area of intact and abraded skin of 6 rabbits for 24 hours. Observations were made immediately after dosing, 24 hours, 3 and 8 days. Reddening was observed (scored 2-3 on a scale up to a maximum of 4) with the intact skin but disappeared after three days. 

In another study, 6 rabbits were exposed to a semi-occlusive application of 500 mg of a 50 % paste of adipic acid in propylene glycol for 24 hours. The paste produced slight to mild irritation in half of the rabbits. A semi-occlusive application of undiluted adipic acid was not corrosive. 

Adipic acid, undiluted (99.8%) or as an 80% aqueous paste, was applied under occlusive conditions to the back and ear of each rabbit (2/group) for 20 hours. Responses were scored at 24 and 72 hours and 8 days. No irritation was observed on the backs of animals. Erythema was observed on the ear at 24 hours (2 out of a maximum of 4) but resolved by 72 hours. 

An adipic acid suspension (50% in propylene glycol) was lightly rubbed in the shaved intact skin of guinea pigs. Animals were observed at 24 and 48 hours. Adipic acid produced mild to no skin irritation. No other details were given. 
 Eye Irritation 
Various studies have been conducted to determine the potential of adipic acid to cause ocular irritation. In some cases, the data is quite limited. In each study the purity of the test substance was 99.8% adipic acid. Overall adipic acid is a severe eye irritant.

In one study, outlined in the OECD SIDS document (MRID 50847716):
      
      0.1 ml of adipic acid (99.8 %) was highly irritating to the eye in a well performed study with 6 rabbits where the animals were scored at 24, 48, 72 hours and 8 days. Irritated conjunctiva (reddening, swelling, secretion) and scar formation, increasing opacity of cornea and inflammation of the iris were observed. The symptoms were not reversible within the 8 days' observation period. Primary irritation index was 41.5 on a scale with a maximum of 110.

Another study showed severe eye irritation after the application of 100 mg adipic acid to eyes of 3 rabbits. Animals were observed for up to 21 days post administration of the test substance. If reversibility was seen before 21 days, the experiment was terminated. Corneal opacity (up to grade 3) and irritation of the iris (up to grade 2) was observed in all animals. The observed effects were reversible within 16 days. (MRID 50847716)

Another eye irritation study in rabbits showed that the installation of 50 mg was "highly irritating". (MRID 50847716) The substance was placed in the conjunctival sac and the eyelids were closed for one second. Observations were taken at 24 and 48 hours and at 8 days post exposure. Irritation and opacity of the cornea persisted over the 8-day observation period; however, the effects on the iris that were observed at 24 and 48 hours were resolved by day 8. 

An additional study administered 10 or 57.1 mg of adipic acid into the right eye of each rabbit (2/dose). Twenty seconds after contact, the eye of one animal in each group was rinsed for one minute; the other animal was left unwashed. Observations of the cornea, iris, and conjunctiva were made at 1 and 4 hours, and at 1, 2, 3, 7, and 14 days. After instilling 10 mg followed by rinsing, mild conjunctival irritation was observed. Irritation subsided within 3 days. In the unrinsed eye, mild conjunctival irritation and a minimal iritic effect were observed. After 7 days only minimal conjunctival irritation was observed and after 14 days, the eye was normal. Administration of 57.1 mg of adipic acid followed by rinsing resulted in moderate to mild conjunctival irritation and transient mild opacity. The effects were reversed within 3 days. In the unrinsed eye, moderate to mild conjunctival irritation, mild opacity of the cornea, and a minimal iritic effect were observed. The eye was normal by day 7. (MRID 50847711, 50847716)
 Skin Sensitization 
As outlined in the CIR document (MRID 50847702):
      The sensitization potential of adipic acid was evaluated using groups of 10 guinea pigs. For induction, 0.1 mL of 1% aqueous adipic acid was given as a sacral intradermal injection, once a week for 4 weeks. After a 2-week nontreatment period, the dermal challenge was performed with 0.05 mL of 50 and 25% adipic acid in propylene glycol. Adipic acid produced very mild or no irritation and it was not a sensitizer.

However, when this study was reviewed by OECD it was considered a (4) "not assignable" in terms of reliability indicating that the reliability can't be determined. The reasons for this determination were, "The study design does not accord to modern guidelines because the number of animals per group was low, no data were presented to justify the induction concentration used, no adjuvant was used, and no positive control or historical data were presented."

According to OECD SIDS (MRID 50847716):

     Despite the wide dispersive use of adipic acid, only very few cases of skin or respiratory tract sensitisation reactions are reported in humans. A sensitisation study in animals according to validated guidelines is not available. Overall, sensitisation is not expected for adipic acid.

 Repeat Dose Toxicity

Various studies have been conducted on adipic acid over the years; however, most of these studies were conducted more than 60 years ago and only the summaries are available to EPA. The summaries below were taken from various sources and every attempt was made to validate and cross reference the material. In most cases the full study report was not available to the EPA. 

 Toxicology Summary Profile
           Table 2:  Repeat Dose Toxicology Profile for Adipic Acid
                                  Study Type
                                     Doses
                                    Results
                                     Oral
5-Day Oral Toxicity (rat)*
0, 3600, 4000, 5000 or 5600 mg/kg/day
14-day LD50= 3615 mg/kg
4-Week Feeding Toxicity (rat)*

0, 10, 20, or 40 mg/day (~max dose 435 mg/kg/day)
No signs of toxicity were observed 
5-Week Feeding Toxicity (rat) *

0, 3333, 6666, 13,333 mg/kg/day
NOAEL = 6666 mg/kg/day
LOAEL= 13,333 mg/kg/day based on unkempt appearance and diarrhea. 
6-Week Capsule Toxicity (guinea pig)**

682-942 mg/kg/day for 5 days and 1032-1739 mg/kg/day for 5 weeks following
No signs of toxicity were observed 
19-Week Feeding Toxicity (rat)

0, 420, 840, 1700, and 3400 mg/kg/day
NOAEL = 1700 mg/kg/day
LOAEL = 3400 mg/kg/day based on low body weight and changes in the intestinal mucosa
33-Week Feeding Toxicity (rat)
0, 1600, or 3200 mg/kg/day
NOAEL = 1600 mg/kg/day

LOAEL = 3200 mg/kg/day based on high mortality 
Chronic Toxicity-2-Year Feeding (rat)

0, 0.1, 1, 3, and 5 % (males) and 0 or 1% (females) in the diet, approximately equivalent to 0, 40, 400, 1262, or 2261 mg/kg/day (M); 0 or 519 mg/kg/day (F)
NOAEL = 1262 (M) or 519 (F) mg/kg/day
LOAEL = 2261 mg/kg/day (M) based on decreased body weight, no effect of treatment seen in females

No evidence of carcinogenicity.

                          Reproductive/Developmental
Teratology-Gavage on Days 6-15 of gestation (rat)

0, 2.9, 13, 62 or 288 mg/kg/day 
Maternal NOAEL = 288 mg/kg/day  
Maternal LOAEL = not determined
Developmental/Offspring NOAEL = 288 mg/kg/day
Developmental/Offspring LOAEL = not determined
Teratology-Gavage on Days 6-15 of gestation (mice)
0, 2.6, 12, 56, or 263 mg/kg/day
Maternal NOAEL = 263 mg/kg/day  
Maternal LOAEL = not determined
Developmental/Offspring NOAEL = 263 mg/kg/day
Developmental/Offspring LOAEL = not determined 
Teratology-Gavage on Days 6-10 of gestation (hamster)

0, 2, 9.5, 44, or 205 mg/kg/day
Maternal NOAEL = 205 mg/kg/day  
Maternal LOAEL = not determined
Developmental/Offspring NOAEL = 205 mg/kg/day
Developmental/Offspring LOAEL = not determined 
Teratology-Gavage on Days 6-18 of gestation (rabbit)
0, 2.5, 12, 54 or 250 mg/kg/day
Maternal NOAEL = 250 mg/kg/day  
Maternal LOAEL = not determined
Developmental/Offspring NOAEL = 250 mg/kg/day
Developmental/Offspring LOAEL = not determined
*=OECD rating of "(3) invalid" provided for informational purposes 
**= OECD rating of "(4) not assignable" based on the lack of experimental details, provided for informational purposes

 Oral Toxicity 
                                                                               
 Subacute
                                                                               
 5-day (oral, rat) 
                                                                               
Adipic acid, dosed as 18.6-24.9% (w/v) suspension in saline, was administered orally to groups of six male Sprague-Dawley rats for 5-days at doses of 3600, 4000, 5000, and 5600 mg/kg/day and observed for 14 days. (MRID 50847702, 50847711, 50847716) After 14 days the animals were euthanized, and gross necropsies were performed. Three animals in the 3600 mg/kg group, 5 animals in the 4000 mg/kg group, and all of the animals in the 4500 to 5600 mg/kg groups died prior to study termination. Observed effects included depression, labored respiration, ataxia and convulsions, which lasted from the second day through the fifth day. The 14-day subacute oral LD50 for adipic acid was estimated to be 3615 mg/kg. No abnormal gross findings were observed. OECD rated the study as a "(3) invalid No GLP, limited documentation. Only limited number of parameters examined, high mortality, no histopathology, examination after 14 days post exposure period, purity not specified" 

 3-4 Week (oral, rat) 
                                                                               
Although limited in scope, the effect of adipic acid on hepatic peroxisome proliferation was evaluated in a 3-week study in which four male F344 rats were fed a diet containing 2% adipic acid dissolved in alcohol before being added to the feed. Adipic acid did not induce peroxisome proliferation or hypolipidemia. In addition, there were no effects on liver size, hepatic catalase, or liver carnitine acetyltransferase activity. (MRID 50847715) 
                                           
Various reviews on adipic acid outline a 4-week study where groups of 17 to 20 female rats were fed a diet containing adipic acid. The CIR (MRID50847702) and OECD (MRID 50847716) documents list the dosing as 0, 10, 20, or 40 mg/day (equivalent to a max dose of 435 mg/kg/day); however, WHO JEFCA (MRID 50847708) lists the dose as 10, 20 or 40 mg/kg/day. No adverse effects were noted in any of the reviews and the no-observable adverse effect level (NOAEL) was reported as >435 mg/kg/day by OECD and CIR. The OECD document gives a rating of "(3) invalid" because the study was not GLP (Good Laboratory practices) compliant and included "short documentation, only limited number of parameters investigated, no histopathology, purity not specified"

  Subchronic
                                                                               
 5-Week (oral, rat) 
                                                                               
Adipic acid was tested is a 5-week dietary study in which groups of 15 to 18 male rats were fed 0, 200, 400, or 800 mg/day (approximately 0, 3333, 6666, or 13,333 mg/kg/day). No effects were seen at 200 or 400 mg/day. Decreased body weight gains, an unkempt appearance, and diarrhea were observed for the first 3 weeks in animals fed 800 mg/day. (MRID 50847702, 50847709, 50847716, 50847708). While these results have been reported in various reviews, the OECD dossier has given a rating of "(3) invalid" because the study was not GLP compliant and included "limited documentation, only limited number of parameters investigated, purity not specified. No histopathology".  

 6-Week (oral, guinea pig) 

Although few details are provided, an oral toxicity study with groups of 5 guinea pigs is mentioned in various reports (MRID 50847702, 50847716, 50847711). Animals were dosed orally using capsules containing 400 mg/day (approximately 682-942 mg/kg/day) adipic acid for 5 days. For the next 5 weeks (5 days/week) animals were dosed with 600 mg/day (approximately 1032-1739 mg/kg/day). No signs of toxicity were observed. This 1943 study was rated "(4) not assignable" by OECD based on the lack of experimental details provided and "unclear whether histopathology has been performed, purity not specified". 

 19-Week (oral, rat) 
                 
Groups of 8 to 10 male rats received sodium adipate* at doses of 0, 50, 100, 200 and 400 mg/day (approximately 0, 420, 840, 1700 and 3400 mg/kg/day), in a protein deficient diet for 19 weeks. Animals were sacrificed after either 7 weeks or at study termination. Weight gain and general behavior were recorded, and histopathological examination of only the kidneys, liver, and intestine was performed. Rats dosed with 400 mg/day showed reduced weight gain and lower weight after 19 weeks. (MRID 50847716)

"Several unexplained intercurrent deaths in control and dose groups occurred, and only 5 - 7 animals in each group survived 19 weeks." (MRID 50847716). Slight effects on the liver and irritation of intestine were seen in the 400 mg/day dose group. 
                                            
Kennedy (MRID 50847711) describes the study further:
                                           
      The toxicity of adipic acid was greater in the case of insufficient protein intake than optimal nutrition. The rats fed 400 mg/day exhibited a significant inhibition of growth, which was still manifest after 19 weeks. The animals revealed no other outer remarkable signs, and the blood picture of the rats was normal, except for a mild anemia in all of the groups. Histological examination revealed nothing remarkable at levels 200 mg/day. Histological findings at 400 mg/day were independent of the level of protein intake. Slight alterations were observed in the liver and kidneys, and marked changes were observed in the intestinal mucosa, offering the picture of a chronic inflammatory condition. 
                                           
The OECD review incorrectly reports two NOAELs for adipic acid in this study (i.e. 1700 and 3400 mg/kg/day). The CIR document lists 3400 mg/kg/day and cites the OECD SID report. EPA does not have the full study report and therefore, must rely on the summaries available. Based on the inconsistencies in the reported NOAEL and the "marked changes" observed in the intestinal mucosa reported by Kennedy, EPA is taking the conservative approach of selecting 1700 mg/kg/day as the NOAEL and 3400 mg/kg/day as the LOAEL based on the potential for changes in the intestinal mucosa. The OECD report states that, "The study is very limited in its reliability because no details are provided on the distribution of intercurrent deaths amongst the treatment/control groups, only kidneys, liver and intestine have been examined histopathologically." However, it also has rated it a "(2) valid with restrictions" and list it as a "critical study for SIDS endpoint". 

*Sodium adipate is the sodium salt of adipic acid and is expected to hydrolyze to adipic acid upon ingestion. 

 33-Week (oral, rat) 
                 
Male and female rats (13-15/dose) were fed 0, 400, or 800 mg/day of adipic acid (approximately 0, 1600, or 3200 mg/kg/day) for 33 weeks. Weight gain and general behavior were recorded, and interim sacrifices were made at 8, 23 and 25 weeks. No signs of toxicity were seen in rats receiving oral doses up to and including 400 mg/kg. Ten of 14 rats fed 3200 mg/kg/day died during the first four weeks of the study; surviving rats had decreased weight gains during this time. According to Kennedy (MRID 50847711), "Slight histological changes were seen in the liver and kidneys and marked inflammation was seen in the intestinal mucous of rats given 800 mg/kg." This is further clarified by JEFCA (MRID 50847709), "At the highest level enlarged hepatic nuclei and polynucleated cells, with increased number and size of Kupffer cells, were observed." The JEFCA document also states, "Toxic effects i.e. apathy, change in the fur, severe diarrhoea, growth depression and high mortality rate occurred especially in the first weeks of the experiment at the highest level only...The gut showed chronic inflammation with much regenerative activity and mucosal damage." 

There is some discrepancy between the different reviews as to the final effect on body weight. According to the OECD document (MRID 50847716), "They recovered by the fifth week, and after 33 weeks, the weights of the high-dose rats were the same as that of the 400 mg/day group. The authors did not record the body weight of control animals at the end of the experiment, i.e. at 33 weeks." According to the CIR report (MRID 50847702), "at study termination, body weights for surviving animals of this group were similar to controls"; however, the CIR document cites the OECD document as a reference which specifically states that final weights of control animals were not reported. Although there is discrepancy in regard to the body weights of the control animals, all of the reviews seem to agree that the effect on body weight gain was not evident at the conclusion of the study (i.e. 33 weeks).

According to the OECD document, "No NOAEL was obtained in this study". However, based on the totality of the reviews, it appears that there was no affect at 400 mg/day (~1600 mg/kg/day) and animals receiving 800 mg/day (~3200 mg/kg/day) exhibited higher mortality than the controls.

  Chronic

In a 2-year oral study (MRID 50847706), groups of 20 male Carworth Farm rats were fed a basal diet containing 0%, 0.1%, 1%, 3%, or 5% adipic acid (approximately 0, 44, 468, 1519 or 2792 mg/kg/day, respectively*). Groups of 10 and 19 females were fed 0% and 1% adipic acid, respectively (approximately 0 or 629 mg/kg/day). This study, conducted by Horn et al., appeared in the journal of Agricultural and Food Chemistry in 1957 and is limited in documentation and scope; however, it still provides an understanding of the long-term toxicity of adipic acid. 

Weekly observations of body weight, food consumption, and general appearance were recorded. Whenever possible, animals that died during the course of the study were autopsied. At the end of the study surviving rats were weighed, killed, and grossly examined. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals, and stomach of approximately half of each group of males were weighed. The kidneys, spleen, liver and heart of each female were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine and testes or ovaries and uterus on "a representative number of animals" was also performed. 

During the "rapid growth period", the weight gains of the 3 and 5% adipic acid groups were significantly less than the control groups. "Throughout the latter half of the study, the average body weights of the various test groups were not remarkable- although the 5% adipic acid dose group was consistently the lowest." (MRID 50847706) There was a slight, but consistent, reduction in food consumption in animals dosed at 5%. The body weight of males in the 5 % group was consistently decreased by 10% or more; however, body weight continued to increase throughout the study. 

The incidence of lung pathology and tumor growth appeared to be equally disturbed among all groups, including the controls. There was no significant gross pathology noted and no difference in organ weights or microscopic examination.

No effects were seen in females at the highest dose tested; therefore, the NOAEL in females is 1% (629 mg/kg/day). Males in the 3% dose group showed a decrease in body weight greater than or equal to 10% from weeks 8-56. Males in the 5% group showed a decreased body weight (>=10%) throughout the course of the study. The journal article doesn't mention the standard deviation and therefore, the statistical significance cannot be determined; however, there appears to be no dose-response since the change is observed at almost twice the dose and subsequently, does not appear to be adverse. In light of the limitation of the study mentioned above, the Agency is erring on the side of caution and treating the effect seen in the 5% dose group as an effect of treatment and therefore, the NOAEL for males is 3% (approximately 1519 mg/kg/day) with a LOAEL of 5% (approximately 2792 mg/kg/day) based on decreased body weight. 

*Approximate doses were determined using the "Compound Consumed" from Table III of the study divided by the average body weight of weeks 0-104 from Table II.

 Inhalation Toxicity 
                                                                               
Very little information was given in any of the reviews regarding the inhalation toxicity of adipic acid. According to CIR (MRID 50847702):

      Mice were exposed to 460 mg/m[3] adipic acid dust for 1.5 mos, or to 13 or 129 mg/m3 adipic acid for 4 mos (details not given).[*] Decreased weight gain, altered oxidase activity, and upper respiratory tract, liver, kidney, and central nervous system effects were observed. 
      *Internal citation: Organisation for Economic Co-Operation and Development. IUCLID data set for adipic acid. http://www.chem.unep.ch/irptc/sids/OECDSIDS/124049.pdf. Accessed July 29, 2010.

In a study outlined in OECD SIDS (MRID 50847716), 2 male and 2 female rats were exposed to 126 mg/m[3] adipic acid dust for 15 days, 6 hrs/day. Weights were recorded each morning, and the animal's condition and behavior was observed. Histopathological examination of the lungs, liver, kidneys, spleen, adrenals, and occasionally heart, jejunum, ileum, and thymus was carried out. No signs of toxicity were observed, and no gross or microscopic findings were noted at necropsy. The OECD report gave this study a rating of "(4) not assignable" because it is "poorly documented, low number of animals, limited histopathology, nose as target organ not examined, MMAD not specified, purity not specified"; however, they list it as "Critical study for SIDS endpoint" 

 Reproductive and Developmental Toxicity
Various experiments on have been conducted which examine the ability of adipic acid to elicit a developmental effect in rats, mice, and hamsters at doses up to 263, 288, and 205 mg/kg/day, respectively. Adipic acid was not embryotoxic, fetotoxic, or teratogenic in these studies. In a fourth study, rabbits were dosed with up to 250 mg/kg/day and did not show any adverse effects to either the pups or dams. Available study details have been compiled below.  
 Rat
A teratology study was conducted with groups of 20-24 pregnant Wistar rats. Animals were given adipic acid by gavage on days 6-15 of gestation at doses of 0, 2.9, 13, 62, or 288 mg/kg/day. (MRID 50847703) A positive control of aspirin was also used. The rats were observed daily for appearance and behavior. Body weights were recorded on days 0, 6, 11, 15, and 20 of gestation, and food consumption was monitored daily. Fetuses were removed from dams on day 20 of gestation and the numbers of implantation sites, resorption sites, and live and dead fetuses were counted. The body weights of live pups and external, visceral, and skeletal abnormalities were recorded. One-third of each litter was examined for soft-tissue abnormalities and the remaining two-thirds for skeletal abnormalities. There were no adverse effects on the maternal or fetal parameters evaluated. The NOAEL for maternal and developmental toxicity was 288 mg/kg/day, highest dose tested.  

 Mice
The same study (MRID 50847703) mentioned in 5.4.1 also looked at the effect of adipic acid in mice. Groups of 20 to 24 pregnant albino CD-1 mice were gavaged with 0, 2.6, 12, 56, or 263 mg/kg/day adipic acid on gestational days 6 to 15. A positive control of aspirin was used. Body weights were recorded on days 0, 6, 11, 15, and 17 of gestation, and food consumption was monitored daily. Fetuses were removed from dams on day 17 of gestation and the numbers of implantation sites, resorption sites, and live and dead fetuses were counted. The body weights of live pups and external, visceral, and skeletal abnormalities were recorded. The urogenital tract of each dam was examined in detail for anatomical normality. One-third of each litter was examined for soft-tissue abnormalities and the remaining two-thirds for skeletal abnormalities. There were no adverse effects on the maternal or developmental parameters evaluated. The NOAEL for maternal and developmental toxicity was 263 mg/kg/day, highest dose tested.  
                                           
 Hamster
Groups of 21 to 24 pregnant female golden hamsters were gavaged daily with adipic acid at dose levels of 0, 2, 9.5, 44, and 205 mg/kg/day from day 6 through 10 of gestation (MRID 50847703). A positive control of aspirin was used. Body weights were recorded on days 0, 8, 10 and 14 of gestation. On day 14 the animals were examined and the number of implantation sites, resorption sites and live and dead fetuses were recorded. The urogenital tract of each dam was examined in detail for anatomical normality. The body weight of each live pup was recorded. All fetuses were examined externally, and one-third of each litter was examined for soft-tissue abnormalities and the remaining two-thirds for skeletal abnormalities. 

According to OECD, "an increase of resorption/implant sites from 3.5 to 7.7% in the highest dose group was observed. Consequently, the average number of live fetuses was reduced from 12.6 to 11.4 a reduction as high as caused by the positive control substance aspirin. Without statistical evaluation it cannot be judged if this dose is a NOEL." Other reviews do not treat this as an effect and state that no compound related effects on dams or fetuses were observed. As outlined in these reviews (i.e., MRID 50847708, and the study itself MRID 50847703), the NOAEL for maternal and developmental toxicity in hamsters was determined to be the highest dose tested, 205 mg/kg/day.

 Rabbit
Pregnant Dutch-belted rabbits were gavaged with adipic acid at dose levels of 0, 2.5, 12, 54 and 250 mg/kg/day, from day 6 through day 18 of gestation. (MRID 50847704) Body weights were recorded on days 0, 6, 12, 18 and 29 of pregnancy. On day 29 dams were examined and the numbers of corpora lutea, implantation sites, resorption sites and live and dead fetuses were recorded. The urogenital tract of each dam was also examined. All fetuses were examined, and body weights of live pups was recorded. Fetuses were maintained in an incubator for 24 hours to evaluate neonatal survival. All surviving pups were sacrificed, examined for visceral and skeletal abnormalities. No compound related effects on dams or fetuses were observed. The NOAEL for maternal and developmental toxicity in rabbits was determined to be 250 mg/kg/day, the highest dose tested. 
 Genotoxicity and Mutagenicity
Various in vitro and in vivo studies have shown that adipic acid is not genotoxic or mutagenic. In vitro studies include an Ames assays and a chromosome aberration test. In vivo studies of adipic acid included: (1) host-mediated assays in mice (2) cytogenetic studies in rats; and (3) dominant lethal assays in rats. Available information on these studies is presented below. 
 In vitro
Adipic acid was tested in Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535, TA1537, and TA1538 or in Escherichia coli (WP2(uvrA)) with or without metabolic activation. The standard plate incorporation assay was performed with the S9 mix containing 10% Aroclor 1254-induced liver S9 from male Sprague-Dawley rats. Adipic acid was negative for mutagenicity. (MRID 50847717)

S. typhimurium strains G46 and TA1530 were plated with adipic acid and Saccharomyces cerevisiae D-3 cultures were shaken with adipic acid and plated. The frequency of mutant colonies was observed. There were no compound-related effects on frequency of mutant colonies. (MRID 50847708, 50847716) Note that no metabolic activation was employed, as this was part of the host-mediated assay described in the following section (5.5.2), and in this assay, the in vivo phase substitutes for metabolic activation. 

Human embryonic lung cultures (strain WI-38) were grown in the presence of 0, 2, 20 or 200 ug/ml adipic acid or positive control compounds. There was no significant test substance-related aberration in the anaphase chromosomes. (MRID 50847708)
 In vivo
Adipic acid was administered to male mice (ICR randombred) by gavage at three dose levels: 100, 2500 or 5000 mg/kg. (MRID 50847708) S. typhimurium TA-1530, G-46 or Saccharamyces cerevisiae D3 were given by intraperitoneal (i.p.) injection 30 minutes after administration of the test compound. Three hours after the injection, each animal was killed and the fluid was removed from their peritoneal cavity. The peritoneal washings were diluted and plated and the mutation frequency of bacteria and the yeast mitotic recombinants (recombinant frequency) was determined. There was no significant increase in mutant frequencies at the dose levels tested with Salmonella TA-1530 and G-46. Tests with Saccharamyces cerevisiae D3 produced a dose-response effect on recombinant frequency. In this case an increased frequency of mutations as well as dose response was observed. In a subacute study (MRID 50847708), adipic acid was administered orally to male mice at the same three dose levels (100, 2500 or 5000 mg/kg/day) for five consecutive days. Thirty minutes after dosing the animals were inoculated with the test organisms and treated in the same fashion as the acute study. There was no significant increase in mutant frequencies with S. typhimurium TA-1530 and G-46, nor significant recombinant count increase with the Saccharamyces cerevisiae D3.

In a cytogenetic rat study, adipic acid was administered, by gavage, as a single dose or as one dose per day for five days, at dose levels of 0, 3.75, 37.5 and 375 mg/kg. A second study was carried out with either a single dose of 5000 mg/kg adipic acid or five doses of 2500 mg/kg adipic acid over 5 days. After sacrifice, bone marrow cells were prepared, fixed and mounted, and chromosomes of a set number of cells were counted. Diploid cells were analyzed for chromatid gaps and breaks, chromosome gaps, breaks and reunions, polyploidy, and other chromosome aberrations. Adipic acid was considered non‐mutagenic. (MRID 50847708, 50847716) 

In the dominant lethal study (MRID 50847708), male rats (10/dose) received 0, 3.75, 37.5, or 375 mg/kg as a single dose in the acute study and as one dose/day for five days in the subacute study. A second dominant lethal assay was run at dose levels of 5000 mg/kg (acute) and 2500 mg/kg (subacute). In both studies, the males were sequentially mated with two females/week for eight weeks (acute study) or seven weeks (subacute study). Females were sacrificed 14 days after mating, and the uterus was examined for corpora lutea, early and late fetal deaths, and total implantations in the uterine horn. In the acute study at 37.5 mg/kg there was a significant decrease in the average number of implantations at weeks 1 and 4, and in corpora lutea at weeks 4 and 7. Significant increases in pre-implantation losses were observed at week 1 in both the 3.75 and 37.5 mg/kg dose groups but not at 375 mg/kg. At these lower doses in the subacute study, and in the acute and subacute studies at the higher doses, no significant differences were observed between negative control and experimental groups.
 Carcinogenicity
Adipic acid was not carcinogenic (i.e. tumor incidence were not affected by treatment) in the 2-year chronic oral toxicity study (described in section 5.3.1.3 above) in which groups of 20 male rats were fed diets containing 0%, 0.1%, 1%, 3%, and 5% adipic acid, and groups of 10 and 19 females were fed 0% and 1% adipic acid, respectively.

 Neurotoxicity

No neurotoxicity studies are available for adipic acid; however, toxicity tests have not provided any evidence that this compound produces neurotoxic effects. 
                                                                               
 Immunotoxicity

No immunotoxicity studies are available for adipic acid; however, no effects were seen in the current toxicity database that would indicate that adipic acid would be immunotoxic.

 TOXICITY ENDPOINT SELECTION

Adipic acid is found naturally in a few food items and is used as an additive in various foods and beverages. It is also used in pharmaceuticals, cosmetics, and various industrial products. No toxicological endpoint of concern has been identified in the database below the limit dose of 1000 mg/kg/day; therefore, a quantitative assessment of human exposure is not necessary.

 SPECIAL CONSIDERATION for INFANTS and CHILDREN

FFDCA Section 408(b)(2)(C) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either applies the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor. 

The available acute and repeat dose toxicity studies on adipic acid indicate that it has low toxicity. There is no indication, based upon the available data, that adipic acid is neurotoxic or immunotoxic and therefore, would not result in increased susceptibility in infants or children. As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. Taking into consideration all available information, there is no concern, at this time, for increased sensitivity to infants and children to adipic acid when used as inert ingredient in pesticides formulations.
 EXPOSURE

Adipic acid is currently approved as a nonfood use inert ingredient. A review of currently approved pesticide products containing adipic acid found that most products were hard surface cleaners. Ecolab, Inc. is requesting that EPA establish an exemption from the requirement of a tolerance for adipic acid under 40 CFR §180.940(a) for use in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils at a maximum concentration of 100 ppm. 
Based on the current and proposed use pattern of adipic acid, dietary and residential exposure from pesticidal uses are expected. However, no endpoint of concern was identified in the database below the limit dose; therefore, a quantitative risk assessment was not necessary.  
 Dietary Exposure
Although dietary exposure to adipic acid may occur from eating foods which naturally contain adipic acid or those for which it has been added as a flavor enhancer as well as foods that come into contact with surfaces treated with pesticide formulations containing this inert ingredient, no endpoint of concern was identified below the limit dose and therefore, a quantitative dietary exposure assessment for adipic acid was not conducted. 
 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). The current and proposed use of adipic acid as an inert ingredient in pesticide formulations and other non-pesticidal uses (e.g., cosmetics) may result in residential exposures; however, there are no toxicological effects of concern below the limit dose in available studies and therefore, it is not necessary to conduct a quantitative assessment of residential (non-occupational) exposures and risks. 

 Occupational Exposure/Risk
The Agency has reviewed the available toxicological information for adipic acid found that there are no adverse toxicological effects observed below the limit dose in the studies submitted; therefore, a quantitative occupational risk assessment is not necessary. 

 AGGREGATE EXPOSURE

The Federal Food, Drug, and Cosmetic Act (FFDCA) section 408 directs EPA to consider available information concerning exposure from the pesticide residue in food and other non-occupational exposures to determine that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.

Because no adverse effect below the limit dose was seen in the toxicity database for adipic acid, a qualitative risk assessment was conducted and subsequently, it is not necessary to aggregate dermal and inhalation residential exposures with estimated dietary exposures. 

    CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA has not found adipic acid to share a common mechanism of toxicity with any other substances, and adipic acid does do not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA assumed that adipic acid 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.

    ENVIRONMENTAL FATE & EFFECTS 

Adipic acid can be found naturally in the environment and in select food items. According to the OECD review, it is a component of tobacco smoke and was detected in particle emissions from the fireplace combustion of several woods and from foliage fuel combustion (MRID 50847716). It was also detectable in the ventilation systems above cooking appliances. Adipic acid occurs naturally in beet juice, sugar cane, ripe fruits of Morinda citrifolia (Indian Mulberry, Noni) and rice straw, indicating biotic formation. Adipic acid was also found in honey obtained from the New Zealand Rewarewa tree (Knightea excelsa) at concentrations of 0.2-0.6 mg/kg.

          Table 3:  Environmental Fate Characteristics of Adipic Acid
Parameter
Value
Source
Vapor Pressure (VP)
0.07 mmHg @ 25°C 
9.7 Pa @ 18.5°C
50847702 
50847716, 50847711
Henry's Law Constant 
(atm-m3/mole at 25°C)
9.7 x 10[-7] Pa m[3]/mol (Bond method) 
8.8 x 10[-2] Pa m³/mol (ratio of VP versus solubility) 
4.71 x10[-12] atm m[3]/mole
50847716

USEPA EPISuite v.4.10
Water Solubility (g/L at 25°C)
30
23
50847702
50847716
Ionization constants at 25 °C
pKa1 
pKa2

4.34
5.44

50847716 
Log Kow at 25 °C
0.08

0.081-0.093
USEPA EPISuite v.4.10 (experimental, Hansch, et al 1995)
50847716 
Log Koc
MCI method 
Kow method

1.386
0.2

USEPA EPISuite v.4.10
Ready Biodegradability 
YES
USEPA EPISuite v.4.10; 50847716
BCF (L/kg wet‐wt)
3.162
USEPA EPISuite v.4.10
Fugacity Model Compartment/Mass Amount (%)
Air 
Water 
Soil
Sediment
Mass Amt (%)        

<0.0001
24.6
75.4
0.0644
Half-Life (hr)

45.9
208
416
1870
USEPA EPISuite v.4.10
 
Under normal environmental conditions adipic acid occurs primarily in the deprotonated form (pKa of 4.34 and 5.44). EPI Suite's Fugacity model predicts that, once released to the environment, 75.4% of adipic acid would be found in the soil, 24.6% would be in the water, 0.644% would be in the sediment and a very small percent (<0.0001%) would partition to air. 

If released to the atmosphere, adipic acid is expected to exist in both the particulate and vapor phases (VP: 9.7 Pa @ 18.5°C). Based on the Henry's Law Constant given in the OECD dossier (i.e.,  9.7 x 10[-7] Pa m[3]/mol (Bond method) and 8.8 x 10[-2] Pa m³/mol (ratio of vapor pressure versus solubility) at 25 °C) and further supported by the value calculated by EPISuite v.4.10 (i.e. 4.71 x10[-][12] atm m[3]/mole), adipic acid has a low potential for volatilization from surface waters. The estimated volatilization half‐lives of adipic acid from model lakes and rivers are many years. 

The Koc indicates whether a compound is likely to partition to soil or sediments from water. The estimated log Koc values for adipic acid are 1.39 (Koc= 24.34 L/kg) and 0.2 (Koc = 1.56 L/kg) based on EPI Suite's MCI and Kow models, respectively. This suggests that adipic acid is not likely to bind to soils or sediments and will tend to remain in water and possibly enter groundwater. It is important to note that Koc may be sensitive to pH. 

Adipic acid is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups. The water solubility (23 g/L at 25°C) and Octanol/Water Partition Coefficient (log Kow 0.08 at 25°C) of adipic acid indicate that it is highly soluble in water and is unlikely to bioconcentrate. However, multiple sources, including JEFCA (2020), Kennedy (MRID 50847711), and PubChem (2020), report that adipic acid is only slightly soluble in water. According to the CIR document (MRID 50847702), the shorter chain alkyl dicarboxylic acids (i.e., malonic, succinic, and glutaric) are very water soluble and as the chain length increases through adipic acid to dodecanedioic acid, water solubility decreases sharply. The document goes on to state:

      In other words, the water solubility of these acids is inversely proportional to their chain length. There is a marked alternation in melting point with changes in carbon number from even to odd.* Odd members (e.g., malonic acid and glutaric acid) exhibit lower melting points and higher solubility than even carbon number alkyl dicarboxylic acids (e.g., succinic acid and adipic acid).
      *Internal Citation: Kroschwitz J., ed. Kirk-Othmer Concise Encyclopedia of Chemical Technology. 4th ed. 2001. New York, NY: Wiley; 1999.

The low bioconcentration factor (BCF), a ratio of a chemical's concentration in the tissue of an aquatic organism to the chemical's concentration in the ambient water. The BCF for adipic acid is 3.162 L/kg wet‐wt, further indicating that there is a low potential for adipic acid to bioconcentrate in aquatic organisms. 

Adipic acid was readily biodegradable in multiple biodegradation tests (MRID 50847716, 50847711). In a MITI test, comparable to OECD Test Guideline 301C, biodegradation was 68 - 90% after 14 days. Under OECD 301B, adipic acid degraded 91% in 28 days. Finally, in the closed bottle test (OECD 301D), 83% of the compound had degraded after 30 days. 

 Ecotoxicity Data

Ecotoxicity studies conducted with adipic acid showed that it is slightly toxic to fish, aquatic invertebrates, and algae. The ecotoxicity data present below has been taken in large part from the 2004 OECD SIDS (MRID 50847716) review of adipic acid.  The results of these studies are summarized in Table 4 and detailed in the sections below.

Table 4: Toxicity of Adipic Acid to Aquatic Species 
Species
Parameter
Dose (mg/L)
Source
 Fish
Pimephales promelas
 96-hr LC50
 97
 MRID 50847714
Leuciscus idus
 96-hr LC50
 NOEC
 230
 147
 MRID 50847716
Danio rerio
 96-hr LC50
 >1000
 MRID 50847716
 Water Flea
Daphnia magna
 48-hr 
 85.6
 MRID 50847716
Algae
Desmodesmus subspicatus
 96-hr EC50
 72-hr EC50
 26.6
 31.3
 MRID 50847716

    Fish

In 1974, EPA conducted a series of studies in which fathead minnows (Pimephales promelas) were exposed to 26 commonly used organic compounds (MRID 50847714). The 96 h-LC50 was 97 mg/l. The LC50 at 24, 48, and 72 hours was 172, 114, and 97 mg/l, respectively. The study was conducted according to US-EPA Method 660/3-75-009 and the pH was reported to be < 5.9 during the test. There was generally no indication of the oxygen content in the test solution (some solutions were identified at low levels) and therefore, it cannot be excluded that the toxicity observed was due to pH effects and possibly oxygen limitations. 

Two additional fish toxicity tests were conducted with adipic acid. The full studies are not available; however, these studies were reviewed and outlined in the OECD SIDS document (MRID 50847716). As stated in the OECD summary:

      In an acute test performed with Leuciscus idus according to the German national standard method DIN 38412 Part 15 a 96 h-LC50 of 230 mg/l was obtained (BASF AG 1980*). Also in this study the pH of the test solutions was in the range of 3.8 to 7. For the concentration 215 mg/l that is in the same order of magnitude with the LC50 the pH was between 4.3 and 4.7 and therefore pH related effects cannot be excluded. For this reason also this study should not be used for the hazard assessment.
      *Internal Citation: BASF AG (1980). Determination of the acute toxicity of adipic acid to Leuciscus idus. Unpublished Report (Report No. 79/557).

      With the species Danio rerio a 96 h-LC50 higher than 1000 mg/l was obtained in a static test in accordance to the guideline proposal of the German Federal Environmental Agency (UBA). An analytical monitoring was conducted and the recovery was around 97 % (Bayer AG 1991*). The pH of the test solution was in the range of 7.4 to 7.7.
      *Internal Citation: Bayer AG (1991). Study of the ecological behaviour of adipic acid. Unpublished Report (Report No. 244A/91).

In addition, Kennedy (MRID 50847711) mentioned two additional studies for which no additional information was available. According to Kennedy: 

      A series of acute lethality studies was conducted on fathead minnows. Twenty-four hour LC50s ranged from 122 to 330 mg/l, 48 h values were 92 mg/l, and 72 and 96 h values were 88 and 97 mg/l.[*1, 2] A lethal dose of 330 mg/l was determined in a group of 10 bluegill sunfish exposed via water to that concentration for 24 h...In rainbow trout, no deaths were produced by 48 h exposure to 100 mg/l; all fish were killed at >200 mg/l.[*3] 
      *Internal Citation: (1) Verrett, M.J. Evaluation of the Health Aspects of Adipic Acid as a Food
      Ingredient. FDA-223 - 75-2004, 1976. (2) Mattson, V.R.; Arthur, J.W.; Walbridge, C.T. Acute Toxicity of Selected Organic Compounds to Fathead Minnows. EPA/600/3-76/097, 1976. (3) Lysak, A.; Marcinek, J. Multiple Toxic Effects of Simultaneous Action of Some Chemical Substances on Fish. Rocz. Nauk Roln. Ser. H. 1972, 94, 53 - 63.
   Aquatic Invertebrates: Water Flea
Daphnia magna were evaluated according to European guideline 79/831/EEC, method C.2 (MRID 50847716). The test solution pH values ranged from 4 (500 mg/l) to 7.7 (15.6 mg/l) and therefore, pH related effects on the daphnids cannot be excluded. The 48 hr EC50 was 85.6 mg/l.
   Algae
A growth inhibition test was performed using Desmodesmus subspicatus, in the presence of adipic acid, and the 96h-EbC50 (EbC50: the concentration of test substance which results in a 50 percent reduction in biomass growth) was determined to be 26.6 mg/l. After 72 hours the EbC50 was 31.3 mg/l. At the start and end of the test, pH values for each concentration were in the range of 3.8 to 10.2. The pH for the concentration of the EbC50 (31.3 mg/l) was 6.0 at test begin and 8.2 after 96 hours. Therefore, any effects found in this study are likely not due to pH effects. (MRID 50847716)
    RISK CHARACTERIZATION

Adipic acid is found in select foods and is intentionally added to various other foods and beverages. It is also used in pharmaceuticals, cosmetics, and various industrial products. Because of its widespread use adipic acid has been the subject of various peer-reviewed assessments (e.g., CIR, OECD SIDS, and the FAO/WHO's JECFA) which were utilized in this risk assessment to make a safety determination for adipic acid. 

Available acute studies on adipic acid include oral, dermal, and inhalation toxicity studies. In addition, various dermal and eye irritation studies, and a dermal sensitization study were available. Adipic acid has very low acute toxicity with an oral LD50 in rats > 5000 mg/kg and 1900 mg/kg in mice. The dermal LD50 in rabbits was >7940 mg/kg as no mortality was seen. The inhalation LC50 in rats was > 7.7 mg/L as once again, no mortality was observed. Adipic acid produced slight/mild skin irritation and was not a skin sensitizer. Adipic acid is an eye irritant.  

Although quite often limited in scope and/or documentation, repeat dose oral toxicity testing in rats for adipic acid included a 4-week, 5-week, 19-week, 33-week, and a 2-year study. A 6-week oral guinea pig study was also carried out. All studies showed no/low toxicity and no reproductive/developmental toxicity was seen in any of the species tested. Adipic acid also tested negative for genotoxic and/or mutagenic effects in various in vitro and in vivo studies. In addition, there was no evidence of carcinogenicity or neuropathological changes or effects reported in any of the studies. The agency does not believe adipic acid will be carcinogenic or neurotoxic. The primary health effect associated with adipic acid is irritation of the intestinal mucosa and decreased body weight at doses above the limit dose.  

JECFA established an Acceptable Daily Intake (ADI) of 0-5 mg/kg bw for general use of adipic acid and its potassium, sodium and ammonium salts. JECFA stated there was no safety concern at current levels of dietary intake. Food use as an inert ingredient under 40 CFR § 180.940(a) in pesticide formulations at a maximum concentration of 100 part per million (ppm) would likely result in very low level of adipic acid in food and would therefore not contribute considerably to the overall body burden from existing sources of adipic acid. 

A review of currently approved pesticide products containing adipic acid found that the majority of products were hard surface cleaners. Based on the current and proposed use pattern of adipic acid, dietary and residential exposure from pesticidal uses are expected. However, no endpoint of concern was identified in the database below the limit dose of 1000 mg/kg/day; therefore, a quantitative risk assessment was not necessary. As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. 

Adipic acid does not present a hazard for the environment and was only slightly toxic to aquatic systems. Overall, low toxicity was seen in acute and repeat dose animal studies. In addition, the widespread use of adipic acid in foods, drugs, and cosmetics, in combination with the occurrence of adipic acid in various foods and beverages, indicate that this compound does not pose a safety risk at current exposure levels, nor would aggregate exposure to adipic acid be expected to pose a risk to any general population or subpopulation, including infants and children, when used as an inert ingredient at a maximum concentration of 100 ppm in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils.

                                       

                                 Bibliography

(MRID 50847702) Cosmetic Ingredient Review (CIR) Expert Panel: Fiume, M. M.; eldreth, HB., Bergfeld, W.F., Belsito, D.V., Klaassen, C. D., Liebler, L., Marks Jr., J. G., Shank, R. C., Slaga, T. J., Snyder, P. W., and Andersen, F. A.. (2012) Final Report of the Cosmetic Ingredient Review Expert Panel on the Safety Assessment of Dicarboxylic Acids, Salts, and Esters. International Journal of Toxicology, 31(Supplement I), 5S-76S.

(MRID 50847703) Food and Drug Research Laboratories, Inc. (FDRL). 1973. Teratologic evaluation of FDA 71- 50 (adipic acid) in mice, rats, and hamsters. Unpublished data submitted to US FDA. Final report prepared under DHEW contract no. FDA 71-260. Maspeth, N. Y. [43 pp.]

(MRID 50847704) Food and Drug Research Laboratories (FDRL). 1974. Teratologic Evaluation of Compound FDA 71-50 (Adipic Acid) in Rabbits. PB-267 202. Unpublished data submitted to US FDA. Final report prepared under DHEW contract no. FDA 71-260. Maspeth, N. Y. [20 pp.]

(MRID 50847705) Grego AV and G Mingrone. 1995. Dicarboxylic acids, an alternate fuel substrate in parenteral nutrition: an update. Clinical Nutrition 14(3): 143-148.

(MRID 50847706) Horn HJ, EG Holland, LW Hazleton. 1957. Safety of Adipic Acid as Compared with Citric and Tartaric Acid. Agric. Food Chem. 5(10):759-762.

(MRID 50847708) International Programme on Chemical Safety World Health Organization (IPCS WHO). 1977. Summary of toxicological data of certain food additives. WHO food additives series no. 12.

(MRID 50847709) Joint FAO/WHO Expert Committee on Food Additive (JECFA). 1967. FAO Nutrition Meetings. Report Series No. 40 A, B, C. WHO/Food Add./67.29. Toxicological evaluation of some antimicrobials, antioxidants, emulsifiers, stabilizers, flour-treatment agents, acids and bases. Food and Agriculture Organization of the United Nations, World Health Organization.

(MRID 50847710) Joint FAO/WHO Expert Committee on Food Additive (JECFA). 2000. World Health Organization, Food Additives Series 44. 974. Aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups. (section 4.2: page 75).

(MRID 50847711) Kennedy GL Jr. 2002. Toxicity of adipic acid. Drug and Chemical Toxicology 25(2) 191‐202

(MRID 50847713) Life Sciences Research Office (LSRO). 1976. Evaluation of the health aspects of adipic acid as a food ingredient. SCOGS-80. Prepared for Bureau of Foods, Food and Drug Administration. Contract No. FDA 223 -75 -2004.

(MRID 50847714) Mattson VR, JW Arthur, CT Walbridge. 1976. Acute toxicity of selected organic compounds to fathead minnows. US EPA, Environmental Research Laboratory. EPA-600/3-76-097 October 1976

(MRID 50847715) Moody DE, JK Reddy. 1978. Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol Appl Pharmacol. 45(2):497-504.

(MRID 50847716) Organization for Economic Cooperation and Development (OECD). (2004) Adipic Acid. SIDS Initial Assessment Report for SIAM 18. 20-23 April 2004, Paris, France. Sponsor Country: Germany 

(MRID 50847717) Prival MJ, VF Simmon, KE Mortelmans. 1991. Bacterial mutagenicity testing of 49 food ingredients gives very few positive results. Mutation Research, 260: 321-329.

(MRID 50847718) Rusoff II, Baldwin RR, Domingues FJ, Monder C, Ohan WJ, Thiessen R, Jr. 1960. Intermediary metabolism of adipic acid. Toxicology and Applied Pharmacology 2: 316‐330.

PubChem, National Institutes of Health https://pubchem.ncbi.nlm.nih.gov/compound/Adipic-acid#section=Collision-Cross-Section retrieved 7/20/20

FAO JEFCA (2020) http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa/jecfa-flav/details/en/c/462/