Hazardous substance assessment - Adipic Acid

Identification

Chemical name:

Adipic acid

CAS #:

124-04-9

Chemical composition:

C₆-H₁₀-O₄

Synonyms:

Hexanedioic acid; 1,4-Butanedicarboxylic acid; 1,6-Hexanedioic acid; Acide adipique; Adipate.

UN #:

Not available

Pictogram(s):

Figure 1 - Text description

The symbol within the pictogram shows a container dripping liquid onto a piece of metal and another container dripping liquid onto a hand. This symbol indicates that hazardous products with this pictogram can

• damage or destroy metal,
• cause irreversible damage to the skin (e.g., burns, blisters, scarring), and/or
• produce tissue damage in the eye or vision loss that is irreversible or not fully reversible within 21 days.

WHMIS classification

Health hazards:

Serious Eye Damage / Eye Irritation: Category 1

Physical hazards:

Combustible Dust – Category 1

Health hazards

Acute Toxicity (Oral):

Does not meet criteria

LD­₅₀: 5,560 mg/kg (rat) ^Footnote 1.

The available data do not meet the classification criteria for Acute Toxicity (Oral).

Acute Toxicity (Dermal):

Does not meet criteria

LD₅₀: >7,940 mg/kg (rabbit) ^Footnote 2.

The available data do not meet the classification criteria for Acute Toxicity (Dermal).

Acute Toxicity (Inhalation – Gas):

No data available

Acute Toxicity (Inhalation – Vapour):

No data available

Acute Toxicity (Inhalation – Dust and Mist):

Does not meet criteria

LC₅₀: >7.7 mg/L, 4 hr ^Footnote 2.

The available data do not meet the classification criteria for Acute Toxicity (Inhalation – Dust and Mist).

Skin Corrosion / Irritation:

Does not meet criteria

In an animal study performed similar to the Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 404, 0.5 g of a 50% aqueous solution of Adipic acid (99.8%) was applied to intact as well as abraded skin of 6 rabbits for 24 hours under occlusive conditions (based on study summary ^Footnote 3). The mean scores (24 and 72 h) for erythema and edema were 1.1/4 and 0/4 respectively, not meeting criteria for classification. The erythema was fully reversible within 72 h. In another non guideline pre GLP study, application of 1 g of 99.8% Adipic acid or 80% aqueous paste to intact skin of 2 rabbits for 20 h under occlusive conditions did not result in skin irritation (based on study summary ^Footnote 3). All time scores for erythema and edema were 0.

The available data do not meet the classification criteria for Skin Corrosion / Irritation.

Serious Eye Damage / Eye Irritation:

Category 1

In a key study performed according to OECD TG 405 and in compliance with GLP, application of 100 mg of Adipic acid (>99.8%) into the conjunctival sac of the right eye of 3 rabbits caused severe irritation (based on study summary ^Footnote 3). The mean score calculated following gradings at 24, 48, and 72 h for the 3 rabbits was 3, 2, and 2/4 for corneal opacity and: 2, 1.3 and 2/2 for iritis. The corneal effects and iritis were fully reversible in 16 and 9 days, respectively. Based on an iritis score of > 1.5 in 2/3 animals, Adipic acid meets the classification criteria for Category 1 as per HPR 8.3.2(1). Similar results were reported in a few other well documented studies (no GLP), where application of 0.1 mL to the conjunctival sac caused an irritated conjunctiva (reddening, swelling, secretion), scar formation, and increasing opacity of cornea and inflammation of the iris (based on study summary ^Footnote 3). The symptoms were not reversible within the 8-day observation period. Based on the results of the key study, Adipic acid meets classification criteria for Category 1 as per HPR 8.3.2(1).

The available data meet the classification criteria for Serious Eye Damage / Eye Irritation – Category 1 [HPR 8.3.2(1)].

Respiratory Sensitization:

Does not meet criteria

Very limited data are available on humans. Two cases of bronchial asthma were reported in workers of a pharmaceutical factory coming into contact with spiramycin powder ^Footnote 4. Since spiramycin was in the form of a salt of Adipic acid, the patients were also tested with Adipic acid alone. In one out of the two subjects, the inhalation of a non-irritant concentration of Adipic acid elicited an immediate asthmatic reaction, which was inhibited by the previous administration of Sodium cromoglycate. These findings suggested a hypersensitivity reaction to Adipic acid by these patients. Another case report of occupation asthma was reported in a 43 year old female who was handling a solder wire containing an Adipic-acid-flux ^Footnote 5. No animal data are available. Due to a very few cases of sensitivity to Adipic acid in humans and no data on animals, the available data do not meet the criteria for classification.

The available data do not meet the classification criteria for Respiratory Sensitization.

Skin Sensitization:

Does not meet criteria

Two pharmaceutical factory workers who developed asthma following exposure to spiramycin present as the salt of Adipic acid tested negative in patch test challenges with Adipic acid ^Footnote 4. A positive response to a patch test with 100% Adipic acid was reported in one research worker in a factory producing polyester resins (based on study summary ^Footnote 3). In an animal study that did not accord to modern guidelines, Adipic acid (99.99%) did not cause skin sensitization in guinea pigs when induced with 1.0% solution of test material in water intradermally and challenged with one drop (~0.05 mL) of 50% and 25% suspension (wt./wt.) of test material in propylene glycol 2 weeks after ^Footnote 2.

The available data do not meet the classification criteria for Skin Sensitization.

Germ Cell Mutagenicity:

Does not meet criteria

A few well conducted in vivo mammalian germ cell gene mutation studies are available. Adipic acid did not induce dominant lethal mutations or chromosome aberrations in rat bone marrow in doses up to 5,000 mg/kg bw (acute studies) and with doses up to 2,500 mg/kg bw/day (five-days subacute studies) when administered by gavage to groups of 5 male rats in cytogenetic or 10 male rats in dominant lethal assays [6]. In another well conducted study, Drosophila melanogaster received Adipic acid via feed at a concentration of 4,000 ppm (based on study summary ^Footnote 3). Genetically marked X and Y chromosomes were used to test simultaneously nondisjunction, chromosome loss and induced recombination or translocation involving the Y-chromosome in offspring. No mutagenic effects were found. Adipic acid was considered not mutagenic in a battery of in vitro tests on bacterial as well as mammalian cells in the presence and absence of metabolic activation ^{Footnote 7,Footnote 8,Footnote 6,Footnote 9,Footnote 10,Footnote 3}.

The available data do not meet the classification criteria for Germ Cell Mutagenicity.

Carcinogenicity:

Does not meet criteria

The International Agency for Research on Cancer (IARC) and The American Conference of Governmental Industrial Hygienists (ACGIH) have not classified Adipic acid as a carcinogen. No increased incidence of tumours was observed in groups of 20 male rats administered 0, 0.1, 1.0, 3.0, or 5.0% Adipic acid in the diet for 2 years; nor in 19 female rats administered 1.0% Adipic acid in the diet for 2 years ^Footnote 11.

The available data do not meet the classification criteria for Carcinogenicity.

Reproductive Toxicity:

Does not meet criteria

In a study combined with 2 year feeding study in rats, histopathological examination of testes, ovaries, and uterus revealed no evidence of an adverse effect on the reproductive organs up to the highest tested doses (3,750 mg/kg/day in males, 750 mg/kg/day in females) ^Footnote 11. The administration of Adipic acid up to 288 and 250 mg/kg/day by gavage to groups of 20 to 24 pregnant rats and hamsters respectively, from gestation days 6 -15 (10 consecutive days) did not result in embryo-toxicity, feto-toxicity, or teratogenicity, nor were there any observed impacts on pregnancy ^Footnote 12.

The available data do not meet the classification criteria for Reproductive Toxicity.

Specific Target Organ Toxicity – Single Exposure:

Does not meet criteria

Oral Route of Exposure: In a single dose acute toxicity study in rats, no toxicity was observed at a dose level of 2,150 mg/kg ^Footnote 1. CNS effects, manifested as irregular respiration, apathy, staggering, and spastic gait, were observed in all animals one day after dosing at 4,640 mg/kg. The dose exceeds the concentration value range for classification.

Dermal Route of Exposure: No data available

Inhalation Route of Exposure: Two human studies have been reported in the secondary literature. A Russian study reported worker inhalation exposure at an Adipic acid manufacturing plant with few details and no histopathology ^Footnote 13. A second human study reported worker exposure to multiple chemicals as well as Adipic acid (based on a summary of a study by Cummings CE and Roseman J, 1985 ^Footnote 3). In a single dose acute toxicity study in rats, exposure to the maximal attainable concentration of 7,700 mg/m³ of Adipic acid (99.8 %) dust for 4 h did not result in any toxic symptoms or macroscopic pathological changes (based on study summary [3]). A brief description of a mouse study was reported in the secondary literature ^Footnote 14. The report provided insufficient details for a determination of a classification.

The available data do not meet the classification criteria for Specific Target Organ Toxicity – Single Exposure.

Specific Target Organ Toxicity – Repeated Exposure:

Does not meet criteria

Oral Route of Exposure: In a chronic 2-year feeding study in rats that did not fully comply with the guidelines, groups of 20 male rats were given 0, 0.1, 1, 3, and 5 % of Adipic acid in the diet (equivalent to doses of 0, and approximately 75, 750, 2,250, and 3,750 mg/kg/day) ^Footnote 11. Groups of 10 or 19 female rats received food containing 0 or 1 % Adipic acid (0 and approximately 750 mg/kg/day, respectively). The percent survival for each test group was higher than for the control group. No difference in body weights was found in female and male rats receiving 0, 0.1, and 1 % Adipic acid; however, the weight gains of the male rats receiving 3 and 5 % Adipic acid were significantly less than the control groups. Necropsy did not reveal any treatment-related effects, also microscopic examination of the organs revealed no compound related effect. Available data do not meet classification criteria.

Dermal Route of Exposure: No data available

Inhalation Route of Exposure: No adverse effects resulted from exposure of rats to 126 µg/L (or 126 mg/m³) particulate dust, 6 hours per day for 15 days ^Footnote 15.

The available data do not meet the classification criteria for Specific Target Organ Toxicity – Repeated Exposure.

Aspiration Toxicity:

No data available

Biohazardous Infectious Materials:

Not applicable

Adipic acid is not a microorganism, protein, or nucleic acid.

Physical hazards

Explosives:

Not Evaluated*

* Explosives are excluded from the Hazardous Products Act and Regulations. Explosives are regulated under the Explosives Act. For more information, visit Natural Resources Canada.

Flammable Gases:

Not applicable

The substance is not a gas. The classification criteria for Flammable Gases do not apply to this substance.

Flammable Aerosols:

No data available

No data are available to determine whether Adipic acid meets the classification criteria for Flammable Aerosols.

Oxidizing Gases:

Not applicable

Adipic acid is not a gas. The classification criteria for Oxidizing Gases do not apply to this substance.

Gases Under Pressure:

Not applicable

Adipic acid is not a gas. The classification criteria for Gases under Pressure do not apply to this substance.

Flammable Liquids:

Not applicable

Adipic acid is not a liquid. The classification criteria for Flammable Liquids do not apply to this substance.

Flammable Solids:

Does not meet criteria

The flammability of Adipic acid was determined in accordance with EEC Directive 92/69 Appendix V part A10 (based on study summary ^Footnote 3). Adipic acid did not burn. It melts in contact with heat and, therefore, was determined to be not "highly flammable".

The available data do not meet the classification criteria for Flammable Solids.

Self-Reactive Substances and Mixtures:

Does not meet criteria

Self-Reactive Substances and Mixtures must have a self-accelerating decomposition temperature (SADT) of ≤75°C to meet the minimum classification in this category. Adipic acid has an auto-ignition temperature of >400^°C (based on study summary ^Footnote 3).

The available data do not meet the classification criteria for Self-Reactive Substances and Mixtures.

Pyrophoric Liquids:

Not applicable

Adipic acid is not a liquid. The classification criteria for Pyrophoric Liquids do not apply to this substance.

Pyrophoric Solids:

Does not meet criteria

Adipic acid is not expected have pyrophoric properties based on read across from a mixture of dicarboxylic acids, C4-C6 (based on study summary ^Footnote 3).

The available data do not meet the classification criteria for Pyrophoric Solids.

Self-Heating Substances and Mixtures:

Does not meet criteria

Self-heating substances and mixtures should reach a temperature of 200°C by self-heating during 24h. In a study conducted in accordance with United Nations Guideline "Recommendations on the transport of dangerous goods", 10th ed, negative results were obtained (based on study summary ^Footnote 1). The temperature of the test sample (in a 100 mm³ container) raised to 140°C during 24 h.

The available data do not meet the classification criteria for Self-Heating Substances and Mixtures.

Substances and Mixtures which, in Contact with Water, Emit Flammable Gasses:

Does not meet criteria

Adipic acid has a chemical structure that does not contain metals or metalloids and is, therefore, excluded from classification [HPR 7.12.1(1)].

The available data do not meet the classification criteria for Substances and Mixtures which, in Contact with Water, Emit Flammable Gases.

Oxidizing Liquids:

Not applicable

Adipic acid is not a liquid. The classification criteria for Oxidizing Liquids do not apply to this substance.

Oxidizing Solids:

Does not meet criteria

Section 7.14.1(1)(b) of the HPR excludes any organic solid from classification that contains oxygen, fluorine or chlorine if those elements are chemically bonded only to carbon or hydrogen. The substance does not have oxidizing properties as it contains oxygen that is chemically bonded to carbon.

The available data do not meet the classification criteria for Oxidizing Solids.

Organic Peroxides:

Not applicable

Adipic acid is not an organic peroxide. The classification criteria for Organic Peroxides do not apply to this substance.

Corrosive To Metals:

No data available

Combustible Dusts:

Category 1

Adipic acid has a maximum explosion pressure of 6.9 bar, a dust deflagration index of 98 m bar/s ^Footnote 16 and Cloud ignition temperature: 550 °C ^Footnote 17. This data shows that Adipic acid can explode as a dust.

The available data meet the classification criteria for Combustible Dust - Category 1 [HPR 7.17.1].

Simple Asphyxiants:

Not applicable

Adipic acid is not a gas. The classification criteria for Simple Asphyxiants do not apply to this substance.

Pyrophoric Gases:

Not applicable

Adipic acid is not a gas. The classification criteria for Pyrophoric Gases do not apply to this substance.

Regulatory and other information

Regulatory information:

Hazardous substance assessments are prepared by Health Canada as educational and information resources. Under the HPA, suppliers of hazardous products must, upon the sale or importation of a hazardous product, provide a safety data sheet and label that meet the requirements set out in the HPR.

Other information:

The information and classifications contained in these hazardous substance assessments are based on publicly available sources, such as peer-reviewed literature or reports by international bodies. New information, including proprietary information, could have an impact on the classification of substances or hazardous products containing them. It is the responsibility of the supplier to ensure the accuracy, sufficiency, and reliability of their hazardous product classifications.

Last updated:

2020

Prepared by:

Workplace Hazardous Materials Bureau, Health Canada