Adipic acid

Endpoint summary

Description of key information

Adipic acid is of very low acute toxicity.

The oral and dermal LD50 in rats are > 5000 mg/kg bw.

In an acute inhalation test neither mortality nor clinical symptoms were observed during and after 4 hour exposure to 7700 mg/m3 of adipic acid.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP but overall good documentation, comparable to OECD TG 401.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

In principle, the methods described in the OECD Guideline 401 were used. Young adult laboratory rats were purchased from breeder. Several groups of 5 rats per sex and dose were treated simultaneously by gavage with preparations of the test substance in suitable vehicle. The concentrations of these preparations were used to achieve comparable volumes per kg body weight. Group-wise documentation of clinical signs was performed over the 14 day study period.

GLP compliance:

no

Remarks:

GLP was not compulsory at the time the study was conducted

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA, Sulzfeld, Germany
- Weight at study initiation:
1470 mg/kg bw dose group: 180 g males, 160 g females
2150 mg/kg bw dose group: 180 g males, 160 g females
3160 mg/kg bw dose group: 190 g males, 170 g females
4640 mg/kg bw dose group: 190 g males, 170 g females
6810 mg/kg bw dose group: 290 g males, 200 g females
10000 mg/kg bw dose group: 270 g males; 180 g females

- Fasting period before study: yes, 16 h prior to application
- Diet: Herlin MRH pellets ad libitum (Company Eggersmann, Rinteln/Weser, Germany)
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

other: 14.7% - 50% suspension in 0.5% carboxymethyl-cellulose

Details on oral exposure:

DOSAGE PREPARATION
- Stock solutions prepared:
14.7% in a 0.5% aqueous carboxymethyl cellulose solution for the 1470 mg/kg bw dose group
21.5% in a 0.5% aqueous carboxymethyl cellulose solution for the 2150 mg/kg bw dose group
31.6% in a 0.5% aqueous carboxymethyl cellulose solution for the 3160 mg/kg bw dose group
46.4% in a 0.5% aqueous carboxymethyl cellulose solution for the 4640 mg/kg bw dose group
50% in a 0.5% aqueous carboxymethyl cellulose solution for the 6810 mg/kg bw dose group
50% in a 0.5% aqueous carboxymethyl cellulose solution for the 10000 mg/kg bw dose group

- Dose volume applied:
10 ml/kg bw of the 14.7% stock solution for the 1470 mg/kg bw dose group
10 ml/kg bw of the 21.5% stock solution for the 2150 mg/kg bw dose group
10 ml/kg bw of the 31.6% stock solution for the 3160 mg/kg bw dose group
10 ml/kg bw of the 46.4% stock solution for the 4640 mg/kg bw dose group
13.62 ml/kg bw of the 50% stock solution for the 6810 mg/kg bw dose group
20 ml/kg bw of the 50% stock solution for the 10000 mg/kg bw dose group

Doses:

1470, 2150, 3160, 4540, 6810, 10000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- The animals were observed for mortality and clinical signs of toxicity;
- Frequency of observations: Several times on the application day, thereafter once each working day;
- Body weights were only recorded at the beginning of the study;
- Necropsy of survivors and animals which died performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

5 560 mg/kg bw

95% CL:

4 650 - 6 770

Mortality:

No mortalities were observed in the 1470 mg/kg bw dose group or the 2150 mg/kg bw dose group. 1 female of the 3160 mg/kg bw dose group and 2 females of the 4640 mg/kg bw dose group died within the first 2 days, while there were no mortalities within the male animals. In the 6810 mg/kg bw dose group all females and 2 of 5 males died within the first two days, in the 10000 mg/kg bw dose group all animals died within 24 h after application (see table 1).

Clinical signs:

other: 1470 mg/kg bw dose group: nothing abnormal observed 2150 mg/kg bw dose group: nothing abnormal observed 3160 mg/kg bw dose group: gasping, apathy, salivation and nose secretion in 1 or 2 animals. Those symptoms disappeared within 24 h. 4640 mg/kg bw dose

Gross pathology:

- Animals which died:
3160 mg/kg bw dose group: brightened liver and kidney; reddened, atonic gut; vessel injection in the gastric mucosa
4640 mg/kg bw dose group: acute dilatation of the heart and acute hyperemia; decay of inner organs
6810 mg/kg bw dose group: acute dilatation of the heart and acute hyperemia, ulceration of the stomach
10000 mg/kg bw dose group: acute dilatation of the heart, ulceration of the stomach, the stomach was atonic, atonic gut
Sacrificed animals: nothing abnormal observed

Dose                compound                sex        mortality 
mg/kg bw)         concentration (%)                (14 days)

10000                50                       m        5/5
                                         f        5/5
6810                 50                       m        2/5
                                         f        5/5
4640                46.4                      m        0/5
                                         f        2/5
3160                31.6                      m        0/5
                                         f        1/5
2150                21.5                      m        0/5
                                         f        0/5
1470                14.7                      m        0/5
                                         f        0/5

Mortality was seen during the first 48 hours. Animals that
died showed acute dilatation of the heart and acute
congestive hypereamia, ulceration of glandular stomach
(bleeding-corrosive gastritis), intestinal atony, reddening
of intestinal mucosa and pale liver. Organs of the survivors were
without findings.

Executive summary:

In rats, an LD50 value of 5560 mg/kg bw was established in a study similar to OECD TG 401 performed with single 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 dilatation of the heart and acute congestive hyperaemia, ulceration of glandular stomach (bleeding-corrosive gastritis), pale liver, intestinal atony and reddening of intestinal mucosa. 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

Endpoint conclusion

Dose descriptor:

LD50

Value:

5 560 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP, short documentation, comparable to OECD TG 403

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Similar to OECD TG 403. Two independent experiments were performed with 7.7  and 5.4 mg/l adipic acid, with 20 animals per concentration.  Head/nose-only exposure was the technique used (system INA 20, BASF;  animals were sitting in tubes and the mouth protruded into the inhalation  chamber). It is unclear whether the eyes of the animals were exposed  also.  A dust atmosphere with a particle-size mass distribution (MMAD50) of 3.5  µm (i.e. 50% of the particles had a MMAD < 3.5 µm) and a geometric  standard deviation (GSD) of 2.6 was used throughout the experiment. The  maximal attainable concentration in this test was 7.7 mg/l. Animals were exposed for 4 hours. Body weights and general appearance were recorded daily throughout the experimental period. After 14 days animals were killed and gross autopsy was performed.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA, Sulzfeld, Germany
- Age at study initiation: 6 - 8 weeks
- Weight at study initiation: 185 + / - 15 g
- Housing: five animals per cage type D III, Becker, Germany
- Diet: Herilan MRH (Eggersmann KG, Riteln/Weser, Germany), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 5 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

other: dust/aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

other: no vehicle

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head - Nose - inhalation system INA 20, BASF
- Exposure chamber volume: 60 l
- Generation of test atmosphere: A dust/aerosol was generated by a dust generator and fed to the inhalation system. The concentration was adjusted by changes of the width of the gap and variations of the vibration amplitude of the dosing device. The air was adjusted to 500l/h compressed air through the injector and 500 l/h blowing air for dilution.
- Method of particle size determination: At earliest 30 min after the start of the experiment, one sample was taken. Prior to sampling the impactor was fitted with a collection disc and a residue particle filter. The impactor was connected to the pump and the apparatus and one sample (9 l) was taken. Therefore the collection disc and the residue particle filter were weight and the content of the preimpactor determined by gravimetry.

TEST ATMOSPHERE
- Analytical method used: gravimetric determination of the concentration
- Samples taken from breathing zone: yes, every half hour one sample per concentration group

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter): 3.5 µm / GSD (Geometric st. dev.): 2.6

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

7.67 mg/l analytical concentration (nominal concentration 43.8 mg/l)
5.41 mg/l analytical concentration (nominal concentration 29.88 mg/l)

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: clinical symptoms and mortality was observed on a daily basis
- Frequency of weighing: prior to the experiment, after one week and at the end of the observation period
- Necropsy of survivors performed: yes

Statistics:

- The concentration-effect-relation was calculated following the binominal test (Wittig, H.: Mathematische Statistik 1974, p 32-35)
- The particle size determination followed the mathematical and graphical analysis for particle size determination (Silverman, L.: Particle Size Analysis in Industrial Hygiene, 1971, p. 235-259)

Sex:

male/female

Dose descriptor:

LC0

Effect level:

> 7.7 mg/L air

Exp. duration:

4 h

Remarks on result:

other: no mortalities observed

Mortality:

No mortalities observed

Clinical signs:

other: Nothing abnormal observed

Body weight:

Constant body weight gain of 25 - 40 g during the 14 days observation period.

Gross pathology:

Nothing abnormal observed

Neither mortality nor symptoms were observed during and after exposure.  No pathological changes were reported at necropsy.

Executive summary:

In a study similar to OECD TG 403, neither mortality, toxic symptoms nor macroscopic pathological changes were observed in 20 rats exposed for 4 hours (nose/head only) to the maximal attainable concentration of 7700 mg/m3 of adipic acid (99.8 %) dust. 50 % of the particles had a MMAD below 3.5 µm.

Endpoint conclusion

Dose descriptor:

discriminating conc.

Value:

7 700 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Number of animals low, purity not specified.

Principles of method if other than guideline:

Adipic acid was tested as a 40% solution in corn oil. Minimum lethal dose was determined using 1-2 rabbits per group (5010 mg/kg bw one animal, 7940 mg/kg bw two animals). A 24- hour dermal exposure under occlusive conditions was conducted. Necropsy was conducted after a 14-day observation period.

GLP compliance:

no

Test type:

other:

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

corn oil

Duration of exposure:

24 hours

Doses:

5010 and 7940 mg/kg

No. of animals per sex per dose:

5010 mg/kg bw one animal, 7940 mg/kg bw two animals

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LD0

Effect level:

7 940 mL/kg bw

No deaths occurred at 5010 mg/kg bw (0/1) or 7940 mg/kg bw
(0/2). Observations included reduced appetite and activity.
Reduced appetite and activity ( one or two days).

Executive summary:

No lethality was reported in rabbits following occlusive dermal administration of up to 7940 mg/kg bw 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 observation period (Solutia Inc. 1975).

Endpoint conclusion

Dose descriptor:

discriminating dose

Value:

7 940 mg/kg bw

Additional information

Hazards identified by OECD/ICCA high production volume chemicals program in 2004:

Oral toxicity:

" In rats, an LD50 value of 5560 mg/kg bw was established in a study similar to OECD TG 401 performed with single 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 dilatation of the heart and acute congestive hyperaemia, ulceration of glandular stomach (bleeding-corrosive gastritis), pale liver, intestinal atony and reddening of intestinal mucosa. 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 (BASF 1978).

No signs of toxicity were observed following administration of a single dose of 5000 mg/kg bw of adipic acid (suspended in saline) to ten male rats (Litton Bionetics Inc. 1974).

In mice, an LD50 value of 1900 mg/kg bw was established after the administration of adipic acid (6 % solution in 0.5 % methyl cellulose) to groups of 13 male animals. Autopsy of animals that died during the experiment showed distention of the stomach and irritation and hemorrhage of the intestines as well as spastic contraction of the caecum. Initial mortality developed overnight and deaths continued throughout the first week, survivors appeared normal (Horn et al., 1957)."

Inhalation toxicity:

"In a study similar to OECD TG 403, neither mortality, toxic symptoms nor macroscopic pathological changes were observed in 20 rats exposed for 4 hours (nose only) to the maximal attainable concentration of 7700 mg/m3 of adipic acid (99.8 %) dust. 50 % of the particles had a MMAD below 3.5 µm."

Dermal toxicity:

"No lethality was reported in rabbits following occlusive dermal administration of 5010 (n = 1) and 7940 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 observation. Due to the low animal number the study is of limited reliability, however the result is consistent with the low acute oral toxicity."

Acute toxicity other routes:

Limited studies are cited in IUCLID database prepared for the OECD/ICCA high production volume chemicals program in 2004. LD50 values are reported between 275 and 600 mg/kg bw after i.p. injection in mice and a LD0 of 2450 mg/kg bw was reported after i.v. injection in rabbits.

Human information:

"Hazards identified by OECD/ICCA high production volume chemicals program in 2004:

There are no acute toxicity studies in humans reported. No overt toxic symptoms were reported after oral administration of up to 7 g of adipic acid per day, for 10 days to one volunteer (100 mg/kg bw. per day) to investigate compound excretion (Weitzel, 1942 and 1947)."

Updated relevant information:

None

Overall:

Adipic acid is of very low acute toxicity. The oral LD50 in rats in a study similar to OECD TG 401 is approximately 5560 mg/kg bw. The LD50 for mice was reported to be 1900 mg/kg bw. In both species severe irritating effects were observed in the gastrointestinal tract. In an inhalation test similar to OECD TG 403 in rats neither mortality nor symptoms were observed during and after 4 hour exposure to 7700 mg/m3 of adipic acid dust. Reduced appetite and activity were the only effects reported following occlusive dermal administration of 7940 mg/kg bw of adipic acid to 2 rabbits for 24 hours.

Justification for classification or non-classification

Adipic acid is of very low acute toxicity. No classification is required according to the EU Regulation no. 1272/2008 (GHS).