Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Adipic acid is slightly irritating to the skin.

Adipic acid is highly irritating, risk of serious damage to eyes.

Respiratory irritation in animals is not sufficiently examined. Due to the acidic character of the substance, a local irritation potential is plausible.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
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, short documentation, 24 h exposure time, purity not specified.
Qualifier:
equivalent or similar to guideline
Guideline:
other: [application time: 24 h (OECD TG 404: 4 h); 6 animals have been used (OECD: 3); observation period 8 days (OECD: 14 d); occlusive testing (OECD: semiocclusive); additionally scarified skin was tested (OECD: no abraded skin test required)]
Principles of method if other than guideline:
Method: §1500.41; Federal Register Vol. 38, No. 187, pp 26019 dated 27.09.1973
GLP compliance:
no
Remarks:
GLP was not compulsory at the time the study was conducted
Species:
rabbit
Strain:
Vienna White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Gaukler, Offenbach, Germany
- Weight at study initiation: 3.1 kg (2.45 kg - 3.43 kg)
- Diet: Ssniff K, standard diet, Intermast, Soest, Germany, ad libitum
- Water: ad libitum
Type of coverage:
occlusive
Preparation of test site:
other: clipped skin as well as clipped and scarified skin on the same animal
Vehicle:
water
Controls:
not required
Amount / concentration applied:
0.5 g of a 50% aqueous solution
Duration of treatment / exposure:
24 hour(s)
Observation period:
24h, 3 and 8 days
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 2.5 X 2.5 cm
- Type of wrap if used: The cloth on which the test substance was applied was covered with a gummed linnen cloth, which was fixed by sticking plasters and wrapped by a gauze bandage.

REMOVAL OF THE TEST SUBSTANCE
- no whashing done

ADDITIONAL INFORMATION
- During exposre animals were fixed and fasted.

SCORING SYSTEM:
- Draize Scale
Irritation parameter:
erythema score
Basis:
mean
Remarks:
6 animals
Time point:
24 h
Score:
2.1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
probability of weak irritation
Irritation parameter:
erythema score
Basis:
mean
Remarks:
6 animals
Time point:
72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
6 animals
Time point:
24 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
6 animals
Time point:
72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
6 animals
Time point:
48 h
Score:
>= 0
Max. score:
4
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
mean
Remarks:
6 animals
Time point:
48 h
Score:
>= 0
Max. score:
4
Remarks on result:
not measured/tested
Other effects:
- Four of the six test animals suffered from parasites in the liver

Reversible reddening was observed at the intact skin which
disappeared after three days. Mild to severe reddening and
edema was observed at the scarified skin. These effects were
reversible after 1 week and scale formation was observed.

Observation scores:

Intact skin:

Reddening:
time        score animal 1/2/3/4/5/6
24 h                     2/2/2/3/2/2
3 days                   0/0/0/0/0/0
8 days                   0/0/0/0/0/0
Oedema observation:
24 h                     0/0/0/0/0/0
3 days                   0/0/0/0/0/0
8 days                   0/0/0/0/0/0

Scarified skin

Reddening:
24 h                      2/3/3/3/2/2
3 days                    2/1/2/1/1/1
8 days                    0/0/0/0/0/0 scale formation in every case


Oedema observation:
24 h                       2/2/2/2/2/2
3 days                     2/0/2/0/1/0
8 days                     0/0/0/0/0/0

Interpretation of results:
GHS criteria not met
Conclusions:
slightly irritating
Executive summary:

500 mg of a 50 % aqueous suspension of adipic acid (99.8 %) was tested on intact and scarified skin of six rabbits, respectively. The compound was applied to an area of 5 x 5 cm, covered and held in contact for 24 hours. Responses were scored immediately (24 hours), and 3 and 8 days after dosing. Reversible reddening was observed at the intact skin (scored 2-3 at 24 h on a scale up to a maximum of 4) which disappeared after three days. Mild to severe reddening and edema was observed at the scarified skin (scores 24 h: 2, 3 days: 0 - 2). These effects were reversible after 1 week (all scores 0) and scar formation was observed.

Thus, adipic acid is slighly irritating to skin. No classification for skin irritation is warranted.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to OECD TG 405 and GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
Concentration: 100 mg
Duration of treatment / exposure:
24 h
Observation period (in vivo):
24 h, 7 and 14 days
Number of animals or in vitro replicates:
3
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 16 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 9 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 9 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 13 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Remarks:
nictating membrane swollen until day7
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Remarks:
nictating membrane swollen until day 9
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 12 days

Under the present test conditions, a single application of 100 mg acipid acid 

per animal into the conjunctival sac of the right eye of  three rabbits caused 

the following changes:
Corneal opacity was observed in all animals: 
- animal no. 1: 1 hour to 72 hours (grade 3), 4 to 6 days (grade 2) and 7  to 15 days (grade 1) after instillation;
- animal no. 2: 1 hour to 72 hours (grade 2) and 4 to 12 days (grade 1)  after instillation;
- animal no. 3: 1 hour (grade 3), 24 to 72 hours (grade 2) and 4 to 12  days (grade 1) after instillation.

The fluorescein test performed 24 hours after instillation revealed  comeal

staining in animal nos. 1 and 3 (3/4 of the surface) and animal  no. 2 (1/2 of

the surface). The fluorescein test performed 7 days after  instiltation

revealed corneal staining in animal nos. 1 and 3 (1/2 of the  surface) and

animal no. 2 (1/4 of the surface). The fluorescein test  performed 14 days

after instillation revealed corneal staining in animal  no. 1 (1/4 of the

surface).

Irritation of the iris was observed in all animals:
- animal no. 1: 1 hour to 4 days (grade 2) and 5 to 8 days (grade 1)

after instillation;
- animal no. 2: 1 hour and 24 hours (grade 2) and 48 hours to 6 days

(grade 1) after instillation;
- animal no. 3: 1 hour to 72 hours (grade 2) and 4 to 8 days (grade 1)

after instillation.

Conjunctival redness (grade 1) was observed in animal no. one 1 hour to

12 days, in animal nos. two and three 1 hour to 72 hours after  instillation.

Conjunctival chemosis (grade 1) was observed in animal nos. one and two 1  hour

to 6 days, in animal no. three 1 hour to 11 days after instillation. 

There were no systemic intolerance reactions.

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
highly irritating, risk of serious damage to eyes
Executive summary:

Severe eye irritation was observed in a study performed according to OECD TG 405, conducted in compliance with GLP after the application of 100 mg adipic acid. Corneal opacity and irritation of the iris was observed in all animals up to grade 3 and grade 2, respectively. The observed effects were reversible within 16 days (LPT 2004)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

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

"Skin irritation:

500 mg of a 50 % aqueous suspension of adipic acid (99.8 %) was tested on intact and scarified skin of six rabbits, respectively. The compound was applied to an area of 5 x 5 cm, covered and held in contact for 24 hours. Responses were scored immediately after dosing (24 hours), 3 and 8 days. Reversible reddening was observed at the intact skin (scored 2-3 on a scale up to a maximum of 4) which disappeared after three days. Mild to severe reddening and edema was observed at the scarified skin (scores 24 h: 2, 3 days: 0 - 2). These effects were reversible after 1 week (all scores 0) and scale formation was observed (BASF 1978d)."

Eye irritation:

"Severe irritation was observed in a recent study according to OECD TG 405, conducted in compliance with GLP after the application of 100 mg adipic acid. Corneal opacity and irritation of the iris was observed in all animals up to grade 3 and grade 2, respectively. The observed effects were reversible within 16 days (LPT 2004)."

Respiratory irritation:

"Evidence of respiratory tract irritation was reported neither in an acute inhalation study where 20 rats were exposed to up to 7700 mg/m3 of adipic acid dust (MMAD 3.5 µm) for 4 hours (BASF 1981) nor in an subacute study with limited documentation where four rats were exposed to 126 mg/m3 of adipic acid dust for 6 hours per day for 15 days. The reliability of the sub-acute study is limited because only four animals were investigated, the MMAD was not determined and histopathology was performed only on nine organs, including the lung (Gage 1970). Both of these studies are however not suited to fully assess the local irritation potential of adipic acid, as the nose was not examined histopathologically. Additionally, cytotoxicity to rat nasal explants has been shown in vitro for adipic acid at 3.5 g/l (Trela and Bogdanffy 1991)."

Studies in Humans:

"7 of 12 workers exposed (for an average of 9.2 years) to various glycols, glycerine, other compounds, and adipic acid dust particles (8 h average concentration 0.47-0.79 mg/m3 [0.08-0.13 ppm]) complained of mucosal irritation (eye, nose, throat). There was no local exhaust ventilation and the workers did not wear respiratory protection. They reported that clouds of adipic acid and other materials were routinely generated during charging of reaction vessels. The investigators suggested that, since the glycol level was kept below 1 ppm, adipic acid was more likely to be the cause of these complaints (Cummings and Roseman 1985). This report is difficult to evaluate, because of the mixed exposure of the workers to a series of different compounds, including adipic acid. Due to the acidic character of adipic acid, a local irritation potential is plausible."

Updated relevant information:

Regularly, medical examination of the staff (7 persons) is performed in an occupational setting. Examination includes medical history, physical examination, lung function, ECG/Ergometry, vision-testing and audiometry. Occupational medical surveillance did not reveal any health effects like irritations of the eyes, skin, mucosa membranes or upper respiratory tract which could be derived to be from possible exposure at workplace.

Justification for classification or non-classification

According to the harmonized classification and labelling approved by the EU, adipic acid is classified with Eye Damage 2 (H319). Based on the results obtained in the most recent eye irritation study (Bayer, LPT 2004) classification with Eye Damage 1 (H318; Causes serious eye damage) according to GHS is adequate.

Categories Display