Carboxylic acids, di-, C4-6

Endpoint summary

Description of key information

Dicarboxylic acid mixture is slightly irritating to the skin. It is highly irritating to the eye with symptoms not reversible within 21 days. Respiratory irritation in animals is not sufficiently examined. Due to the acidic character of the dicarboxylic acid mixture, a local irritation potential in the respiratory tract cannot be excluded.

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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically defensible or guideline method was used, no GLP

Guideline:

other: US Federal Hazardous Sustances Act

Deviations:

not specified

Remarks:

for further details, see below

Principles of method if other than guideline:

0.5 g applied as finely ground sample moistened with water
Study was conduced according to Federal Hazardous Substance Act

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

water

Controls:

not required

Duration of treatment / exposure:

24 hours

Observation period:

7 days

Number of animals:

6

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0 - <= 2

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0 - <= 2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0 - <= 2

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

7 days

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0 - <= 2

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

7 days

Other effects:

Slight scabbing at lines of abrasions.

The individual scores of 3 animals were shown; the other three treated animals show comparable effects.

Interpretation of results:

not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

not irritating

Executive summary:

In a skin irritation study according to the US Federal Hazardous Substance Act with limited documentation 500 mg of a dicarboxylic acid mixture moistened with water was applied to the shaved intact or abraded skin of six rabbits, respectively, for 24 h. Slight scabbing at line of abrasion was observed. Mean scores for erythema or oedema after 24, 48 and 72 were 1.2 or 0.43, respectively. All effects were reversible by day 7.

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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically defensible or guideline method was used, no GLP

Guideline:

other: US Federal Hazardous Substance Act

Deviations:

not specified

Remarks:

for further details see below

Principles of method if other than guideline:

30 mg test compound was applied as finely ground sample (Dosage equivalent to 0.1 ml)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Vehicle:

water

Controls:

not required

Duration of treatment / exposure:

24 h

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

6

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Remarks on result:

other: not determined

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Remarks on result:

other: not determined

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Remarks on result:

other: not determined

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

10 - <= 15

Max. score:

80

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

10 - <= 40

Max. score:

80

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0 - <= 5

Max. score:

80

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

5 - <= 10

Max. score:

10

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

5 - <= 10

Max. score:

10

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

5 - <= 10

Max. score:

10

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

14 - <= 16

Max. score:

20

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

14 - <= 16

Max. score:

20

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

14 - <= 16

Max. score:

20

Reversibility:

not fully reversible within: 7 days

Other effects:

Day 21: Slight ulceration in three instances, slight to moderate discharge; nictitating membrane not visibel

The individual scores of 3 animals were shown; the other three treated animals show comparable effects.

Interpretation of results:

moderately irritating

Remarks:

Criteria used for interpretation of results: other: Federal Hazardous Substance Act

Conclusions:

Test material was irritating to the eye; the observed effects were not fully reversible within 21 days.

Executive summary:

In an eye irritation study performed again according to the US Federal Hazardous Substance Act in the same laboratory six rabbits were dosed with 30 mg dicarboxylic acid mixture for 24 hours. Severe erythema and slight edema and copious discharge was observed 10 minutes after installation. After 1 and 24 hour the following observations were recorded: translucent to opalescent areas of corneal cloudless, iris showed sluggish/no reaction to light, slight to moderate edema, copius discharge. The effects gradually improved between 48 and 168 hours but were not reversible after 21 days (slight ulceration in three instances, slight to moderate discharge; nictitating membrane not visible).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Additional information

In a skin irritation study according to the US Federal Hazardous Substance Act with limited documentation 500 mg of dicarboxylic acid mixture moistened with water was applied to the shaved skin of six rabbits, respectively, for 24 h. Slight scabbing at line of abrasion was observed. Mean scores for erythema or oedema after 24, 48 and 72 were 1.2 or 0.43, respectively. All effects were reversible by day 7 (Birch 1979).

 

Additional skin irritation studies are available. In one experiment 2 rabbits were occlusive dosed with dicarboxylic acid mixture for 20 h. Scores were evaluated at 24, 48 and 72 h. No edema were observed for both animals and mean erythema scores were 2 and 1,33 for animal 1 and 2, respectively. The effects were not fully reversible in animal 1 at the end of the experiment, day 8 (BASF 1973). In another experiment six rabbits were treated with the 0.5 ml liquid test substance (50% solution) for 24 h using occlusive conditions on the intact and scarified skin. The animals were observed for 7 days. No erythema or edema were observed in any animal.

 

In an eye irritation study performed according to the US Federal Hazardous Substance Act six rabbits were dosed with 30 mg dicarboxylic acid mixture for 24 hours. Severe erythema and slight edema and copious discharge was observed 10 minutes after installation. After 1 and 24 hour the following observations were recorded: translucent to opalescent areas of corneal cloudless, iris showed sluggish/no reaction to light, slight to moderate edema, copius discharge. The effects gradually improved between 48 and 168 hours but were not reversible after 21 days (slight ulceration in three instances, slight to moderate discharge; nictitating membrane not visible). Two additional studies confirm that dicarboxylic acid mixture induces severe eye irritation not reversible within the observation time of 8 days (BASF 1973, 1979).

 

Additional sources/reviews cited in chapter "Additional Toxicological Information" support that dicarboxylic acid mixture is not/slightly irritating to the skin and irritating to the eye.

 

Respiratory irritation in animals is not examined, however, due to the acidic character of the dicarboxylic acid mixture, a local irritation potential cannot be excluded. No evidence of respiratory tract irritation was reported for adipic acid 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).

 

Reliable human data are not available in the literature. In one study the authors reported that clouds of adipic acid and other materials were routinely generated during charging of reaction vessels. In 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, and throat). There was no local exhaust ventilation and the workers did not wear respiratory protection (Cummings and Roseman 1985). Due to the limitations mentioned this study is not reliable and can not be used to derive a threshold for local irritation.

 

A Threshold Limit Value (TLV-TWA) of 5 mg/m3 was established for adipic acid by the American Conference of Governmental Industrial Hygienists (ACGIH) in 2001, based on the data reported by Krapotkina et al (1981) that the threshold for irritation of the human eye was 20 mg/m3. Clinical examinations of worker engaged in adipic acid manufacture found that inhaling adipic acid produced functional disorders of the autonomic nervous system and gastrointestinal tract and in the mucosa of the upper respiratory tracts.

Supported by occupational medical experiences with adipic acid , glutaric acid and succininc acid available within the lead company, Lanxess, the dicarboxylic acid mixture is allocated to the moderate hazard band. Regularly, medical examination of the staff (7 persons) is performed. 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. Parallel to the medical examination the concentration of those hazardous substances in the air at the workplace were determined. The maximum concentration of adipic acid and glutaric acid were 11.6 mg/m3 and 1.23 mg/m3, respectively, between 2006 and 2009 (Currenta 2010).

Effects on eye irritation: severe eye damage

Justification for classification or non-classification

Dicarboxylic acid mixture should be classified with R41 "risk of serious damage to eyes" according to the current classification criteria 67/548/EWG and as an eye irritant Category 1 "irreversible effects on the eye" according to regulation no. 1272/2008 (GHS).