reaction products of acetic anhydride and adipic acid

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP, near guideline study, published in peer reviewed literature. No restrictions, fully adequate for assessment. Read-across justification: The available toxicological data for the target and source substances is outlined in the data matrix (Annex I). The toxicological properties of the target substance are related mainly to acetic acid/acetate since the anhydride components of the substance are hydrolytically unstable. When the target substance comes in contact with water or moisture a complete hydrolysis will take place to form no other hydrolysis products than acetic acid/acetate and adipic acid. Thus, the use of data from acetic acid and adipic acid is justified to evaluate toxicological properties of the target substance. Furthermore, data from acetic anhydride is used in the assessment. Experimental data obtained with the source substances indicate that the substances has low oral (LD50 > 1780 – 3310 mg/kg bw) and inhalation (LC50 1680 - 7700 mg/m3) acute toxicity. Furthermore, the acetic acid and acetic anhydride are irritating to skin at concentration < 25% and corrosive to skin at ≥ 25%. Acetic anhydride and acetic acid are not tested for sensitisation due corrosive properties; adipic acid did not show any evidence of sensitising in an animal study. The source substances did not show positive response in genetic toxicity studies available. Repeated toxicity studies via oral route conducted for acetic acid showed NOAEL values ≥ 210 mg kg bw/day and via inhalation route for acetic anhydride 4.2 mg/m3.. Reproduction toxicity studies conducted for acetic acid did not show any adverse effects on reproduction at the highest concentration tested (1600 mg/kg bw/day).

Data source

Reference

Reference Type:

publication

Title:

An objective method for the evaluation of eye irritation in vivo

Author:

Jacobs GA and Martens MA

Year:

1989

Bibliographic source:

Fd Chem Toxic. Vol 27. No. 4 pp 255-258

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

ultrasonic pachometry included, 6 rabbits used

Principles of method if other than guideline:

Phase 1 - 3 animals tested and scored clinically; Phase 2 - 3 animals tested, scored and corneal swelling measured using ultrasconic pachometer.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Acetic acid

EC Number:

200-580-7

EC Name:

Acetic acid

Cas Number:

64-19-7

Molecular formula:

C2H4O2

IUPAC Name:

acetic acid

Details on test material:

- Name of test material (as cited in study report): Acetic acid
- Physical state: liquid
- Analytical purity: 99.5%
- Other: obtained from Merck, Darmstadt, FRG

Test animals / tissue source

Species:

rabbit

Strain:

other: Rsk:NZW

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Six healthy rabbits used in two phases, each phase separated by about 6 months (3 rabbits per phase)
- No further details reported

ENVIRONMENTAL CONDITIONS
- No details reported.

IN-LIFE DATES: No dates reported

Test system

Vehicle:

other: 10% acetic acid in water tested

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 uL
- Concentration (if solution): 10%

Duration of treatment / exposure:

4 h

Observation period (in vivo):

4, 24, 48, 72, 96 and 168 h

Number of animals or in vitro replicates:

3 / phase

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The eyes were not washed following instillation

SCORING SYSTEM:
- Erythema, chemosis, iritis and corneal opacity were scored according to Draize scores

TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein - none reported
Ultrasonic pachometry used to assess corneal thickness in Phase 2 rabbits

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

other: erythema score

Basis:

mean

Time point:

other: 24, 48 & 72 h

Score:

2.67

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: erythema score, 10% acetic acid

Results 2

Irritation parameter:

other: % corneal swelling

Basis:

mean

Time point:

other: 24, 48 & 72 h

Score:

87

Reversibility:

not specified

Remarks on result:

other: % corneal swelling, 10% acetic acid

Irritant / corrosive response data:

Instillation of 10% acetic acid resulted in a mean erythema score of 2.67, which is considered to justify the classification "irritant" according to EEC classification, and a mean % corneal swelling of 87%.
There was shown to be a good correlation between corneal opacity and corneal swelling in this study and from this it was deduced that 80% mean corneal swelling corresponds to a corneal opacity value of 2, the EEC threshold for classification as an irritant.
was irritant to the rabbit eye

Other effects:

None reported

Any other information on results incl. tables

Table 1 - Eye irritation scores for 10% acetic acid

Mean erythema score	Mean chemosis score	Mean corneal opacity score	Mean % corneal swelling
2.67 *	1.67	1.72	87 *

Means are for 6 rabbits, except for mean % corneal swelling which is for 3 rabbits.

* these values justify the term irritant

The mean erythema, chemosis and corneal opacity scores were calculated for all six rabbits and the scores at the three observation times, 24, 48 and 72 h, were pooled. In this study mean erythema was calculated by reading the erythema of the upper eyelid, the lower eyelid and the nictitating membrane. The mean of thee readings was considered to be the erythema of the palpebral conjunctiva of a rabbit at a given time.

Corneal swelling was expressed as a percentage and calculated according to the formula:

%CS=        [(corneal thickness at time t  / corneal thickness at time 0) - 1] x 100.

The mean % swelling is calculated over 3 rabbits for each observation time.

Applicant's summary and conclusion

Conclusions:

10% acetic acid was shown to be irritating to the rabbit eye using the mean erythema score and % corneal swelling as measured using ultrasonic pachometry.

Executive summary:

To eliminate the difficulties of subjective judgement in assessing eye irritants, the relationship between corneal swelling, measured objectively using ultrasonic pachometry, and the reading of other symptoms was investigated in this study, using 34 substances. Erythema, oedema and corneal opacity were evaluated according to EEC directive 83/467/EEC. Good correlations were found between the mean percentage corneal swelling after 24, 48 and 72 h and mean corneal opacity (r=0.94) and erythema scores (r=0.93) after the same observation times.

10% acetic acid was shown to be irritating to the rabbit eye using the mean erythema score and % corneal swelling as measured using ultrasonic pachometry.