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Administrative data

Description of key information

No valid data could be identified for assessment of the skin irritating potential of isobutyric acid.
To compensate for this lack of data, information resulting from valeric acid as supporting substance is used as substitute.
For eye irritation, a valid study is available.
Skin irritation / corrosion (supporting substance valeric acid)
Valeric acid was demonstrated to be corrosive in a primary skin irritation study according to OECD TG 404 (Hoechst AG, 1983).
Eye irritation (isobutyric acid)
Isobutyric acid was demonstrated to be corrosive in a valid primary eye irritation test similar to OECD TG 405 (BASF, 1974).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The reactive group of both substances is the carboxylic acid function, which plays the key role in causing irritating / corrosive effects. For longer chain carboxylic acids, the irritating potential will decrease. C4 and C5 carboxylic acids will cause similar irritating / corrosive effects.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substancens are assessed as pure chemicals with negligable impurieties (GC purity >98%). Valeric acid is closely related to isobutyric acid regarding physical-chemical properties.. Both substances are short chain carboxylic acids differing in the length of their carbon chain by only one carbon atom (C5 and C4). Isobutyric asid is a branched carboxylic acud beariug a methyl group in the 2-position. According to chemistry textbook knowledge no impact on the functional group and its dermal effect should be largley affected by this fact. Other physical and chemical properties are quite similar.

3. ANALOGUE APPROACH JUSTIFICATION
Short chain carboxylic acids up to C6 are known to be corrosive. With decreasing chain length number the corrosion potential will increase. For C4 and C5 carboxylic acid a simelar dermal effect regarding irritation and corrosion can be assumed. As the major effect is grounded in the functional caroxylich acid group the influence of the carbon chain is of lower impact and is justified in case of comparison of a C4 to a C5 carboxylic acid.
Reason / purpose:
read-across source
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG
- Weight at study initiation: 3.4 - 4.2 kg
- Housing: individually in cages, in air-conditioned rooms
- Diet (e.g. ad libitum): Altrumin 2123 rabbit diet, ad libidum
- Water (e.g. ad libitum): deionized and chlorinated water, ad libidum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml on a 2.5 x 2.5 cm patch
Duration of treatment / exposure:
60 minutes
Observation period:
0.5-1, 24, 48, 72 hrs after removal of the patch and at day 7 and 14
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2,5 x 2,5 cm
- Type of wrap if used: special wound healing patches, Fa. Baiersdorf AG, Hamburg, covered and fixed with a semiocclusive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): removal of test substance without washing as far as possible
- Time after start of exposure: 60 minutes

SCORING SYSTEM: according to Draize
Remarks on result:
other: scoring was impeded due severe rigidification, bulging and discoloration of the exposed area

One hour after removal of the patch, the treated skin of the test animals was green-brown discolored. In the course of observation period the treated skin surface hardened. It became dry and brittle, bulged and changed color via dark red to yellowish brown. After 14 days, severe skin effects were still present. One animal showed peeling of large skin areas, combined with a deep skin lesion and beginning scaring. The skin of one animal was sclerotic and bulged, and the skin of the third animal peeled in large scales.

 

 

Scoring for erythema and edema (maximum score = 4)

 

 

Erythema

Edema

 

1 h

24 h

48 h

72 h

7 d

14 d

1 h

24 h

48 h

72 h

7 d

14 d

Rabbit 1

*

*

*

*

*

*

3

1

0

0

*

*

Rabbit 2

2

2

2

2

*

0

2

2

2

1

*

0

Rabbit 3

*

*

*

*

*

*

2

2

1

1

*

*

 

* scoring not possible due to severe hardening, bulging and discoloration

Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Remarks:
Migrated information R 34 Criteria used for interpretation of results: EU
Conclusions:
Classification: corrosive (causes burns)
Executive summary:

In a primary dermal irritation study according to OECD TG 404, 3 New Zealand White rabbits were exposed dermally to single doses of 0.5 ml of undiluted valeric acid for a one-hour period. Animals then were observed for 14 days. Skin reactions were scored according to OECD TG 404 (method of Draize).

In this study, valeric acid was corrosive to the rabbit's skin after a one-hour contact period, as evidenced by severe skin lesions and scar formation which persisted until the end of the 14-days observation period (Hoechst AG, 1983).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given; comparable to guideline study (deviations: dose only 50 µL, observation period 8 d)
Principles of method if other than guideline:
Acute eye irritation test; specific internal BASF standard method
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 2.74 kg; male: 3.06 kg
Vehicle:
unchanged (no vehicle)
Controls:
other: The adjacent eye served as saline control
Amount / concentration applied:
TEST MATERIAL
- Amount applied : 0.05 ml
Duration of treatment / exposure:
8 days
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
2
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24-48 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Time point:
other: 8 d
Score:
2
Max. score:
2
Reversibility:
not reversible
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 - 48 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 - 48 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Irritant / corrosive response data:
irrevesible damage; irritis evolved over time from 24 h (score 0) to day 8 (score 2). Similarly, chemosis developed from score 2 at 24 h to score 3 at 8 d.

Descriptive scores of the raw data have been converted to Draize numerical scores.

Animal

Reading

Opacity

Iritis

Redness

Chemosis

Comment

1

24 h

3

0

0

2

2

24 h

3

0

0

2

 pus

1

48 h

3

0

1

2

2

48 h

3

0

0

2

pus

1

8 d

3

2

not reported

3

2

8 d

2

2

not reported

3

mean

24 - 48 h

3

0

0.3

2

 

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an acute eye irritation test using an internal BASF method, isobutyric acid caused irreversible damage to the rabbit's eye after application of 50 µL test substance. This is only half of the volume required by test guidelines (OECD, EU). Under test conditions completely conform to guideline requirements, the effects observed will be even more pronounced.
Executive summary:

In a primary eye irritation test, 50 µL of isobutyric acid (purity 99%) was instilled into the conjunctival sac of one eye each of two male Vienna White rabbits. Animals then were observed for 8 days. The original irritation readings were converted to the Draize score at a later date. Readings were taken 24 h, 48 h and 8 d after application of test substance.

 

The treated eyes showed severe opacity and chemosis, which persisted until the end of the observation period (8 d). Iritis developed over time with highest scores (2) at day 8.

 

In this study, isobutyric acid was tested to be corrosive to the eye (irreversible effects on the eye - Category 1) based on the irreversibility of the effects observed.

 

This pre-guideline study bears some deviations from actual test guidelines (amount of test substance, observation period, time of irritation score readings). Nevertheless, the data are assessed to be sufficiently valid to represent the eye damaging potential of isobutyric acid as the correct amount of test substance would result in even more pronounced effects. Using available results conforms to the tiered testing and evaluation strategy for eye irritation/corrosion and further testing can be avoided.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion

 

For isobutyric acid, no valid studies concerning skin irritation / corrosion could be identified. There are only publications of low reliability (RL3 or 4).

 

To assess the skin irritation / corrosion potential of isobutyric acid, data for valeric acid as supporting substance will be used based on following reasons.

 

Valeric acid is closely related to isobutyric acid. Both substances are short chain carboxylic acids differing in the length of their carbon chain by only one carbon atom (C5 and C4). Physical and chemical properties will be quite similar. The reactive group of both substances is the carboxylic acid function, which plays the key role in causing irritating / corrosive effects. Short chain carboxylic acids up to C6 are known to be corrosive. For longer chain carboxylic acids, the irritating potential will decrease. C4 and C5 carboxylic acids will cause similar irritating / corrosive effects. Thus, it is justified to use valeric acid as supporting substance in the evaluation of irritation / corrosion potential of isobutyric acid.

 

Supporting substance valeric acid

 

The irritation / corrosion potential of valeric acid was studied in a valid primary skin irritation test (Hoechst AG, 1983)

 

Hoechst AG, Rupprich 1983

 

In a primary dermal irritation study according to OECD TG 404, 3 New Zealand White rabbits were exposed dermally to single doses of 0.5 ml of undiluted valeric acid for a one-hour period. Animals then were observed for 14 days. Skin reactions were scored according to OECD TG 404 (method of Draize).

 

In this study, valeric acid was corrosive to the rabbit's skin after a one-hour contact period, as evidenced by severe skin lesions and scar formation, which persisted until the end of the 14-days observation period (Hoechst AG, 1983).

 

Corrosion / irritation potential of isobutyric acid

 

Based on the result for valeric acid, isobutyric acid is assessed also to be corrosive.

 

Eye irritation

 

For the assessment of the eye irritating potential of isobutyric acid, one valid study is available (BASF AG, 1974). In the study of Smyth (1962), the method and the scoring system used are greatly different from actual guideline requirements. Thus, results are not suited to assess the irritation / corrosion potential or the tested substances.

 

The BASF study (pre-guideline study) bears some deviations from actual test guidelines (amount of test substance, observation period, time of irritation score readings). Nevertheless, the data are assessed to be sufficiently valid to represent the eye damaging potential of isobutyric acid, as the correct amount of test substance would result in even more pronounced effects. Using available results conforms to the tiered testing and evaluation strategy for eye irritation / corrosion and further testing can be avoided.

 

BASF AG 1974

 

In a primary eye irritation test, 50 µL of isobutyric acid (purity 99%) was instilled into the conjunctival sac of one eye each of two male Vienna White rabbits. Animals then were observed for 8 days. The original irritation readings were converted to the Draize score at a later date. Readings were taken 24 h, 48 h and 8 d after application of test substance.

 

The treated eyes showed severe opacity and chemosis, which persisted until the end of the observation period (8 d). Iritis developed over time with highest scores (2) at day 8.

 

In this study, isobutyric acid was tested to be corrosive to the rabbit's eye based on the irreversibility of the effects observed.


Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification