Isobutyric anhydride

Endpoint summary

Description of key information

Eye and skin data is available for isobutyric anhydride, but it is lacking in several areas.  Primarily, the studies were conducted in 1978, were not done to today's guidelines, and are lacking in detail.   Read-across to the acid hydrolysis products is available, but excess water is required for complete acid production, and such an environment was not present in these studies.  Also, there was no attempt made to quantitate hydrolysis.  Thus, data from the acid, while relevant, should be a worst case situation.

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: Basic data given: according to an acceptable internal BASF method

Qualifier:

no guideline followed

Principles of method if other than guideline:

Internal method (BASF test): Two animals were treated for 5 and 15 min, 2 and 20 hours using occlusive conditions. An application site of 2.5 x 2.5 cm was covered with the liquid test substance. In addition skin tissue from the ear was tested by wrapping the ear. These results from the ear, however, would not be taken into account for evaluation as they do not represent testing of the dorsal/lateral flank of the back. After the application time the skin was washed. The animals were observed 8 days and the skin changes were recorded on working days.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: mean: 2.82 kg

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Duration of treatment / exposure:

5 and 15, 2 and 20 hours

Observation period:

24 and 48 hours and 8 days

Number of animals:

2 male rabbits

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm of the back per treating time point

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 5 and 15 min, 2 and 20 hours, respectively

SCORING SYSTEM: Draize (data were re-evaluated according to the scoring system of Draize, as recommended by the actual guideline requirements)

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24 and 48 hours

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: after 2 hours of treatment

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24 and 48 hours

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: after 2 hours of treatment

		Exposure period: 5 min			Exposure period: 15 min			Exposure period: 2 h			Exposure period: 20 h
Readings	Animal	Erythema	Edema	Additional findings	Erythema	Edema	Additional findings	Erythema	Edema	Additional findings	Erythema	Edema	Additional findings
24 h	1	2	0	c	2	2	c	3	3	c	3	3
	2	2	0	c	2	2	c	3	3	c	3	3
48 h	1	1	0		1	0		3	3	c	3	3	c
	2	2	1	c	2	1	c	3	3	c	3	3
8 d	1	0	0	d	0	0	d	2	1	d	4	2	Np
	2	0	0	d	0	0	d	2	2	d	4	2	Np
Mean 24 - 48 h	1	1.5	0.0		1.5	1.0		3.0	3.0		3.0	3.0
	2	2.0	0.5		2.0	1.5		3.0	3.0		3.0	3.0
Mean		1.8	0.3		1.8	1.3		3.0	3.0		3.0	3.0

c: comprehensive; d: desquamation; N: necrosis; p: parchmenty

Interpretation of results:

irritating

Remarks:

Migrated information

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

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines/standards

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

only 2 animals tested; 50µl instead of 100µl instilled; no observation point after 72 hours, Maximum observation time was 8 days

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: mean: 3.08 kg

Vehicle:

unchanged (no vehicle)

Controls:

other: treatment of the control eye with physiol. saline

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µl
- Concentration (if solution): unchanged

Duration of treatment / exposure:

not washed out

Observation period (in vivo):

1, 24, 48 hours and after 8 days

Number of animals or in vitro replicates:

2 male rabbits

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize (re-evaluation according to the scoring system of Draize as recommended by the actual guideline requirements

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

all animals

Time point:

other: 24 and 48 hours

Score:

1.8

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

iris score

Basis:

mean

Remarks:

all animals

Time point:

other: 24 and 48 hours

Score:

0.5

Max. score:

2

Reversibility:

fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

all animals

Time point:

other: 24 and 48 hours

Score:

1.8

Max. score:

3

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

all animals

Time point:

other: 24 and 48 hours

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 8 days

Table 1: Individual results:

Readings	Animal	Cornea	Iris	conjunctiva			Symptoms
		opacity		redness	swelling	discharge
1 h	1	1	0	2	2	2
	2	1	0	2	2	2
24 h	1	1	0	1	2	1
	2	2	0	2	2	1
48 h	1	2	1	2	2	3
	2	2	1	2	2	3	Na
8d	1	1	0	1	0	1
	2	1	0	1	0	0	Na
mean 24 - 48 h	1	1.5	0.5	1.5	2.0	2.0
	2	2.0	0.5	2.0	2.0	2.0
mean		1.8	0.5	1.8	2.0	2.0

Na: Scar

Interpretation of results:

irritating

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

For both eye and skin studies, toxicity data has been used from isobutyric anhydride studies, and from read-across to the corresponding acid. The hydrolysis of the anhydride in water is rapid, and thus the read-across is valid. A hydrolysis study is presented in section 5.1.2 of this dossier, and illustrates that at physiological pH the half life is between 5 and 10 minutes. This indicates that read-across to isobutyric acid is appropriate for all studies where water is present, as the anhydride will quickly hydrolyze to the acid. The lead registrant believes that the study results tend to underestimate the potential toxicity of the anhydride. Since the studies are normally conducted under carefully controlled conditions, with highly pure test article, and with test subjects (rabbits) that don't sweat, the corrosive properties may be minimized. In the "real" world, high humidity, workers that are perspiring and test article that may have been exposed to moisture (thus generating acid) will produce a "worst case" for the anhydride that controlled testing may understate. Thus, a classification of "corrosive" is used to reflect a more realistic classification and promote worker safety.

 

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Justification for selection of skin irritation / corrosion endpoint:
Only one study for the anhydride is available. Isobutyric acid data is included as the anhydride will hydrolyze to the acid in aqueous conditions. Note that the acid generally produces more severe results than the anhydride due to incomplete hydrolysis in eye and skin studies ( as water is not freely available).

In the key study, the result was "irritating". We are calling this "corrosive" to account for the greater likelihood that under normal conditions of use, greater ambient amounts of water will be available, which would result in a greater extent of hydrolysis and a greater extent of irritation/corrosion.

Justification for selection of eye irritation endpoint:
Only one study for the anhydride is available. Isobutyric acid data is included as the anhydride will hydrolyze to the acid in aqueous conditions. Note that the acid generally produces more severe results than the anhydride due to incomplete hydrolysis in eye and skin studies ( as water is not freely available).

In the key study, the result was "irritating". We are calling this "corrosive" to account for the greater likelihood that under normal conditions of use, greater ambient amounts of water will be available, which would result in a greater extent of hydrolysis and a greater extent of irritation/corrosion.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification

Isobutyric anhydride is classified for skin and eye corrosion based on experimental results.

Isobutyric anhydride is classified as a CLP category 1, even though the experimental evidence suggests that category 2 may be more appropriate. The reason for this deviation is that in our experience, hazard warnings for many anhydrides are potentially understated. Most experiments are carried out using fresh test article under ideal conditions in the laboratory. However, in the real world, exposure of the anhydride to water and/or very humid atmospheres can result in significant amounts of acid being present in the anhydride. As the manufacturer has no control over the use and storage of the product, it seems prudent to assume that at some point in the life cycle of the anhydride that some acid may form after exposure to water, and as such, the higher skin and eye classification is warranted.