Isobutyraldehyde

Endpoint summary

Description of key information

The test substance does not cause skin irritation.
The test substance is irritating to the eyes.

The substance did not cause respiratory irritation in humans (see IUCLID section 7.10.5)

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Remarks:

Pharma Forschung Toxikologie und Pathologie, Hoechst Aktiengesellschaft, 6230 Frankfurt 80

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund
- Age at study initiation: 3 – 5 months
- Weight at study initiation: 1.9 – 2.4 kg
- Housing: 1 animal per cage
- Diet: ad libitum Altromin 2123 (standard diet for rabbits), Altromin-GmbH, Lage/Lippe
- Water: demineralized water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 50 ± 20
- Air: air-conditioned
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

4 h

Observation period:

The assessments were done 30 - 60 minutes as well as 24, 48 and 72 hours after removal of the patch. Since skin findings were observed after 72 hours, a secondary assessment was done after 7 days.

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: band-aid

REMOVAL OF TEST SUBSTANCE
- Washing: lukewarm water
- Time after start of exposure: 4 hours

SCORING SYSTEM: The erythema and eschar formation as well as the edema formation were evaluated numerically.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 24 - 72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

erythema score

Basis:

animal: #2, #3

Time point:

other: 24 - 72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal: #1, #3

Time point:

other: 24 - 72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 24 - 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritant / corrosive response data:

One hour after removal of the patch no skin irritation was noticed. 24 - 72 hours after removal of the patch the skin showed marginal discernible up to clearly transcribed erythema, one animal showed a very slight edema. After 7 days these findings were reversible. 48 hours - 7 days the skin of 2 animals was scarious and rough.

Interpretation of results:

not irritating

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Remarks:

Pharma Forschung Toxikologie und Pathologie, Hoechst Aktiengesellschaft, 6230 Frankfurt 80

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund
- Age at study initiation: 3 – 5 months
- Weight at study initiation: 2.3 – 2.8 kg
- Housing: 1 animal per cage
- Diet: ad libitum Altromin 2123 (standard diet for rabbits), Altromin-FmbH, Lage/Lippe
- Water: demineralized water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 50 ± 20
- Air: air-conditioned
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated right eye of the same animal

Amount / concentration applied:

0.1 mL in the conjunctival sac of the left eye

Duration of treatment / exposure:

24 h

Observation period (in vivo):

The assessments of the eyes were done 1, 24, 48 and 72 hours after application of the test substance. Additional to the assessment dates 24 and 72 hours as well as after 7 days the cornea were investigated for damages under UV light (after instillation of a drop of fluorescein/sodium solution). Since findings were observed after 72 hours, a secondary assessment was done after 7 days.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: The test substance was washed off with physiological saline solution after 24 hours.

TOOL USED TO ASSESS SCORE: fluorescein
Assessment of eyes were done 1, 24, 58 and 72 hours after application of the test substance.

Irritation parameter:

cornea opacity score

Basis:

animal: #1, #2

Time point:

other: 24 - 72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

other: 24 - 72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 24 - 72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 48 h

Irritation parameter:

iris score

Basis:

animal #2

Time point:

other: 24 - 72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

other: 24 - 72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal: #1, #2

Time point:

other: 24 - 72 h

Score:

2.3

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

other: 24 - 72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 24 - 72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

other: 24 - 72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

other: 24 - 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritant / corrosive response data:

1 - 72 hours after application the conjunctiva showed clearly injected vasodilation up to diffuse strong reddening and slight swelling up to swelling with half-closed eyelid. The iris of 2 animals was occasionally reddened. These 2 animals also showed diffuse cornea opacity with easy discernible translucent areals. In addition, a clear colorless resp. white and mucous discharge was seen. All irritation effects were reversible within 7 days.

Interpretation of results:

irritating

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation

In a GLP compliant skin irritation study performed according to OECD guideline 404, three New Zealand White rabbits were exposed to the test substance (Hoechst AG, 1988). 0.5 mL of the test substance was added to the back of these rabbits under semiocclusive conditions. After an exposure period of 4 hours, the substance was removed, the application site was washed, and effects were scored according to the the OECD Guideline. The mean scores at the observation times after 24 - 72 hours were 0.7, 1.7, and 1.7 (erythema) for animal 1, 2, and 3, respectively, and 0, 0.3, and 0 (edema) for animal 1, 2, and 3, respectively. All effects were reversible within 7 days.

 

In a skin irritation study (BASF 1974) performed according to BASF-internal standards, two Vienna White rabbits were treated with the undiluted test substance for 20 hours under occlusive conditions. After the exposure period the patch was removed. Necrosis was observed in one rabbit directly at the end of the exposure and in the second rabbit on day 8.

 

Smyth et al. (1954) published information stating that the grade of skin irritation was 1 out of 10. This indicated least visible capillary injection from treatment in rabbits exposed to 0.01 mL of the undiluted substance for a period of 24 hours.

 

Effects on the skin were only observed under occlusive conditions and after an exposure time of 20h (BASF 1974). This experimental setting exceeds by far the requirements of the current OECD guideline 404, which recommends the use of semi-occlusive coverage and 4 h-treatments. The results of the BASF study consequently are overpredictive of the substance's properties. In the study performed by Hoechst, which was performed according to the OECD guideline and GLP, no skin irritating effects were observed. This result is supported by Smyth et al., who did not observe skin irritation after 24h of non-occlusive exposure. Based on this information the test substance is not considered to be irritating to the skin.

 

Eye irritation

In a GLP compliant eye irritation study performed according to OECD guideline 405, undiluted substance was applied to the eye of 3 New Zealand White rabbits (Hoechst AG 1988). The test substance was washed off with physiological saline solution after 24 hours and induced mean scores of 1.7; 1.7; 0 for cornea opacity, 2.3; 2.3; 1.3 for conjunctiva redness, 0.3; 1.0; 0 for iritis, and 1.7; 2.0; 0.3 for chemosis, respectively during the relevant reading period (24, 48 and 72 h). All effects were reversible within 7 days.

 

Smyth et al. (1954) published information stating that the grade of eye irritation was 5 out of 10 for isobutyraldehyde. This value is based on a single observation of only corneal injuries after 24h of an unknown number of rabbits. The authors compared the severity to that of acetone, which is an eye irritant.

Lebrun et al. (2021) summarised results from several in vitro eye irritation tests,  to differentiate between GHS cat. 2 and a non-classification for eye irritation. However, due to the complexity of the analysis and space constraints, GHS category 1 was not analysed further in this review. Isobutyraldehyde was a true positive, and hence irritating compound, in the Bovine Corneal Opacity and Permeability (Laser Light-Based Opacitometer and OP-Kit), EpiOcular™, OptiSafe and Short Time Exposure test.

Additionally, Kandarova et al. (2018), predicted isobutyraldehyde for GHS Cat. 2 in a combinded EpiOcular time-to-toxicity test method.

The overall assessment is based on the most reliable GLP study according to OECD guideline 405 (Hoechst AG 1988). All other available data support the conclusion that isobutyraldehyde causes eye irritation.

 

Respiratory irritation

The OECD SIDS reports a study in 15 human volunteers who were exposed to 210ppm (620mg/m³) isobutyraldehyde for 30 minutes. No irritation was observed, but the substance caused nausea in some subjects. In animal studies, local effects in the nose occured at very high concentrations only. These concentrations would be unbearable for humans due to the strong smell of the substance.

As a conclusion, respiratory irritation is not considered a relevant hazard at concentrations that can be endured by humans without causing nausea or vomiting.

Justification for classification or non-classification

Based on the available information classification for skin irritation is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.

 

Based on the available information isobutyraldehyde needs to classified as Eye Irrit 2, H319: Causes serious eye irritation in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.

Based on the limited information available in humans, isobutyraldehyde does not need to be classified for respiratory irritation.