Isovaleraldehyde

Endpoint summary

Description of key information

Valid data could be identified for assessment of the skin and eye irritating potential of isovaleraldehyde.
In a primary dermal irritation study, isovaleraldehyde proved to be slightly irritating to the skin (ECETOX, 1995). But classification is not required according to EU regulations.
In a primary eye irritation study, isovaleraldehyde was demonstrated to be irritating to the eye (BASF AG, 1974).
In a sensory irritation experiment, a RD50 of 757 ppm was determined during inhalation exposure of mice to isovaleraldehyde (Steinhagen, 1984) indicating the potential of respiratory irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

For the assessment of the skin and eye irritation potential of isovaleraldehyde (3-methylbutanal. 3-methylbutyraldehyde), one valid study is available in each case (skin irritation: ECETOC 1995, eye irritation: BASF 1974). The other data identified originate from studies with serious methodological deficiencies which make their results not valid (RL3).

 

Skin irritation

 

ECETOC (1995) is a database reporting skin irritation results from investigations, which previously have been evaluated and assessed as reliable. If necessary, primary data have been procured from the authors. Only data from studies have been included, which were conducted according to OECD test guideline 404 (1981, 1992) and following GLP principles. Thus, the reliability of this data is high.

 

The study of BASF (1974) includes serious methodological deficiencies (exposure period 1 min, 5 min, 15 min, 20 h, but not 4 h, occlusive wrapping, amount of test substance not reported). The effects reported are notedly more pronounced than the effects observed in the ECETOC study but this is related to the divergent experimental conditions.

 

For assessment of the skin irritating potential of isovaleraldehyde, the study of ECETOC is selected as key study and given preference over the study of BASF, as the study was performed under GLP and test conditions comply with guideline requirement. Data of this study are assessed as reliable fulfilling the guideline requirements for a skin irritation/corrosion study while the BASF study did not follow a guideline protocol.

 

ECETOC 1995

 

In a primary dermal irritation study according to OECD test guideline 404 and conducted under GLP conditions, four albino rabbits were dermally exposed to 0.5 mL of isovaleraldehyde (purity 98.5 %) for 4 hours. Animals were then observed for 7 days but not for 14 days. Irritation was scored by the method of Draize/OECD test guideline 404.

 

Skin reactions could be observed in all animals starting 1 h after removal of the patch with a maximum erythema and edema score of 2 and 2.5 respectively (day 1). Scores had subsided at day 7 but irritation effects had not completely disappeared. Considering the day 7 scores, it is estimated that irritation effects are reversible within 15 days.

 

Isovaleraldehyde is slightly irritating to the skin (ECETOC, 1995). But it does not require classification according to EU regulations based on irritation scores and reversibility of irritating effects.

 

Eye irritation

 

In a primary eye irritation/corrosion test, 2 rabbits were exposed to 0.05 mL of isovaleraldehyde each. Irritation reactions of cornea and conjunctivae were recorded starting at 24 hour after application. Effects persisted up to a maximum of 8 days. At the end of the observation period (8 days) all irritation effects had subsided.

 

For rabbit 1, the mean (24, 48, 72 h) cornea and conjunctivae scores were 1 and 1.78 respectively. For rabbit 2, the mean cornea and conjunctivae scores were 0.33 and 2 thus reaching the EU criteria for classification (CLP regulation 1272/2008; Irritating to eyes - Category 2) (BASF 1974).

 

For recent primary eye irritation tests in vivo, test guidelines require the application of 0.1 mL test substance. Considering the data available and the time course of the eye irritating effects, it is estimated that with the higher dose, scores will be elevated but still remain below the criteria for irreversible effects and the reversibility of effects within 21 days will be maintained. Based on the data available, isovaleraldehyde will be classified as irritating to eyes (Category 2).

 

This study bears some deviations from actual test guidelines. Nevertheless, the data are assessed to be sufficiently valid to evaluate the eye irritation potential of isovaleraldehyde. Using available results conforms to the tiered testing and evaluation strategy for eye irritation/corrosion and further testing can be avoided.

 

Respiratory irritation

 

In a sensory irritation experiment conducted following accepted scientific principles, B6C3F1 mice and Swiss-Webster mice were exposed head only in groups of 4 to graduate concentrations of isovaleraldehyde vapor. Respiratory rates were recorded by means of a body plethysmograph. The average maximum decrease in respiratory rate for 1 min was computed from the response of each group of animals. The RD50 value was calculated from the resulting concentration-response curve.

 

RD50 values of 757 ppm and 1008 ppm were determined for B6C3F1 and Swiss-Webster mice respectively demonstrating that isovaleraldehyde is respiratory irritating (Steinhagen 1984). (The endpoint study record for this study is located in IUCLID Section 7.9.3 - Specific investigations: other studies).

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation

 

Based on available data, isovaleraldehyde (3-Methylbutanal) does cause slight and reversible skin irritation. But classification according to EU regulations (Directive 67/548/EEC and Regulation (EC) No 1272/2008) is not required. Classification criteria (mean erythema and edema scores) are not exceeded and effects will be reversible within 14 days.

 

Eye irritation

 

The eye irritation study of BASF includes some deviations from test guidelines (amount of test substance only 0.05 mL, only 2 animals tested, observation period only 8days).

 

The mean scores (gradings at 24, 48, and 72 h) taken were moderate (0.3 - 2). The effects observed were totally reversible within 8 days. This data would indicate classification as irritating to eyes (Category 2) according to Regulation (EC) No 1272/2008 but no classification according to Directive 67/548/EEC.

 

Actual test guidelines require the application of 0.1 mL test substance in an in vivo eye irritation test. Considering the data available and the time course of the irritating effects observed, it is estimated that with the higher dose, scores will be elevated but the effects would still be reversible within the observation period (14 days or 21 days).

 

In order to avoid further testing and additional use of test animals, classification will be based on the test results available under application of the above considerations.

 

Isovaleraldehyde will be classified as irritating to the eye based on both, Directive 67/548/EEC (R 36: Irritating to eyes) and Regulation (EC) No 1272/2008 (irritating to eyes - Category 2).