Isovaleraldehyde

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

No skin sensitisation tests could be identified for isovaleraldehyde (3-methylbutyraldehyde).

 

For several other short chain aldehydes comparable in size, skin sensitisation tests were conducted. These results will be used for the assessment of the skin sensitising potential of isovaleraldehyde in a read across approach. General conditions and results of these tests are listed in the table below.

  

Sensitisation tests with aldehydes (ordered by aldehyde size)

 

Study	Substance	Reliability	GLP	Test type	Guideline	Results	Interpretation
BASF AG 2004	Propionaldehyde	2	yes	LLNA	OECD 429	Test conc.: 1%, 3%, 10% SI (10%) = 1.16 Part of the ear (administr. site) was cut out to assess irritation, slight irritation was noticed	negative; not sensitising Note: low test concentration due to irritating properties
RCC / Celanese 1999	Propionaldehyde	1	yes	GPMT (Magn/Kligm)	OECD 406	Epidermal induction: 30% Challenge conc.: 30% 24h: 8/10;    48h: 8/10 Rechallenge conc.: 30% 24h: 0/10;    48h: 4/10	positive; strong sensitising
Bio/dynamics / Celanese 1981	Propionaldehyde	2	no	GPMT (Bühler)	OECD 406	Epidermal induction: 50% Challenge conc.: 25% 24h: 0/20;    48h: 0/20 Rechallenge conc.: 40% 24h: 1/19;    48h: 1/19	equivocal response
Celanese 1981	Butyraldehyde	2 (slight deviations from guideline)	no	GPMT (Bühler)	OECD 406	Epidermal induction: 50% Challenge conc.: 10% 24h: 0/20;    48h: 0/20 Rechallenge conc.: 25% 24h: 2/20;    48h: 1/20	negative (only low sensitising potential)
NTP 1990	Isobutyraldehyde (2-Methylpropionaldehyde)	2 (?) (no valid test protocol accord. to EU regulations)	no data	MEST	-	Induction conc.: 3 to 30% Challenge conc.: 30% (direct dermal application (25µL) for 5 consecutive days	negative; not sensitising
Dow 2008	2-Methybutyraldehyde	2 (slight deviations from guideline)	yes	LLNA	OECD 429	Test conc.: 10%, 25%, 100% SI (100%) = 4.4;    EC3 = 70%	positive; weakly sensitising Note: no consecutive test concentration
Hüls AG 1997	3,5,5-trimethylhexanal (isononanal)	1	yes	GPMT (Magn/Kligm)	OECD 406	Epidermal induction: 100% Challenge conc.: 30% 48h: 10/10;    72h: 6/10	positive; strong sensitising

 

Fabjan and Hulzebos addressed the skin sensitising properties of aldehydes, problems encountered with the different test systems, and classification under REACH. Several SAR of aldehydes for skin sensitisation were evaluated, and applicability of SARs and structural alerts for skin sensitisation in the REACH framework was elucidated. Results from standard sensitisation tests, i.e. the Local Lymph Node Assay (LLNA; method OECD 429), Guinea pig maximization test (OECD 406), and the Buehler test (OECD 406) on a variety of structurally different aldehydes were taken into consideration.

The Schiff base training set contains aldehydes which all gave positive results, either in the LLNA or GPMT/Buehler test. For read across purposes some of the saturated short chain aldehydes are tabulated below.

 

	Name	CAS #		Sensitisation		Reference
			LLNA		GPMT/Bue
C1	Formaldehyde	50-00-0	+ (0.70%)		+	Gerberick (2004)
C3	Propionaldehyde	123-38-6	n.i.		+	Cronin & Basketter (1994)
C4	Butyraldehyde	123-72-8	n.i.		+	ECB (2000g)
C4	Glutaraldehyde	111-30-8	+ (0.1%)		n.i.	Gerberick (2004)
C6	Hexanal	66-25-1	+ (45%)		n.i.	Patlewicz (2004)
C8	2-ethylbutyraldehyde	97-96-1	+ (68.15%)		n.i.	Patlewicz (2002)
C12	2-methylundecanal	110-41-8	+ (6.8%)		n.i.	Patlewicz (2002)

 

+ = positive; n.i. = no information;Formaldehyde,Glutaraldehyde: classified sensitiser; EC 1272/2008

References relate to Fabjan & Hulzebos (2008) Toxicology in vitro 22:468-490

 

According to the authors, all substances in the training and external set were classified as sensitising. Differences in potency were observed, but the cause for this is generally difficult to determine. For aldehydes the log Kow descriptor did not improve the definition of the domain. It is assumed that substances which fit within the domain of proposed alerts (“Schiff base”) may be classified as sensitising according to EU C&L rules (EC, 2001).

Overall, the authors stated that, in general, a compound which is able to cause contact allergy must have electrophilic properties (or metabolism generates electrophilic metabolites). The most common electrophile-nucleophile reactions involved in skin sensitisation are Michael-type reactions, Schiff-base formation, and nucleophilic substitution reactions. Simple aliphatic aldehydes undergo Schiff base formation, and these require classification according to the EU classification system under REACH, though they generally are weak sensitisers which are often not detected in the LLNA but in Guinea pig tests (Fabjan and Hulzebos, 2008).

To conclude, a distinct skin sensitisation test for isovaleraldehyde is not available. Thus based on evidence obtained by cross reading from other related aliphatic aldehydes, isovaleraldehyde is assessed to be a weak skin sensitizer. This is supported by basic chemical properties of aldehydes forming Schiff bases with proteins which in turn can induce an immune response.

Migrated from Short description of key information:
Isovaleraldehyde is assumed to be skin sensitising.

Respiratory sensitisation

Endpoint conclusion

Additional information:

Migrated from Short description of key information:
No data located.

Justification for classification or non-classification

Cross reading to related C3 to C9 aldehydes indicate, that isovaleraldehyde is weakly skin sensitizing (see above Skin sensitisation - Discussion). Under Directive 67/548/ECC, isovaleraldehyde requires classification as skin sensitising with R 43 (May cause sensitisation by skin contact) and under Regulation (EC) No. 1272/2008 as skin sensitiser - Category 1.