Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

The sensitization to skin was analyzed in a local lymph node assay (LLNA) performed according to OECD guideline 429 and EPA OPPTS 870.2600 (Betts, 2005). In this study, groups of four female CBA strain mice received three times applications of 25 µl of citronellol at concentrations of 50, 25, 10, 5 and 2.5% in 1:3 ethanol:diethyl phthalate to the dorsum of the ears. After the third application, the mice received injection3H-methyl-thymidine 3H (Tdr). Following the preparation of the lymph node suspension, the lymphocyte proliferation (EC3) was counted and an EC3 value of 43.5% w/v or 10875 µg/cm² could be calculated. Thus, citronellol was consequently classified as a likely sensitizer based on the classification scheme of Basketter (2000) and Gerberick (2001), although the substance showed irritation effects at this concentration.

In contrast to the guideline study, three further separate animal tests have been reported which all turned out to be negative.

In a Buehler delayed contact hypersensitivity test ten male and female Hartley albino guinea pigs received  applications of 0.3 ml of the test material at 25% in DEP under occlusion to clipped shoulders using 25 mm Hilltop Chamber (Buehler, 1992). The procedure was repeated once a week for three weeks, for approximately six hours each. After a two week rest period, the animals received challenge applications in the same manner as the induction application, but to the previously untreated sites with 2.5, 7.5 or 25% test material in DEP. When the sites were evaluated 24 and 48 hours later, no sensitizing effects were noted.

This result was also obtained in another Buehler-test, where ten guinea pigs were used for testing citronellol at a concentration of 10% (BBA, 1973).

In another study, an Open epicutanous test (OET) with six guinea pigs was conducted (Klecak, 1985). For induction, the animals received 21 applications in 21 days or 20 applications in 28 days of 0.1 ml pure citronellol to the clipped flank. No sensitizing effects were observed when the skin sites were evaluated 24 and 48 hours after the challenge application of 6% citronellol. The same negative result was also found in an earlier study by the same author, where also 6 guinea pigs were tested with a citronellol at a concentration of 6% (Klecak, 1979).

No sensitizing effects were also found in a guinea pig maximization test, where concentrations of 10% citronellol were used for induction and challenge (Ishihara, 1986).

A study with rats using induction by the inhalation route (0.3 and 2.8 mg/m³ for 21 days) and dermal challange (open epicutaneous) showed sensitising properties of citronellol (Kostrodymov, 1981).

 

In addition to animal studies, several studies with human were available for assessment.

As part of a European study where 26 fragrances were tested in a total of 21 325 patients, citronellol was found to be clearly allergenic but less important in terms of sensitization frequency (Schnuch, 2007). In 0.4% of 2003 tested patients, a positive reaction was found when tested at a 1% concentration for 24 or 48 h.

In a human repeat insult patch test (HRIPT) 101 subjects (29 male and 72 female) received nine occlusive dermal applications of 25% dl-citronellol in 3:1 DEP:EtOH for induction (determined by the RIFM expert panel to be 29525 µg/cm2). The test substance was applied in 25 mm Hilltop Chambers to the back of each volunteer for 24 hours per application in three successive weeks (Harrison 2005). Approximately 2 weeks after the last induction application, a 24 h challenge application with 25% citronellol in 3:1 DEP:EtOH was made to a naive site. In this HRIPT citronellol did not induce dermal sensitization in human subjects under the chosen testing conditions.

In support, no reaction was found in a Human Maximization Test, carried out on 25 volunteers at a concentration of 6% for induction and challenge (Greif, 1967).

In addition, there is a broad variety of further patch tests in literature, in which citronellol has been applied to patients skin, showing that citronellol had caused allergic dermatitis from which these patients were suffering.

Overall, the available results of studies with animals and human do provide sufficient evidence that citronellol is a skin sensitizer.

Justification for classification or non-classification

The present data on dermal sensitization fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a classification with R43 and "Skin sensitisation" (Category 1) is warranted.