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:

In animal studies, citral induced sensitisation both in the guinea pig maximization test and in the mouse local lymph node assay (LLNA).

Citral (synthetic or natural product) was tested for its sensitising activity in the guinea pig maximization test with a protocol comparable to OECD Guideline 406 (Key study: BASF, 1978a, 1978b). Concentrations for intradermal and percutaneous induction were 25% citral in paraffin oil, and 10% for the percutaneous challenge (N=10 test animals). As the control group without induction treatment showed slight signs of irritation after the challenge with 10% citral (N=5 test animals), two rechallenges were performed with 5% concentration (N=5 test and control animals each). Citral induced clear signs of sensitisation in all test animals. Furthermore, the sensitizing activity of citral was investigated in the LLNA according to OECD Guideline 429 at test concentrations ranging from 2.5% to 50% (Key study: Lalko and Api, 2006). Citral was found to be a sensitizer based on an EC3 value of 6.3% or 1575 µg/cm2 (vehicle ethanol:diethylphthalate 1:3). These positive test results are supported by further reliable positive data from a guinea pig maximization test (Basketter and Allenby, 1991) and further LLNAs (Basketter 1991; Lalko 2008). In an evaluation of local lymph node assay data in a review by Lalko and Api,EC3 values ranged between 1.2% to 13% based on the chosen vehicle, and a weighted mean is set at 5.7% (1414 µg/cm2).

 

In addition to animal studies, several studies with human were available for assessment. In a human repeat insult patch test (HRIPT) 101 subjects (30 male and 71 female) received nine occlusive dermal applications of 1.2% citral in 1:3 EtOH:DEP with 0.2% tocopherol for induction (determined by the RIFM expert panel to be 1400 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 (RIFM 2004). Approximately 2 weeks after the last induction application, a 24 h challenge application with 1.2% citral in 1:3 EtOH:DEP with 0.2% tocopherol was made to a naive site. In this HRIPT citral did not induce dermal sensitization in human subjects under the chosen testing conditions.

In a human repeat insult patch test (HRIPT) with 105 women a solution of 8% citral in petrolatum caused skin reactions after application of the second and the third patch in 5 and 16 individuals, respectively. After diluting the concentration of the test substance to 4% no skin reactions were observed during the remainder of the induction and the challenge phase.

A broad variety of diagnostic patch tests with patients from dermatological clinics are avaliable confirming the sensitising potential observed in experimental animals (Lalko 2008, Schnuch 2007, An et al. 2005). A threshold for dermal sensitization induction by citral was derived by Lalko et al. based on a complete literature search in on-line databases and the toxicologic database of the Research Institute for Fragrance materials (Lalko 2008). Data from 5 repeated insult patch test (HRIPT) and 14 human maximization test (HMT) were considered for this quantitative assessment. An overall dose dependent decrease in the incidences of positive responses has been observed in the HMTs assessed. On the basis of the available HRIPT data, an overall NOEL of 1400 µg/cm2 has been defined for citral.

 

In total, the weighed mean EC3 value of 1414 µg/cm2 in the animal assay, and the NOEL of 1400 µg/cm2 for sensitisation of humans are of comparable magnitude.


Migrated from Short description of key information:
Guinea pig maximisation test: positive test result (BASF 1978a, 1978b)
LLNA: positive test result (Lalko and Api 2006, 2008); EC3 weighted mean 5.7% corresponding to 1414 µg/cm2 (Lalko and Api, 2008)

Respiratory sensitisation

Endpoint conclusion
Additional information:
Migrated from Short description of key information:
No data available

Justification for classification or non-classification

The present data on dermal sensitization fulfill the criteria laid down in 67/548/EEC and CLP, and a classification R43 May cause sensitization by skin contact” or “Skin sensitisation” Category 1 is warranted.