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EC number: 226-394-6
CAS number: 5392-40-5
citral induced sensitisation both in the guinea pig maximization test
and in the mouse local lymph node assay (LLNA).
(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
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
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
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.
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.
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”
sensitisation” Category 1 is warranted.
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