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EC number: 905-562-9
CAS number: -
The multi-constituent substances covered by
this registration comprise individual xylene isomers (m-xylene,
o-xylene, p-xylene) and ethyl benzene (>10% - <20%). The following
information is available to characterise their sensitisation potential.
The sensitisation potential of mixed xylene (comprising
xylene isomers and ethyl benzene) when tested in the standard local
lymph node assay was reported by Basketter et al. (1996), who obtained a
stimulation index of 3.1 following topical treatment of mice with neat
(100%) substance. However while this finding is suggestive of
sensitisation (according to the strict interpretative criteria of the
Guideline), it appears to be a false positive given the absence of
structural alerts present, the very weak response obtained (recorded
only at the very highest concentration tested), and a lack of any
corroborative information from clinical experience, or from other human
studies (discussed Basketter and Kimber, 2010). A subsequent statistical
analysis of LLNA data for 134 chemicals (including mixed xylenes)
performed by Basketter et al. (1999) concluded that a SI “cut-off” value
of 3.5 would lead to greater specificity in the interpretation of LLNA
results, and also reduce the occurrence of occasional false positive
results such as the SI = 3.1 for undiluted mixed xylenes (Basketter and
Kimber, 2010). Overall it is concluded that this publication does not
provide convincing evidence that mixed xylene possesses a potential to
induce or elicit skin sensitisation.
The sensitisation potential of mixed xylene
was also assessed in a modified local lymph node assay where increased
ear-draining lymph node weight and cell counts were used to quantify
lymph node cell proliferation by 9 laboratories participating in a
ring-trial. [3H]TdR incorporation in vitro by lymph node cells was also
assessed in a single laboratory (assay not conducted by other
laboratories). Acute skin inflammation (a potential confounder that can
lead to "false positive" results) was also determined based on changes
in ear tissue weight. Treatment with mixed xylenes was associated with a
statistically significant increase in ear-draining lymph node weight and
cell count in 7 of the 9 laboratories, and an increase in ear tissue
weight in 3 of 9 laboratories. An increased (but not quantified)
increase in 3[H]TdR incorporation by lymph node cells was also reported
by one laboratory. Based on these findings, mixed xylene was considered
an allergen by a majority of laboratories participating in the trial.
However the methodology used was evaluated by an ECVAM Workshop
(reported by Basketter et al., 2008) which concluded the assay methods
deviated from the Guideline in terms of the strain of mouse, the choice
of vehicle, the time of lymph node/lymph node cell collection, and the
magnitude of the SI used to differentiate positive and negative samples.
Overall, the ECVAM Workshop concluded that these differences represented
a major change in methodology that required further validation. The use
of [3H]TdR incorporation by lymph node cells in vitro (as opposed to
incorporation of [3H]TdR following i.v. injection in vivo, as required
by the Guideline) was not discussed by the ECVAM Workshop but is another
change relative to the Guideline. When conducting a weight of evidence
evaluation of the sensitisation potential of mixed xylenes, Basketter
and Kimber (2010) also noted that these deviations meant that deviations
meant that the findings were of limited toxicological relevance. Overall
it is concluded that this publication does not provide convincing
evidence that mixed xylene possesses a potential to induce or elicit
There is no relevant non-human information
for the individual isomers or for ethyl benzene.
From widespread use, there have been no
reports of skin sensitising properties of mixed xylene as a result of
skin contact. In a human maximization test (Kligman, 1966), mixed xylene
was tested at 100% and subjects were challenged at 25%. No skin
sensitization resulted. This test is considered to be a highly sensitive
detector of skin sensitizing potential; the results for more than 80
chemicals were presented in the publication which demonstrates the very
considerable predictive sensitivity of this assay.
As cited in Opdyke (1975), Kligman (1974)
reported that ethyl benzene produced no sensitisation reactions in 25
volunteers subjected to a maximisation test with 10% ethyl benzene (no
data on purity) in petrolatum.
Mixed xylene gave a marginal (SI = 3.1)
response in a standard LLNA at the highest concentration tested (100%;
Basketter et al., 1996) however an absence of chemical structural
alerts, the very weak response obtained, and a lack of any corroborative
human information indicates that this is a false positive (Basketter and
Kimber, 2010). Results suggestive of a positive response obtained from a
non-standard LLNA are considered unreliable given the extent of the
methodological deviations present (Basketter et al., 2008; Basketter and
Kimber, 2010). Results from a human maximisation test on mixed xylene
(Kligman, 1966) using an induction concentration of 100% were negative.
Overall there is no convincing evidence that mixed xylene possesses a
potential to induce or elicit skin sensitisation. Xylene gave a very
slightly positive result in the LLNA when tested undiluted, but the
result fits well with the criteria for a false positive. It is an
unreactive chemical that would not be identified on the basis of
chemical structure as being a potential skin sensitizer. Added to which
is the clinical evidence demonstrating that xylene does not cause skin
sensitization in humans, even when tested in a very rigorous human
predictive assay. Thus, the overwhelming is that xylene (including mixed
xylene and the individual isomers) should not be classified as a skin
sensitizer. The RAR (2008) for ethyl benzene concluded that there are no
reports on skin sensitisation caused by the substance at the workplace
and that no sensitisation potential is expected.
Xylene is an unreactive chemical that would
not be identified on the basis of chemical structure as being a
potential skin sensitizer. In addition, there is no clinical evidence
demonstrating that xylene causes skin sensitization in humans, even when
tested in a very rigorous human predictive assay. Therefore, mixed
xylene does not warrant classification as a skin sensitizer under DSD or
CLP. In conclusion, mixed xylene streams do not warrant classification
as a respiratory sensitizer under DSD or CLP.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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