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EC number: 256-032-2
CAS number: 42978-66-5
No reliable carcinogenicity study available.
publication by Nylander-French showing concerns for the test substance
regarding carcinogenicity was marked as “disregarded” in IUCLID, because
the test system is unsuitable for this class of substances, aside from
several shortcomings in the publication.
Because of its high background incidence of
skin tumours, high false positive rate, sensitivity to dermal irritation
and other limitations, the Tg.AC
(v-Ha-ras) transgenic model is no longer
used for assessing carcinogenicity. In addition acetone was used as
inappropriately vehicle inducing drying, irritation, inflammation and
hyperplasia of the skin.
of Tg.AC (v-Ha-ras) mice contains several copies of the v-Ha-ras
oncogene, which are transcriptionally silent until activated by
abrasion/wounding, UV light or chemical exposure. Consequently, irritant
substances such as TPGDA, which damage the skin after repeated
application, will always produce a positive result in this model
regardless, whether they are carcinogenic or not (Tennant et al., 2001;
Cannon et al., 1997).
In the study
by Nylander-French, the two substances, namely the test substance and an
analogue were topically applied without occlusion. The analogue has a
vapour pressure of 40hPa compared to 0.000044hPa for the test substance.
For one, this means that exposure to the amounts stated in the paper for
the analogue have not occurred because the analogue evaporates quickly.
More importantly, other than the test substance, the undiluted analogue
does not cause skin irritation in mice when applied non-occlusive (Rohm
& Haas, 1986). No detailed information on skin irritation is available
in the publication. Data are only provided for skin thickness and only
for an acute range finder study, but not for the main study. In the
range finder 3 or 4 mice were treated seven times within 15 days with
several concentrations of both test substances. Treatment with 1.7%
(12μmol) of the test substance more than doubled the epidermal
thickness. Considering the longer treatment time of 20 weeks in the main
study, 10μmol (1.5%) of the test substance likely caused significant
skin irritation. A smaller increase in skin thickness was already
observed at 5 μmol, but in the absence of single animal data and
standard deviations, the relevance of this finding is hard to assess.
For comparison, only three treatments of a 3% solution to the ears of
CBA mice increased the ear weight by 21% in an LLNA assay (2004),
supporting the observation of skin irritation at low concentrations.
further hints from the study that support irritation as the cause of
skin irritation rather than a carcinogenic potential. There was no
apparent dose response relationship. Instead, there was a sharp
threshold between 1 and 5 μmol, corresponding to the threshold of
irritation, above which an equal amount of papillomas was induced after
a comparable latency time.
conclusion, this study falsely uses a transgenic model unsuitable for
irritant substances at irritant concentrations of TPGDA. The lacking
dose response relationship and sharp threshold, which corresponds to the
threshold of irritation, also supports irritation as the cause for the
induction of papillomas. The comparison of the test substance to a
highly volatile, non-irritant substance under non-occlusive conditions
is not valid in this context. The study should be disregarded for the
assessment of the test substance.
study performed with the test substance was available (1985). The
purpose of this investigation was to determine the carcinogenic
potential of the test substance. In addition, the study provided
information about the chronic dermal toxicity of the test substance.
Fifty male mice were treated with the test substance (25 mg, 10%
solution in mineral oil) dermally twice a week for 80 weeks. The skin
was examined histologically for non-neoplastic and neoplastic lesions.
Histological examination of other organs was performed in 40% of the
animals. Under the conditions chosen, no skin tumors were observed.
However, the study was disregarded for assessment, because the methodology
used is outdated. According to the study design, animals were treated
only twice a week and only one dose level was tested.
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