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Toxicological information

Carcinogenicity

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Description of key information

No reliable carcinogenicity study available.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The 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.

The genome 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.

There are 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.

In 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.

Another 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.

Justification for classification or non-classification