Registration Dossier

Toxicological information

Carcinogenicity

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Description of key information

There are two dermal carcinogenicity studies available for the read-across substance DEA in rats and mice. Based on their outcome there is no concern for carcinogenic potential of the test item.

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 adverse effect observed
Dose descriptor:
LOAEL
40 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
GLP and guideline study.

Additional information

No experimental data on carcinogenicity is available for the test item. However, experimental data for the read-across source substance 3 is available and a read-across approach is applied. Please refer to read-across justification document attached in IUCLID Section 13. Furthermore, only key studies of the source substance are taken into account. For further supporting information please refer to respective dossier of each source substance.

In rats, ethanolic DEA solutions were dermally applied to 50 male and 50 female F344 rats at dose levels of 0, 16, 32, 64 mg/kg bw/day in males or 0, 8, 16, 32 mg/kg bw/day in females for 5 days per week during a period of 103 weeks. The survival of dosed male and female rats was not affected. Mean body weights of the high dose males (64 mg/kg bw/day) were less than those of the vehicle controls during weeks 8 – 89, while the top dose females (32 mg/kg bw/day) revealed body weight reductions after week 97. DEA led to skin irritation (acanthosis, hyperkeratosis, exudation) predominantly at doses of 32 mg/kg bw/day and above at the site of application. In the kidney the incidences and severities of nephropathy in dosed female groups were significantly greater than those in the vehicle controls, DEA was not carcinogenic in this study and the NOAEL for local irritation was 16 mg/kg bw/day and 32 mg/kg bw/day for systemic toxicity in males. In females the LOAEL was 8 mg/kg bw/day for local irritation and systemic toxicity.

 

In the mouse oncogenicity study (B6C3F1), the test conditions were similar. Fifty animals per dose group and gender received topically ethanolic DEA solutions of 0, 40, 80 and 160 mg/kg bw/day, 5 times per week for 103 weeks. Survival of dosed female mice was reduced (44/50, 33/50, 33/50; 23/50 for the control, low-, mid- and high-dose groups, respectively). This was attributed to liver neoplasms observed, while there was no effect on survival in males. The mean body weights of the mid/high-dose males were lower at≥weeks 88/77, respectively. The mean body weights of the low- and mid-dose females were reduced from week 73 onwards, those of the high-dose females at≥week 53. In male mice, the incidences of hepatocellular adenoma and of hepatocellular adenoma and carcinoma (combined) were significantly increased in all dosed groups, while the incidences of hepatoblastoma showed an increase in the mid- and high-dose groups. In the female mice, the incidences of hepatocellular neoplasms were significantly higher in all treated groups compared to the control. Non-neoplastic lesions were seen only in the liver of all dosed male and female mice and consisted of cytoplasmic alteration, characterized by mild to moderate enlargement of centrilobular hepatocytes, and syncytial alteration, characterized by scattered hepatocytes with three or more small nuclei. The incidences of renal tubule adenoma in males occurred with a positive trend; but the incidences of carcinoma and hyperplasia did not follow this pattern. An extended evaluation of kidney step sections revealed additional adenomas and hyperplasias in all dosed groups. The combined analysis of single and step sections indicated a dose-related increase in the incidences of renal tubule hyperplasia and renal tubule adenoma or carcinoma (combined), and an increase in the incidences of renal tubule adenoma in male mice. Incidences of thyroid gland follicular cell hyperplasia were increased in dosed male and female mice compared to vehicle controls. Hyperkeratosis, acanthosis, and exudate were treatment-related changes in the skin at the site of application and the LOAEL for local and systemic effects was 40 mg/kg bw/day (National Toxicology Program, 1999).

The liver tumors in mice in the NTP study (1999) were considered to be directly related to the observed increase in the cellular proliferation rate, which is due to the observed enzyme induction, weak peroxisome proliferation and choline depletion with subsequent disturbance of its metabolism. While nitrosamine formation has been highlighted as a matter of concern for DEA, and for this reason it has been banned for use in cosmetics in the EU, nitrosamine formation was ruled out under the conditions of this study. Benign kidney tumors (adenomas) were only observed in male mice at the high dose level at a low incidence, when using serial sections. Based on the increased S-phase synthesis observed in this organ, it is conceivable that a similar non-genotoxic mode of action involving choline deficiency is responsible for the renal tubular adenomas.

 

Various mechanistic in vitro and in vivo studies identified that DEA induced choline depletion is the key event in the toxic mode of action. For detailed information on the studies please refer to REACH Registration Dossier of DEA.

Mechanistic research specifically on DEA indicates that, to the extent DEA can potentially induce tumors in mice, it does so by a mechanism that is not relevant to humans. Therefore, based on the available data, DEA is not considered carcinogenic for humans.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data on a read-across substances are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The read-across source substance was found to be not carcinogenic. Therefore, there is no indication for the test item to have a carcinogenic potential. As a result the substance is not considered to be classified as carcinogenic under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.