Bis(hydroxylammonium) sulphate

Carcinogenicity

Description of key information

CAS No. 10039-54-0:
12/24 months, rat, oral: LOAEL = 0.2 mg/kg bw/d in males and NOAEL = 0.4 mg/kg bw/d in females for systemic effects (BASF 2001, Val. 1)
CAS No. 5470-11-1:
No data available.
CAS No. 7803-49-8:
No data available.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC for classification and labelling of dangerous substances and preparations, the criteria for classification of the test material as a category 3 carcinogen are fulfilled and the labelling proposal to cover this potential hazard therefore should remain as Xn, R40 (limited evidence of a carcinogenic effect) according to EU criterial and as Category 2 according to GHS criteria.

Additional information

CAS No. 10039-54-0:

Valid data are available to assess the carcinogenic potential of the test material after oral administration.

In a standard combined chronic toxicity/carcinogenicity toxicity study according to OECD TG 453, hydroxylammonium sulfate (purity commercial grade) was administered to groups of 50 male and 50 female Wistar rats daily in the drinking water at dose levels of 0, 5, 20 and 80 ppm for 24 months (main groups), and additional to groups of 10 animals per sex and dose for 12 months (satellite groups) for evaluation of hematology parameters. The doses administered corresponded to a mean daily hydroxylammonium sulfate intake in the main groups of about 0, 0.2, 1.0, and 3.7 mg/kg bw/d in males and 0, 0.4, 1.6, and 6.2 mg/kg bw/d in females; and in the satellite groups of about 0, 0.3, 1.1, and 4.5 mg/kg bw/d in males and 0, 0.4, 1.6, and 6.2 mg/kg bw/d in females.

There was no statistically significant body weight loss, and no significant effect on mortality in the hydroxylammonium sulfate treatment groups when compared to control groups, and furthermore, no treatment-related clinical signs were noted in either sex throughout the study. At termination, mean absolute and relative spleen weights were statistically significant increased in the 80 ppm females. Gross observations on the spleen showed a slightly increased number of males with macroscopically diagnosed masses at 80 ppm. Microscopy yielded further evidence of spleen injury in 20 ppm and 80 ppm males and females at sacrifice. The only neoplasms showing an increased incidence were tumours of the spleen in both male and female rats when compared to controls. The spleen tumours observed in male and female rats were diagnosed as hemangiosarcomas and hemangiomas. In male rats the incidence of hemangiosarcomas in the spleen was increased from 4/50 among controls and all treatment groups, to 7/50, 9/50 and 8/50 in the 5, 20, and 80 ppm groups, respectively. Two of the hemangiosarcomas of the 80 ppm dosed males and one of the control males metastasized into other organs. In females, there was a biologically equally distribution of hemangiosarcomas in the spleen over the control group animals and the hydroxylammonium sulfate-treated animals (0/5/20/80 ppm: 2/1/1/3). Whereas the number of females with hemangiomas was slightly increased in the 80 ppm dose group (0, 5, 20, 80 ppm: 0/1/1/4). It was shown that there was a slightly increased incidence of hemangiosarcomas in the spleen of male rats at all hydroxylammonium sulfate treatment groups. Although, the incidence of hemangiosarcomas in the spleen seen in male rats was small, not dose-related and the difference to controls did not attain statistically significance, the increase of this tumour type was considered to present an effect of hydroxylammonium sulfate treatment. This was supported by the fact that the incidence of hemangiosarcomas in the spleen seen in all treatment groups was generally higher than concurrent intra laboratory historical controls which underlines the biologically significance of this finding. Tumours developed earlier in hydroxylammonium sulfate treated animals than in controls. Furthermore, the following findings occurred in the spleen: hyperplasia and ectasia of capillarys, lined by a normal endothelium which lacked pleomorphism and mitotic activity and separated by a small amounts of fibrous tissue. These findings diagnosed as angiomatous hyperplasia were seen in all dose groups and controls. However, high frequencies of these spleen lesions were observed in males and females at 80 ppm. Persistent hyperplasia may be indicative as site of tumour development. So, these findings of angiomatous hyperplasia in the spleen were considered as a precursor lesion of angiomatous tumours (hemangioma, hemangiosarcoma). In the satellite groups (treatment for 12 months), very few neoplastic findings were noted which were biologically equally distributed over the control group and the hydroxylammonium sulfate treatmen groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment. Overall, this combined chronic toxicity/carcinogenicity study in the rat is acceptable and does satisfy the guideline requirement for carcinogenicity testing (OECD TG 453) in rats. Results of this standard study have shown that hydroxylammonium sulfate is carcinogenic in rats after treatment with dosages of ≥5 ppm (equivalent to about ≥0.2 mg/kg b/d) in males and of 80 ppm (equivalent to about 6.2 mg/kg bw/d) in females. In male rats an increased incidence of hemangiosarcomas was noted in all hydroxylammonium sulfate-treated groups. Hemangiomas were observed in four females from the 80 ppm dose group. Both numbers of hemangiosarcomas in male rats and hemangiomas observed in female rats were outside the range of historical control background data. Angiomatous hyperplasia in the spleen considered as a precursor lesion of angiomatous tumours was observed at an increased number in males and females at 80 ppm. Therefore, 5 ppm (equivalent to about 0.2 mg/kg bw/d (= LOAEL) in males and 0.4 mg/kg bw/d (= NOAEL) in females) is considered to be the lowest dose level for tumour development in the spleen in male and female rats in this study (BASF AG 2001, Val. 1).

 

Additional information on carcinogenic effects of the test material was available from studies with limited validity:

Lifetime administration of 10 mM (equivalent to ca. 246 mg/kg bw/d) hydroxylammonium sulfate in the drinking water resulted in a considerable reduction in mammary neoplasm incidence in female C3H/HeN mice, but not in female C3H/HeJ(+) mice. Ovarian neoplasms and cysts were common in all groups (test groups and control groups), indicating ovarian dysfunction, but these were not affected by treatment. The incidences of other cryptogenic neoplasms found in controls in significant numbers, i.e. liver carcinomas, lymphomas, lung adenomas and adrenal cortex tumours were only marginally affected by the treatment. However, an increased incidence of vascular neoplasms of the spleen in hydroxylammonium sulfate-treated female C3H/HeN mice and vascular neoplasms of the lymph nodes in hydroxylammonium sulfate-treated male C3H/HeJ(+) mice indicated a subline-related action on the reticuloendothelial system. The survival of control mice was 35-58% at two years and this was not increased in either subline by hydroxylammonium sulfate (Stenbaeck et al., 1987, Val. 4).

In an early report describing the chronic and carcinogenic effects of hydroxylammonium sulfate in male Swiss-Webster and female C3H/HeN mice, hydroxylammonium sulfate (purity: commercial grade) was given in drinking water in doses of 0, 10 or 20 mmol/l (equivalent to 0, 100 or 200 mg/kg bw/d, calculated on an assumed water consumption of 15% of body weight) to four-week old mice. Groups of 5 male and 10 female mice were administered with hydroxylammonium sulfate for 52 weeks. After termination of treatment, one group of female mice received pure water up to 104 weeks of age. No tumours were noted in mice kept on hydroxylammonium sulfate for as long as one year. Usually the condition and appearance of the experimental mice seemed better than that of controls. Furthermore, in female C3H/HeN mice which drank hydroxylammonium sulfate solution for one year, there were no spontaneous mammary tumours, even in those surviving 2 years (Yamamoto et al., 1967, Val. 4).

Hydroxylammonium sulfate treatment, started at an early age, prevented the formation of spontaneous mammary tumours in female C3H/HeN mice, but when administration started later in life no such effects was seen (Evarts et al. 1977, Val. 3).

When hydroxylammonium sulfate was given after DMBA treatment it decreased the number and size of tumours per tumour bearing animal, but increased the median latency period (latency period 102 d as compared to 63 d positive control). No differences were found when hydroxylammonium sulfate application started two weeks prior to DMBA administration (Evarts et al. 1979, Val. 3).

 

There is no indication given to assume that the tumours induced in the spleen of rats may be related to primary genotoxic effects (as BHAS has no or a low genotoxic potential). The existence of other/alternative (non-genotoxic) mechanisms is assumed. It might be supposed that the carcinogenicity is mediated via accelerated destruction of erythrocytes and tumour growth was released in BHAS-treated rats by chronic cell injury and persistent cell proliferation. At present, no other mode of action has been identified. The exact mechanisms remain unclear. A species-specific mechanism of tumour formation irrelevant for humans was not identified (EU Risk Assessment, 2008).