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Toxicological information

Carcinogenicity

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Description of key information

Hydroylammonium sulphate, an analogue of hydroxylammonium nitrate, is considered carcinogenic in rats after animals displayed neoplastic lesions as a result of proliferative regeneration after chronic oral administration. This result is likely to be translatable to humans.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
No data.
Reliability:
2 (reliable with restrictions)
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Animals were Wistar (Chbb:THOM, SPF) rats.
Route of administration:
oral: drinking water
Vehicle:
not specified
Details on exposure:
Drinking water containing the test chemical was provided ad libitum.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Satellite group: 12 months.
Main group: 24 months.
Frequency of treatment:
Treated drinking water was provided ad libitum for the duration of the study.
Post exposure period:
Not applicable.
Remarks:
Doses / Concentrations:
0 (control), 5, 20 and 80 ppm
Basis:
nominal conc.
reported as 0, 0.2, 1, 3,7 and 0, 0.4, 1.6, 6.2 mg/kg bw/day for males and females respectively in the study group and 0, 0.3, 1.1, 4.5 and 0, 0.4, 1.6, 6.2 mg/kg bw/day for males and females, respectively in the satellite group.
No. of animals per sex per dose:
Satellite group: 10/sex/dose
Main group: 50/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
Animals were observed frequently for signs of toxicity mortality and body weight recorded.
Sacrifice and pathology:
Animals from all treatment groups were sacrificed and necropsied at the end of the study period.
Other examinations:
No data.
Statistics:
No data.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically higher spleen weights in female administered the highest dose
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
gross abnormalities in the spleen of male and female animals at 20 and 80 ppm, respectively.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
haemangiosarcomas and haemagiomas in the spleen of male and female animals at 5ppm
Details on results:
There were no statistically significant body weight loss and no significant effect on mortality or clincial signs in the treated animals compared to control animals.

At study termination, the mean absolute and relative spleen weights were statisticaly higher in female animals administered the highest dose compared to control animals. In male animals at the highest dose there was a slightly increased number of males with macroscopically diagnosed masses at 80 ppm. Further microscopic evaluation revealed increased evidence of spleen injury at 20 and 80 ppm for males and females animals. respectively.

In treated animals there was an increased evidence of spleen tumours in both male and female animals; these were diagnosed as haemangiosarcomas and haemangiomas. Two of the haemangiosarcomas in the spleen of the 80 ppm dose males and one of the control males metastasized into other organs. There was slightly increased incidence of haemangiosarcomas in the spleen of mae rats for all treatment groups, although the incidence of haemangiosarcomas in the spleen seen in male rats was small, not dose related and was not statistically different. However, this was considered a toxic effect of the test chemical as the incidence of of haemangiosarcomas was considered above average in the control group compared to historical means.

The spleen of all animals were considered to be angiomatous, this was characterised by hyperplasia and ectasia of capillarys lined by a normal endothelium which lacked pleomorphism and mitotic activity and separated by small amounts of fibrous tissue. Although this was obsesrved in all animals including controls, higher incidences were observed in animals administered the higher dose. These findings were considered as a precusor lesion of angiomatous tumours (haemangioma and haemangiosarcoma).

Neoplastic findings in the satellite groups were considered to be incidental or spontaneous in origin and were not related to treatment.


Relevance of carcinogenic effects / potential:
Chronic oral admimistration of hydroxylammonium sulphate casued hyperplasia and tumours in the spleen of rats, it is therefore considered to be carcinogenic in rats. The observed carcinogenic effects in the spleen of rats is likely to be translatable to humans.

Neoplastic Lesions

Male rats

Female rats

Dose

0

5

20

80

0

5

20

80

No of animals examined

50

50

50

50

50

50

50

50

Hemangiosarcoma (%)

4 (8)

7 (15)

9 (18)

8 (16)

2 (4)

1 (2)

1 (2)

3 (6)

Hemangioma (%)

0 (0)

0 (0)

0

0 (0)

0 (0)

1 (2)

1 (2)

4 (8)

Hemangiosarcoma and hemangioma (%)

4 (8)

7 (15)

9 (18)

8 (16)

2 (4)

2 (4)

2 (4)

7 (15)

Spleen

Male rats

Female rats

Dose (ppm)

0

5

20

80

0

5

20

80

Hyperplasia, angiomatous

4

9

4

16

14

13

12

34

Conclusions:
Hydroxylammonium sulphate is considered to cause carcinogenic effects in the spleen of rats after chronic oral administration. A NOAEL of 5 ppm (reported as 0.2 and 0.4 mg/kg bw/day for male and female animals, respectively) can be derived based on hyperplasia in the spleen which was considered to be angiomatous and a precursor to neoplastic lesions.
Executive summary:

In a chronic toxicity study with Wistar rats, animals (50/sex/dose) were administered hydroxylammonium sulphate via their drinking water at doses of 0 (control), 5, 20 and 80 ppm for either 12 or 24 months (satellite and main study groups, respectively). Animals did not display any adverse effects or clinical signs of toxicity over the study period. At study termination mean spleen weights were statistically higher in treated animals compared to control animals. Furthermore, there was a higher incidence of hemangiosarcomas and hemangiomas in the spleen of animals administered the test chemical for 24 months (main group) compared to control animals. A NOAEL of 5 ppm (reported as 0.2 and 0.4 mg/kg bw/day for male and female animals, respectively) can be determined based on tumour development in the spleen. This study was conducted according to OECD guideline TG453 and is considered reliable, therefore hydroxylammonium sulphate is considered to be carcinogenic in rats exposed after chronic oral administration of the chemical.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
0.2 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Only one study was located, however the study is considered to be reliable and was conducted to standardised guidelines for carcinogenicity studies

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Hydroxylamine nitrate is classified as Carc 2.

Additional information

The oral administration of hydroxylammonium sulphate is considered to cause carcinogenic effects as a result of proliferative regeneration in the spleen of rats after chronic oral administration. A NOAEL of 5 ppm (reported as 0.2 and 0.4 mg/kg bw/day for male and female animals, respectively) can be derived based on hyperplasia in the spleen which was considered to be angiomatous and a precursor to neoplastic lesions. This effect is likely to be translatable to humans and therefore hydroxylammonium sulphate, an analogue for hydroxyammonium nitrate, is considered to be carcinogenic. Only one chronic study was located, so although the results from this study are considered reliable, it cannot be substantiated. No data on the effects of hydroxyammonium nitrate via other administration routes were located.


Justification for selection of carcinogenicity via oral route endpoint:
Only one study was located, however the study is considered to be reliable and was conducted to standardised guidelines for carcinogenicity studies

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: spleen