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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well reported study conducted to OECD guidelines, however there if no indication if the study was conducted to GLP

Data source

Reference
Reference Type:
secondary source
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Hydroxylammonium sulphate
IUPAC Name:
Hydroxylammonium sulphate
Test material form:
not specified
Details on test material:
Purity: Commercial grade.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
not specified
Details on oral exposure:
No data.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable.
Duration of treatment / exposure:
Satellite group: 12 months.
Main group: 24 months.
Frequency of treatment:
The test chemical was administered via the drinking water which was provided ad libitum.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Satellite group (male): 0, 5, 20 80 ppm( reported as 0, 0.3, 1.1, 4.5 mg/kg bw/day)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
Satellite group (female): 0, 5, 20 80 ppm (reported as 0, 0.4, 1.6, 6.2 mg/kg bw/day)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
Main group (males): 0, 5, 20 80 ppm (reported as 0, 0.2, 1, 3.7 mg/kg bw/day)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
Main group (females): 0, 5, 20 80 ppm (reported as 0, 0.4, 1.6, 6.2 mg/kg bw/day)
Basis:
nominal in water
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:
A satellite study was conducted to define the haematotoxic potential of the test substance, hydroxylammonium sulphate. In the satellite animals, assays of blood parameters were performed every three months.
Positive control:
No positive control animals were used in the study.

Examinations

Observations and examinations performed and frequency:
Food consumption, water consumption and body weight were determined once a week for the first 13 weeks. Thereafter water consumption and body weight was recorded monthly and food consumption determined every 3 months.

Animals were examined daily for signs of toxicity or mortality. Comprehensive clinical examinations and palpation of the animals were performed once a week.

Haematology was carried out on animals from the satellite group, after 3, 6, 9 and 12 months. Haematology was carried out in the animals from the main study group at 12, 18 and 24 months.
Sacrifice and pathology:
Complete necropsy and microscopy was performed on all animals at the study termination (12 and 24 months for satellite and main study animals, respectively).
Other examinations:
No data.
Statistics:
No data.

Results and discussion

Results of examinations

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):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
20 ppm
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
80 ppm
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
80 ppm
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
20 ppm
Histopathological findings: neoplastic:
no effects observed
Details on results:
At 3, 6, 9, 12 and 24 months animals had dose-related haemolytic anemia which was more pronounced in male rats.


Satellite Group
At the highest dose animals had increased relative spleen weight, increased congested vessels (characterised by dilated blood filled vascular spaces) increased haemosiderin deposits and extramedullary haematopoiesis. Animals also had significant alterations to blood parameters: decreased red blood cell count, haemoglobin and haematocrit; increased mean corpuscular volume and haemoglobin, platelet count, reticulocyte count, heinz bodies and Howell- Jolly bodies.
At the second highest dose male animals also showed haemosiderin deposits in the spleen.

Main Group
At the highest dose animals showed similar toxicological effects in the spleen as the satellite animals. In addition animals also displayed an increased degree of diffuse haemosiderin storage in the liver and increased haematopoiesis in the bone marrow. At the highes dose, animals also had some change to blood cells; increased Howell Jowell bodies, anisocytosis, microcytosis and polychromasia.
At the second highest dose, female animals also showed increased haemosiderin storage in the spleen

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
0.2-0.3 mg/kg bw/day
Based on:
dissolved
Sex:
male
Basis for effect level:
other: Based on haemotoxic effects
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)
Dose descriptor:
NOAEL
Remarks:
0.4 mg/kg bw/day
Based on:
dissolved
Sex:
male/female
Basis for effect level:
other: Based on haemotoxic effects
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Animals displayed dose-related haemolytic anemia along with compensatory effects characterised by extramedullary haematopoiesis in the spleen and the liver and increased red blood cell regeneration in the bone marrow. A NOAEL of 5 ppm (reported as 0.2 - 0.3 and 0.4 mg/kg bw/day for male and female rats, respectively) based on heamotlytic effects can be derived.
Executive summary:

In a chronic oral study in Wistar rats, hydroxylammonium sulphate was administered via their drinking water at concentrations of 0 (control), 5, 20 and 80 ppm for either 12 (satellite study) or 24 months (main study). The animals did not show any clinical signs of toxicity and food consumption, water consumption and body weight were not significantly different from control animals over the study period. Animals displayed dose-related haemolytic anemia along with compensatory effects characterised by extramedullary haematopoiesis in the spleen and the liver and increased red blood cell regeneration in the bone marrow. A NOAEL of 5 ppm (reported as 0.2 - 0.3 and 0.4 mg/kg bw/day for male and female rats, respectively) based on heamotlytic effects can be derived. This study is considered reliable and therefore hydroxylammonium sulphate is considered to be a haemotoxic agent in rats. Using this substance to read-across, it can be considered that hydroxylammonium nitrate is haemotoxic in rats.