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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2006
Report date:
2005

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
ammonium sulfate
IUPAC Name:
ammonium sulfate
Details on test material:
Source: Yoneyama Kagaku Kogyo (Osaka, Japan)

Test animals

Species:
rat
Strain:
other: F344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan (Atsugi, Japan)
- Females: nulliparous and non-pregnant: yes
- Fasting period before study: no, but animals were fasted overnight prior to the terminal necropsy
- Housing: three or four rats per plastic cage, on sterilized soft wood chips
- Diet: ad libitum, basal diet CRF-1 (Oriental Yeast; Tokyo, Japan), mixed with test substance
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 24 ± 1
- Humidity (%): 55 ± 5
- Air changes (per hr): 18
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): The test chemical-supplemented diet was replaced regularly within 2-week intervals.
- Powdered basal diet CRF-1 (Oriental Yeast; Tokyo, Japan) was mixed with the test substance, after mixture the feed was pelleted.
- Storage temperature of food: Refrigeration or at room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytics performed, no details given. No analysis of homogeity of the feed included.
Duration of treatment / exposure:
52 weeks
Frequency of treatment:
Continuous exposure through feed.
Doses / concentrationsopen allclose all
Dose / conc.:
0.1 other: %
Dose / conc.:
0.6 other: %
Dose / conc.:
1.5 other: %
Dose / conc.:
3 other: %
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on preliminary 13-week study (no details given in the publication).

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS AND DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Every 2 weeks until week 10 and every 5 weeks thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at sacrifice
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight
- How many animals: all
- Parameters: Red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, differential leukocyte counts and reticulocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at sacrifice
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight
- How many animals: all
- Parameters: total protein, albumin, albumin/globulin ratio, total bilirubin, total cholesterol, triglyceride, blood urea nitrogen, creatinine, calcium, inorganic phosphorus, sodium, potassium, chloride, aspartate transaminase, alanine transaminase, alkaline phosphatase and c-glutamyl transpeptidase.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals at termination and all animals that died or became moribund during the treatment period.

ORGANS WEIGHED: Brain, lungs, heart, spleen, liver, adrenals, kidneys and testes. As for adrenals, kidneys and testes, weights of each side were separately recorded and the total of both sides was used for calculation of group mean.

HISTOPATHOLOGY: Yes
Brain, lungs, heart, spleen, liver, adrenals, kidneys, testes, the nasal cavity, trachea, aorta, pituitary, thyroids, parathyroids, salivary glands, tongue, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, pancreas, urinary bladder, epididymides, prostate, seminal vesicles, ovaries, uterus, vagina, mammary glands, skin, mesenteric and submandibular lymph nodes, thymus, sternum, femur including bone marrow, sciatic nerve, trigeminal nerve, spinal cord (cervical, thoracic and lumber cords), eye, Harderian gland and thigh muscle.

Histopathology was performed on all organs and tissues in the control and 3.0% group animals and macroscopically abnormal sites in the 0.1% and 0.6% group animals.
Statistics:
Variance in data for body weights, hematology, serum biochemistry and organ weights was checked for homogeneity by the Bartlett test. When the data were homogeneous, one-way analysis of variance (ANOVA) was used. In the heterogeneous cases, the Kruskal–Wallis test was applied. When statistically significant differences were indicated, Dunnett's multiple test was employed for comparison between control and treated groups. Incidences of non-neoplastic lesions were compared with the Fisher's exact probability test or the Mann–Whitney's U-test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No obvious findings were observed.
Mortality:
no mortality observed
Description (incidence):
No mortality was found in any groups throughout the treatment period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related change in the body weights was found.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant test substance-related change in the food intake was found. A tendency for increased food intake was noted in high dose males.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No significant variation was found in erythrocytic parameters and platelet count among the groups. Some slight changes were found in white blood cell count parameters (reticulocyte count was increased compared to control with -62.5% and 29.1% for the groups exposed to 0.1 and 0.6, respectively (high dose group was unaltered compared to control), white blood cell count decreased with -13.7%, -11% and -4.2% for the groups exposed to 0.1, 0.6 and 3.0%, respectively). Since there was no dose-relation these effects were considered to be incidental.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No dose-related alteration was found in any of the serum biochemical parameters. A slight increase was seen for T-Bil for the groups exposed to 0.1 and 0.6% (from 0.1 mg/dL (controls) to 0.2 (0.1% group) and 0.3 mg/dL (0.6% group)), however the high dose group had the same level as the controls. Similar pattern was seen for aspartate transaminase, alanine transaminase and alkaline phosphatase (aspartate transaminase: +23.9% and +52.3%; alanine transaminase: +43.6% and +76.4%; alkaline phosphatase: 10.5% and 18.1% for the groups exposed to 0.1% and 0.6%, respectivley). Also for these parameters, the high dose group showed same levels as the controls. In anbsence of a dose-relationship of the effects these results were considered non-adverse.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Kidney weights were increased at 3.0% in both sexes (in males: +11.2% (absolute) and +10% (relative); females: 10.5% (relative)). No changes compared to controls were found in the other organs of exposed animals.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no obvious macroscopic findings in any of the groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, 4/10 males were found to have focal necrosis in the liver (1/10 in conrols). In females, bile duct prolifereation was seen in 3/10 high dose rats (not seen in controls, and 9/10 high dose rats had altered hepatocellular foci (also seen in 7/10 control females).
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
A malignant pheochromocytoma of the adrenal in the male 3.0% group, two adenomas in the anterior pituitary in females of the 3.0% group (none found in control groups). These were considered coincidental findings.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
0.6 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
3 other: %
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes

Any other information on results incl. tables

The actual daily intake of the test substance was calculated to be 42, 256 and 1527 mg/kg bw/day for males and 48, 284 and 1490 mg/kg bw/day for females.

Parallel to the chronic feed study summarized here, a carcinogenicity study on ammonium sulfate in F344 rats was performed. Male and female rats (50 animals/sex/group) were exposed to 0%, 1.5% and 3.0% in a 104-week carcinogenicity study through feed. Ammonium sulfate did not exert any significant influence on the incidences of tumors in any of the organs and tissues examined. The results of this study were in alignment with the chronic toxicity study, i.e. the no observed adverse effect level of ammonium sulfate was found to be at 0.6% in the diet, which is equivalent to 256 and 284 mg/kg bw/day in males and females, respectively, and the compound was non-carcinogenic under the conditions of this study.

Applicant's summary and conclusion

Conclusions:
Based on a chronic toxicity study in rats with ammonium sulphate, the NOAEL was found to be 0.1% in feed, which was calculated to correlate to 256 mg/kg bw/day (males) and 284 mg/kg bw/day (females).
Executive summary:

A chronic toxicity study was performed with ammonium sulphate in male and female rats (10/sex/group), with exposure through feed at 0%, 0.1%, 0.6% and 3.0%. During the treatment period, clinical signs and mortality were observed daily, and body weight and food consumption were recorded every 2 weeks until week 10 and every 5 weeks thereafter. After sacrifice, hematological examinations and serum biochemistry were performed. Full necropsy was done (including organ weights) and histopathology was performed on controls and high dose groups. No effects were found on survival rate, body weights, and hematological, serum biochemical or histopathological parameters at any dose levels in the chronic toxicity study. Kidney weights were increased at 3.0% in both sexes (in males: +11.2% (absolute) and +10% (relative); females: 10.5% (relative)). No changes compared to controls were found in the other organs of exposed animals. In the high dose group, 4/10 males were found to have focal necrosis in the liver (1/10 in conrols). In females, bile duct prolifereation was seen in 3/10 high dose rats (not seen in controls, and 9/10 high dose rats had altered hepatocellular foci (also seen in 7/10 control females). Based on these results, the NOAEL was found to be 0.1% in feed, which was calculated to correlate to 256 mg/kg bw/day (males) and 284 mg/kg bw/day (females).