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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: To GLP, studies performed according to peer-reviewed methods.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1993

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: NTP peer-reviewed methods
Principles of method if other than guideline:
Male and female rats were fed diets containing varying concentrations of MnSO4 for 103 weeks.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): manganese (II) sulphate monohydrate
- Physical state: crystalline, solid
-Appearance: white, slightly efflorescent
- Analytical purity: 97.7 ± 0.4%
- Impurities (identity and concentrations): sodium (640 ppm), potassium (120 ppm) and silicon (160 ppm).
- Stability under test conditions: No bulk stability studies were performed.
- Storage condition of test material: Bulk chemical was stored in the dark at room temperature.

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals and environmental conditions:
Rats were approximately 41 days old at the start of the study.

Administration / exposure

Route of administration:
oral: feed
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 5000, 15000 ppm, equivalent to 0, 60, 200 or 615 mg/kg in male and 0, 70, 230 or 715 mg/kg in females
Basis:
nominal in diet
No. of animals per sex per dose:
70 male and 70 female rats per group
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
All animals were observed twice daily. Clinical findings were recorded weekly for the first 13 weeks and monthly thereafter.
Sacrifice and pathology:
All animals were necropsied. At necropsy all organs were examined for gross lesions and all major tissues were fixed and preserved for histopathological examinations.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Effect levels

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Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
other: food intake and concentration in diet
Sex:
male
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEL
Effect level:
230 mg/kg bw/day (nominal)
Based on:
other: food consumption and concentration in feed
Sex:
female
Basis for effect level:
body weight and weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CLINICAL SIGNS AND MORTALITY: Survival of male rats exposed to 15000 ppm was significantly lower than that of the controls. This was attributed to increased incidences of advanced renal disease relating to the ingestion of MnSO4.

BODY WEIGHT AND WEIGHT GAIN: The final mean bodyweight of male rats exposed to 15000 ppm was 10% lower than that of the controls. The mean body weights of all the other exposed groups were similar to the controls.

HAEMATOLOGY AND CLINICAL CHEMISTRY: No differences in haematology and clinical parameters attributable to the ingestion of MnSO4 were observed.

TISSUE MANGANESE CONCENTRATIONS: At both the 9 and 15 month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of male and female rats exposed to 5000 and 15000 ppm, with an accompanying depression of hepatic iron.

GROSS PATHOLOGY: The ingestion of diets containing 15000 ppm MnSO4 was associated with a marginal increase in the average severity of nephropathy in male rats. In these rats, lesions associated with renal failure, uremia, and secondary hyperparathyroidism were observed.

No increased incidence of neoplasms in male or female rats was attributed to ingestion of MnSO4.

Applicant's summary and conclusion

Conclusions:
MnSO4 is relatively non-toxic at the doses examined, and the parameters assessed in the study, over a 2 year period of exposure, via the oral route.