Fatty acids, tall-oil, manganese salts

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic 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

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

Test material information

Constituent 1

Reference substance name:

Manganese sulphate monohydrate

IUPAC Name:

Manganese sulphate monohydrate

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 or test system 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

1

Dose descriptor:

NOAEL

Effect level:

72.8 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Mn

Sex:

male

Basis for effect level:

body weight and weight gain

2

Dose descriptor:

NOAEL

Effect level:

83.7 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Mn

Sex:

female

Basis for effect level:

body weight and weight gain

3

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

food intake and concentration in diet

Sex:

male

Basis for effect level:

body weight and weight gain

4

Dose descriptor:

NOAEL

Effect level:

230 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

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.