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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted on read-across material
Remarks:
Conducted to GLP and according to peer reviewed methods. Read-across from manganese sulphate to manganese dinitrate is justified based on having both high water solubility and structural similarities. Specifically, both substances have anions containing multiple oxygens. In addition the percentage contribution of Mn2+ in both substances is comparable.
Justification for type of information:
See the read-across report attached in Section 13
Cross-reference
Reason / purpose:
other: Read-across target
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted on read-across material
Justification for type of information:
See the read-across report attached in Section 13
Reason / purpose:
read-across source
Dose descriptor:
NOAEL
Effect level:
1 700 mg/kg bw/day (nominal)
Based on:
other: Food intake and concentration in food.
Sex:
male
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
not specified
Sex:
female
Critical effects observed:
not specified

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:
Groups of 10 male and 10 female rats were fed diets containing 0, 1600, 3130, 6250, 12500 or 25000 ppm manganese sulphate. Clinical findings were recorded weekly, feed consumption was recorded weekly by cage. Rats were weighed at the beginning of the studies and weekly thereafter. At the end of the exposure period, blood was collected for haematology analyses. A necropsy was performed on all animals and organs were weighed. A complete histopathological analysis was performed on all control and high-dose animals.
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:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Stone Ridge, NY)
- Age at study initiation: 50 days



Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1600, 3130, 6250, 12500 or 25000 which was equivalent to doses from 110 to 1700 mg/kg in males and 115 to 2000 mg/kg in females
Basis:
nominal in diet
No. of animals per sex per dose:
10 male and 10 female per dose group
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Clinical findings were recorded weekly, feed consumption was recorded weekly by cage. Rats were weighed at the beginning of the studies and weekly thereafter. At the end of the exposure period, blood was collected for haematology analyses.
Sacrifice and pathology:
A necropsy was performed on all animals and organs were weighed. A complete histopathological analysis was performed on all control and high-dose animals.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
-BODY WEIGHT AND WEIGHT GAIN: The mean bodyweight gain in males receiving 3130 ppm was marginally lower than that of the controls and was significantly lower in the three highest female dose groups than the controls.
-FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Feed consumption by exposed rats was similar to that of the controls. Females ingested an average of 20% more manganese sulphate than males in the corresponding exposure groups.
-HAEMATOLOGY: Neutrophil counts were significantly higher in all exposed male groups. Lymphocyte counts were significantly lower in the three highest dose groups.
In females: leukocyte counts were significantly lower in the three highest dose groups.
A significant increase in the percent haematocrit and erythrocyte counts occurred in males exposed to the three highest dose levels.
-ORGAN WEIGHTS: Absolute and relative liver weights of all exposed males and of the female 25000 ppm group were significantly lower than the controls.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 700 mg/kg bw/day (nominal)
Based on:
other: food intake and concentration in food.
Sex:
male
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
other:
Sex:
female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No clear relationship between observed differences and the ingestion of manganese sulphate has been defined.

Table 1.Survival, Body Weights, and Feed Consumption of Rats in the Rats in the 13-Week Feed Study of Manganese (II) Sulphate Monohydrate

 

Concentration (ppm)

Survivala

Mean body weight and weight changesbrelative

Final Weight Feed to controls (%)

Consumptionc

Initial

Final

Change

Week 1

Week 13

 

Male

 

 

 

 

 

 

 

0

10/10

136±5

291±4

155±4

 

14.9

13.1

1, 600

10/10

142±4

294±5

152±4

101

14.5

13.5

3,130

10/10

149±3

291±4

141±4

100

14.8

13.6

6, 250

10/10

148±2

294±3

146±3

101

15.0

9.6

12, 500

10/10

150±11

290±6

140±11

99

14.9

14.9

25, 000

10/10

140±4

284±6

144±4

97

14.1

14.4

Female

 

 

 

 

 

 

 

0

10/10

99±1

184±2

84±2

 

10.7

9.2

1, 600

10/10

103±1

181±2

79±2

99

10.8

9.3

3,130

10/10

96±1

175±2*

80±3

95

10.9

9.2

6, 250

10/10

101±1

176±2*

75±1**

96

10.7

14.3

12, 500

10/10

106±1**

178±1*

73±2**

97

10.7

10.5

25, 000

10/10

104±1**

174±3**

70±2**

95

12.1

10.3

* Significantly different (P≤0.05) from the control group by Williams’ or Dunnett’s test

** P≤0.01

a Number of animals surviving at 13 weeks/ number initially in group

b Weight given as mean ± standard error

c Feed consumption is expressed as grams per animal per day

 

Applicant's summary and conclusion

Conclusions:
The high level of MnSO4 consumed on a daily basis for 13 weeks in this study, without mortality, supports the lack of acute toxicity. Although some changes in lung weight and certain haematological parameters were significant compared to controls, the lack of clinical and histopathological findings despite the very high daily oral dose over a sub-chronic period, is an indication of the relatively low toxicity of MnSO4, at least for the parameters studied in this report. Read-across from manganese sulphate to manganese dinitrate is justified based on having both high water solubility and structural similarities. Specifically, both substances have anions containing multiple oxygens. In addition the percentage contribution of Mn2+ in both substances is comparable.