Sodium permanganate

Endpoint summary

Description of key information

Key Short-Term Repeated Dose Oral Toxicity in Rats: Read-Across Source MnSO4 – NTP (1993)

The 14 day NOAEL was 25 000 ppm.

 

Supporting Short-Term Repeated Dose Oral Toxicity in Mice: Read-Across Source MnSO4 – NTP (1993)

The 14 day NOAEL was considered to be 50 000 ppm.

 

Key Sub-Chronic Repeated Dose Oral Toxicity in Rats: Read-Across Source MnSO4 – NTP (1993)

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3 130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6 250 ppm and higher.

 

Supporting Sub-Chronic Repeated Dose Oral Toxicity in Mice: Read-Across Source MnSO4 – NTP (1993)

No NOAEL could be identified for males on the basis of reduced body weight gain in all treated groups. The NOAEL for females can be considered to be 25 000 ppm, on the basis that body weight gain and haematology parameters were affected in the 50 000 ppm group.

 

Repeated Dose Inhalation Toxicity

The substance is considered to be corrosive, therefore inhalation exposure must be minimised by the use of suitable engineering controls and/or PPE.  The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study.  Further testing by the inhalation route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

 

Repeated Dose Dermal Toxicity

The substance is considered to be corrosive, therefore dermal exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the dermal route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please see the read across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male

Basis for effect level:

other: All exposed males exhibited absolute and relative liver weights that were lower than controls.

Remarks on result:

not determinable

Remarks:

No NOAEL determined.

Dose descriptor:

NOAEL

Effect level:

3 130 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Effects on body weight gain were seen at doses of 6250 ppm and above.

Critical effects observed:

not specified

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 August to 2 December 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study conducted by the National Toxicology Program

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Remarks:

FDA

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were male and female F344/N rats obtained from Charles River Breeding Laboratories (NY). At receipt, the rats were an average of 31 days old. They were quarantined for 19 days prior to exposure. Before the beginning of the studies, five male and five female rats were randomly selected for parasite evaluation and gross observation for evidence of disease. At the end of the studies, serologic analyses were performed on 5 control animals/sex using the protocols of the NTP Sentinel Animal Program.
Rats were housed 5 per cage, individuals were identified by ear clip/notch and toe clip. Feed (NIH-07 open formula meal rat and mouse diet, Ziegler Brothers, Inc.) and water were available ad libitum. The rats were housed in polycarbonate cages (Lab Products, Inc.) on stainless steel racks, with heat-treated hardwood chips as bedding.
The temperature of the animal room was 23.3±2°C, the relative humidity was 40-80%. Fluorescent lighting was provided for 12 hours/day, and there were aproximately 12 air changes per hour.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A premix with manganese (II) sulfate monohydrate and feed was prepared by blending with a spatula; premix and remainder of feed was layered in a
Patterson-Kelley twin-shell blender and mixed for 15 minutes with an intensifier bar on for the first 5 minutes. Dose formulations were prepared once.
Groups of 10 male and 10 female rats were fed diets containing 0, 1600, 3130, 6250, 12500, or 25000 ppm manganese (II) sulfate monohydrate. The level of manganese in the diet received by controls was approximately 92 ppm. The appropriate feed was supplied twice weekly and was available ad libitum.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability analyses of the dose formulations were conducted by the analytical chemistry laboratory using a spectrophotometric method. Homogeneity was confirmed; stability of the dose formulations was established for 2 weeks in the dark at room temperature and for 1 week exposed to air and light. A subsequent study confirmed the stability of the dose formulations for 3 weeks under the conditions listed above. No direct speciation was performed. However, complete recovery from dose formulations was achieved and other likely species are not soluble in dilute acid which was used for extraction. These findings strongly support the conclusion that the manganese remained in the divalent state. The dose formulations were prepared weekly. Dose formulations were discarded 21 days after the date of preparation.
Periodic analyses of the dose formulations of manganese (II) sulfate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods. Dose formulations were analyzed three times during the study. All dose formulations were within the specified 10% of the target concentration.

Duration of treatment / exposure:

93-94 days (13 weeks)

Frequency of treatment:

Daily -ad libitum in diet

Remarks:

Doses / Concentrations:
0, 1600, 3130, 6250, 12500 or 25000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 rats/sex/dose

Control animals:

yes, plain diet

yes, historical

Details on study design:

Animals were assigned to treatment groups by weight intervals. Animals from each interval were randomized and proportionately assigned to cages, then the cages were assigned to dose groups using an appropriate table of random numbers.
Dose levels were chosen for this study based on the results obtained in the 14 day repeat dose toxicity test: 25000 ppm was chosen as the highest dose for the 90 day study based on a reduction in mean body weight gain in the 50000 ppm male and female rats.

Positive control:

A positive control was not included.

Observations and examinations performed and frequency:

Clinical findings were recorded weekly. Feed consumption was recorded weekly by cage. The rats were weighed at the beginning of the studies and weekly thereafter. At the end of the study, blood was collected from the vena cava of all animals for haematology analyses (haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, and leukocyte count and differential).

Sacrifice and pathology:

A necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, left testicle, and thymus were weighed. Tissues for microscopic examination were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 µm, and stained with haematoxylin and eosin.
A complete histopathologic examination was performed on all control and high-dose animals. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, blood, bone marrow (sternum), brain, cecum, colon, duodenum, oesophagus, heart, kidney, liver, lung, mammary gland, mandibular lymph node, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial or clitoral gland, prostate gland, salivary gland, spleen, stomach, testes/epididymis, thyroid, gland, trachea, thymus, urinary bladder, and uterus.

Other examinations:

No other examinations reported.

Statistics:

Pairwise comparisons and were used to identify differences between control and treated groups. The significance of pairwise comparisons was determined according to the methods of Dunnett (1955), Williams (1971, 1972), Shirley (1977), Dunn (1964), Jonckheeres test (1954) or the Mann-Whitney U test.

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

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

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

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

No rats died during the study. The mean body weight 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 (Table 1). Final mean body weights of all exposed animals were within 5% of those of the controls. Feed consumption by exposed rats was similar to that by the controls (Table 3). Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1700 mg/kg body weight in males and 115 to 2000 mg/kg in females. Females ingested an average of 20% more manganese (II) sulfate monohydrate than males in the corresponding exposure groups.
Absolute and relative liver weights of all exposed males and of the female 25000 ppm group were significantly lower than those of the controls. The absolute and relative lung weights of all exposed females were also significantly lower than those of controls. No other biologically significant organ weight differences were observed between exposed and control animals. Although the total leukocyte counts were similar in exposed and control males, neutrophil counts were significantly higher in all exposed male groups, whereas lymphocyte counts were significantly lower in the 6250, 12500, and 25000 ppm groups. In contrast, the total leukocyte counts of 6250, 12500, and 25000 ppm females were significantly lower, primarily because of lower lymphocyte counts. A marginal but significant increase in percent hematocrit and erythrocyte counts occurred in males exposed to 6250, 12500, or 25 000 ppm. The relationship between these differences and the ingestion of manganese (II) sulfate monohydrate is not clear. No clinical or histopathologic findings were attributed to administration.

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male

Basis for effect level:

other: All exposed males exhibited absolute and relative liver weights that were lower than controls

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

NOAEL

Effect level:

3 130 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Effects on body weight gain were seen at doses of 6250 ppm and above

Critical effects observed:

not specified

Table 1. Survival, body weights and feed consumption

Concentration (ppm)	Survival^a	Mean body weight and Weight Changes^b(g)			Final Weight Relative to Controls (%)	Feed Consumption^c
		Initial	Final	Change		Week 1	Week 13
Male
0	10/10	136±5	291±4	155±4		14.9	13.1
1600	10/10	142±4	294±5	152±4	101	14.5	13.5
3130	10/10	149±3	291±4	141±4	100	14.8	13.6
6250	10/10	148±2	294±3	146±3	101	15.0	9.6
12500	10/10	150±11	290±6	140±11	99	14.9	14.9
25000	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
1600	10/10	103±1	181±2	79±2	99	10.8	9.3
3130	10/10	96±1	175±2*	80±3	95	10.9	9.2
6250	10/10	101±1	176±2*	75±1**	96	10.7	14.3
12500	10/10	106±1**	178±1*	73±2**	97	10.7	10.5
25000	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 14 days/number initially in group

b Weights given as mean ± standard error.

c Feed consumption is expressed as grams per animal per day.

Conclusions:

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6250 ppm and higher.

Executive summary:

Groups of 10 male and 10 female rats received diets containing 0, 1600, 3130, 6250, 12500, or 25000 ppm manganese (II) sulfate monohydrate for 90 days. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1700 mg/kg body weight in males and 115 to 2000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6250, 12500, or 25000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6250, 12500, and 25000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6250, 12500, and 25000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent haematocrit and erythrocyte count in the 6250, 12500, and 25000 ppm groups. No clinical or histopathologic findings in rats were chemical related.

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6250 ppm and higher.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please see the read across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

Reference 4

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 to 15 February 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Range-finding study conducted by the National Toxicology Program, generally similar to OECD guidelines

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Remarks:

range-finding study not conducted according to GLP

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were male and female F344/N rats obtained from Charles River Breeding Laboratories (MI). At receipt, the rats were an average of 31 days old. They were quarantined for 19 days prior to exposure. Before the beginning of the studies, five male and five female rats were randomly selected for parasite evaluation and gross observation for evidence of disease.
Rats were housed 5 per cage, individuals were identified by ear punch/notch and toe clip. Feed (NIH-07 open formula meal rat and mouse diet, Ziegler Brothers, Inc.) and water were available ad libitum. The rats were housed in polycarbonate cages (Lab Products, Inc.) on stainless steel racks, with heat-treated hardwood chips as bedding.
The temperature of the animal room was 23.3±2°C, the relative humidity was 40-80%. Fluorescent lighting was provided for 12 hours/day, and there were aproximately 12 air changes per hour.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A premix with manganese (II) sulfate monohydrate and feed was prepared by blending with a spatula; premix and remainder of feed was layered in a
Patterson-Kelley twin-shell blender and mixed for 15 minutes with an intensifier bar on for the first 5 minutes. Dose formulations were prepared once.
Groups of five male and five female rats were fed diets containing 0, 3130, 6250, 12500, 25000, or 50000 ppm manganese (II) sulfate monohydrate. The level of manganese in the diet received by controls was approximately 92 ppm. The appropriate feed was supplied twice weekly and was available ad libitum

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability analyses of the dose formulations were conducted by the analytical chemistry laboratory using a spectrophotometric method. Homogeneity was confirmed; stability of the dose formulations was established for 2 weeks in the dark at room temperature and for 1 week exposed to air and light. A subsequent study confirmed the stability of the dose formulations for 3 weeks under the conditions listed above. No direct speciation was performed. However, complete recovery from dose formulations was achieved and other likely species are not soluble in dilute acid which was used for extraction. These findings strongly support the conclusion that the manganese remained in the divalent state. The dose formulations were prepared once. Dose formulations were discarded 21 days after the date of preparation.
Periodic analyses of the dose formulations of manganese (II) sulfate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods. Dose formulations were analyzed once. All dose formulations were within the specified 10% of the target concentration.

Duration of treatment / exposure:

14 days

Frequency of treatment:

Daily -ad libitum in diet

Remarks:

Doses / Concentrations:
0, 3130, 6250, 12500, 25000, or 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

Five rats/sex/dose

Control animals:

yes, plain diet

yes, historical

Details on study design:

Animals were assigned to treatment groups by weight intervals. Animals from each interval were randomized and proportionately assigned to cages, then the cages were assigned to dose groups using an appropriate table of random numbers.

Positive control:

A positive control was not included.

Observations and examinations performed and frequency:

Clinical findings were recorded daily days 1 to 8, then twice daily days 9 to 14. Feed consumption was recorded weekly by cage. The animals were weighed at study initiation, on day 7, and at the end of the studies.
At the end of the study, blood from the vena cava of all animals was collected for haematology analyses (haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, and leukocyte count and differential).

Sacrifice and pathology:

A gross necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, left testicle, and thymus were weighed. Tissue samples of the livers from high-dose and control rats were collected for manganese concentration analyses. Histopathologic examinations were not conducted.

Other examinations:

The managanese concentration in tissue was determined.

Statistics:

Pairwise comparisons and were used to identify differences between control and treated groups. The significance of pairwise comparisons was determined according to the methods of Dunnett (1955), Williams (1971, 1972), Shirley (1977), Dunn (1964), Jonckheeres test (1954) or the Mann-Whitney U test.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

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

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

All rats survived to the end of the study. The mean body weight gain of the male 50000 ppm group at the end of the 14-day study was 57% less than that of the control group, and the final mean body weight of this group was 13% lower than that of the controls. The mean body weight gain of 50000 ppm females was 20% less than that of the controls and the final mean body weight was 7% lower than that of the controls. Males and females in each exposure group consumed approximately equal amounts of manganese (II) sulfate monohydrate per body weight (25 to 370 mg/kg). During the first week, feed consumption by 50000 ppm males was 19% lower than controls, whereas that by 50000 ppm females was 15% lower. During the second week, however, feed consumption by both male and female 50000 ppm groups was similar to that by controls. Data are shown in Table 1.
Males exposed to 50000 ppm and all exposed groups of females exhibited diarrhoea during the second week. In the haematology evaluation, the total leukocyte and neutrophil counts were significantly increased in 50000 ppm groups, particularly males. Other slight changes in haematology parameters were not considered related to chemical ingestion. At necropsy, the absolute and relative liver weights of 50000 ppm male rats were significantly lower than those of the controls. Manganese concentrations in the livers of 50000 ppm males and females were more than twice those of controls (males: control, 2.80 µg/g; 50000 ppm, 5.92 µg/g; females: 2.40 µg/g, 6.82 µg/g).

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

Table 1. Survivial, body weights, and feed consumption

Concentration (ppm)	Survival^a	Mean body weight and Weight Changes^b(g)			Final Weight Relative to Controls (%)	Feed Consumption^c
		Initial	Final	Change		Week 1	Week 2
Male
0	5/5	183±14	241±12	58±2		17.2	17.2
3130	5/5	176±6	235±5	59±3	98	16.6	17.2
6250	5/5	182±15	242±13	60±3	101	16.7	17.7
12500	5/5	176±7	235±6	58±3	98	16.7	17.7
25000	5/5	186±7	243±6	57±1	101	17.0	18.1
50000	5/5	185±5	210±6*	25±2**	87	13.9	16.8
Female
0	5/5	140±3	165±4	25±2		12.2	11.4
3130	5/5	144±5	171±5	27±3	104	14.2	11.8
6250	5/5	134±4	157±3	23±2	95	11.8	11.0
12500	5/5	136±5	163±6	27±1	99	13.2	11.9
25000	5/5	139±5	166±4	27±1	101	13.3	12.0
50000	5/5	134±5	153±5	20±1	93	10.4	12.1

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

** P ≤0.01

aNumber of animals surviving at 14 days/number initially in group

bWeights given as mean ± standard error.

cFeed consumption is expressed as grams per animal per day.

Conclusions:

The 14 day NOAEL was 25000 ppm.

Executive summary:

Groups of five male and five female rats received diets containing 0, 3130, 6250, 12500, 25000, or 50000 ppm manganese (II) sulfate monohydrate for 14 days. All rats survived to the end of the study. Male rats exposed to 50000 ppm had a mean body weight gain 57% lower and a final mean body weight 13% lower than those of the controls. The mean body weight gain of 50000 ppm females was 20% lower and the final mean body weight was 7% lower than those of the controls. During the second week, 50000 ppm males and females exhibited diarrhoea. Manganese concentrations in the livers of 50000 ppm males and females were more than twice those of controls (males: control, 2.80 µg/g; 50000 ppm, 5.92 µg/g; females: 2.40 µg/g, 6.82 µg/g).

The 14 day NOAEL was considered to be 25000 ppm.

Reference 5

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

Please see the read across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Sex:

male

Basis for effect level:

other:

Remarks on result:

not determinable

Remarks:

No NOAEL identified.

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Sex:

female

Basis for effect level:

body weight and weight gain

haematology

Critical effects observed:

not specified

Reference 6

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

30 August to 30 November 1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted by the National Toxicology Program

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Remarks:

FDA

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were male and female B6C3F1 mice, obtained from Simonsen Labs, Inc. (CA). At receipt, the mice were an average of 43 days old, and they were quarantined for 20 days prior to exposure. Before the beginning of the studies, five male and five female mice were randomly selected for parasite evaluation and gross observation for evidence of disease. At the end of the studies, serologic analyses were performed on five male and five female controls using the protocols of the NTP Sentinel Animal Program.
Mice were housed 5 per cage, individuals were identified by ear clip/notch and toe clip. Feed (NIH-07 open formula meal rat and mouse diet, Ziegler Brothers, Inc.) and water were available ad libitum. The mice were housed in polycarbonate cages (Lab Products, Inc.) on stainless steel racks, with heat-treated hardwood chips as bedding.
The temperature of the animal room was 23.3±2°C, the relative humidity was 40-80%. Fluorescent lighting was provided for 12 hours/day, and there were aproximately 12 air changes per hour.

Details on oral exposure:

A premix with manganese (II) sulfate monohydrate and feed was prepared by blending with a spatula; premix and remainder of feed was layered in a
Patterson-Kelley twin-shell blender and mixed for 15 minutes with an intensifier bar on for the first 5 minutes. Dose formulations were prepared once.
Groups of 10 male and 10 female mice were fed diets containing 0, 3130, 6250, 12500, 25000 or 50000 ppm manganese (II) sulfate monohydrate. The level of manganese in the diet received by controls was approximately 92 ppm. The appropriate feed was supplied twice weekly and was available ad libitum.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability analyses of the dose formulations were conducted by the analytical chemistry laboratory using a spectrophotometric method. Homogeneity was confirmed; stability of the dose formulations was established for 2 weeks in the dark at room temperature and for 1 week exposed to air and light. A subsequent study confirmed the stability of the dose formulations for 3 weeks under the conditions listed above. No direct speciation was performed. However, complete recovery from dose formulations was achieved and other likely species are not soluble in dilute acid which was used for extraction. These findings strongly support the conclusion that the manganese remained in the divalent state. The dose formulations were prepared weekly. Dose formulations were discarded 21 days after the date of preparation.
Periodic analyses of the dose formulations of manganese (II) sulfate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods. Dose formulations were analyzed three times during the study. All dose formulations were within the specified 10% of the target concentration.

Duration of treatment / exposure:

90-91 days (13 weeks)

Frequency of treatment:

Daily - ad libitum in diet

Remarks:

Doses / Concentrations:
0, 3130, 6250, 12500, 25000 or 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 mice/sex/dose

Control animals:

yes, plain diet

yes, historical

Details on study design:

Animals were assigned to treatment groups by weight intervals. Animals from each interval were randomized and proportionately assigned to cages, then the cages were assigned to dose groups using an appropriate table of random numbers.
Dose levels were chosen for this study based on the results obtained in the 14 day repeat dose toxicity test: there were no overt signs of toxicity therefore the dose levels remained the same.

Positive control:

A positive control was not included.

Observations and examinations performed and frequency:

Clinical findings were recorded weekly. Feed consumption was recorded weekly by cage. The mice were weighed at the beginning of the studies and twice weekly thereafter. At the end of the study, blood was collected from the vena cava of all animals for haematology analyses (haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, and leukocyte count and differential).

Sacrifice and pathology:

A necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, left testicle, and thymus were weighed. Tissues for microscopic examination were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 µm, and stained with haematoxylin and eosin.
A complete histopathologic examination was performed on all control and high-dose animals. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, blood, bone marrow (sternum), brain, colon, duodenum, oesophagus, gallbladder, heart, kidney, liver, lung, mammary gland, mandibular lymph node, nose, ovary, pancreas, parathyroid gland, pituitary gland, prostate gland, salivary gland, spleen, stomach, testes/epididymis, thyroid, gland, trachea, thymus, urinary bladder, and uterus.

Other examinations:

No other examinations reported.

Statistics:

Pairwise comparisons and were used to identify differences between control and treated groups. The significance of pairwise comparisons was determined according to the methods of Dunnett (1955), Williams (1971, 1972), Shirley (1977), Dunn (1964), Jonckheeres test (1954) or the Mann-Whitney U test.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

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

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

One control male mouse and one female mouse receiving 3130 ppm died of unknown causes during this study (Table 1). Mean body weight gains of all exposed males were significantly lower than that of the control group, and the final mean body weight of the 50000 ppm group was 13% lower than that of the controls. The mean body weight gain of 50000 ppm females was significantly lower than that of the controls. Feed consumption by exposed male and female mice was similar to that by the controls (Table 1). Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7400 mg/kg body weight in males and 390 to 6900 ppm in females. The absolute and relative liver weights of 50000 ppm male mice were significantly lower than those of the controls; absolute and relative liver weights of females were similar to those of the controls. The percent haematocrit, haemoglobin concentrations, and mean erythrocyte volumes of 50000 ppm male and female mice were significantly lower than those of the controls. These findings suggest microcytic anemia and may be related to a sequestration or deficiency of iron. Although the total leukocyte counts in the two highest male exposure groups were significantly lower than that in the control group, this may not be related to manganese (II) sulfate monohydrate ingestion. A few mice in the male and female exposure groups exhibited fight wounds. Three 50000 ppm males had mild epithelial hyperplasia and hyperkeratosis
of the forestomach.

Dose descriptor:

NOAEL

Sex:

male

Basis for effect level:

other: Reduced body weight gain was seen in all exposed male groups

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Sex:

female

Basis for effect level:

body weight and weight gain

haematology

Critical effects observed:

not specified

Table 1. Survival, body weights and feed consumption

Concentration (ppm)	Survival^a	Mean body weight and Weight Changes^b(g)			Final Weight Relative to Controls (%)	Feed Consumption^c
		Initial	Final	Change		Week 1	Week 13
Male
0	9/10^d	25.0±0.5	31.4±0.6	6.6±0.5		3.4	3.0
3130	10/10	25.7±0.3	30.5±0.5	4.8±0.4**	97	3.0	3.0
6250	10/10	26.3±0.2*	31.0±0.3	4.7±0.4**	99	3.4	3.3
12500	10/10	26.0±0.3	30.9±0.4	4.9±0.4**	98	3.4	3.8
25000	10/10	25.9±0.2	30.6±0.5	4.7±0.5**	97	2.6	3.3
50000	10/10	25.1±0.4	27.4±0.3**	2.3±0.4**	87	3.0	4.7
Female
0	10/10	20.0±0.2	24.2±0.3	4.2±0.3		2.4	2.3
3130	9/10^e	20.0±0.3	24.2±0.5	4.1±0.3	100	3.3	2.4
6250	10/10	20.5±0.2	24.3±0.3	3.8±0.3	100	2.8	2.2
12500	10/10	21.0±0.3	24.5±0.3	3.5±0.3	101	2.7	3.0
25000	10/10	20.3±0.3	24.2±0.4	3.9±0.4	100	3.1	3.4
50000	10/10	20.1±0.2	22.8±0.3**	2.7±0.2**	94	2.8	3.0

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

** P≤0.01

a Number of animals surviving at 14 days/number initially in group

b Weights given as mean ± standard error.

c Feed consumption is expressed as grams per animal per day.

d Week of death: 11

e Week of death: 6

Conclusions:

No NOAEL could be identified for males on the basis of reduced body weight gain in all treated groups. The NOAEL for females can be considered to be 25000 ppm, on the basis that body weight gain and and haematology parameters were affected in the 50000 ppm group.

Executive summary:

Groups of 10 male and 10 female mice received diets containing 0, 3130, 6250, 12500, 25000, or 50000 ppm manganese (II) sulfate monohydrate for 90 days. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7400 mg/kg body weight in males and 390 to 6900 mg/kg body weight in females. No deaths were chemical related. The mean body weight gains of exposed male mice and of 50000 ppm female mice were significantly lower than those of controls. The absolute and relative liver weights of 50000 ppm males were significantly lower than those of controls. The percent haematocrit and haemoglobin concentration of males and females exposed to 50000 ppm were lower than those of the controls, and the mean erythrocyte volumes were significantly lower than those of the controls. The total leukocyte counts of males in the 25000 and 50000 ppm groups were significantly lower than that of the controls. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Epithelial hyperplasia and hyperkeratosis of the forestomach occurred in three 50000 ppm males.

No NOAEL could be identified for males on the basis of reduced body weight gain in all treated groups. The NOAEL for females can be considered to be 25000 ppm, on the basis that body weight gain and and haematology parameters were affected in the 50000 ppm group.

Reference 7

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

Please see the read across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Critical effects observed:

not specified

Reference 8

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

29 March to 14 April 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Range finding study conducted by the National Toxicology Program, generally similar to OECD guidelies

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Remarks:

range-finding study not conducted according to GLP

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were male and female B6C3F1 mice, obtained from Charles River Breeding Laboratories (MI). At receipt, the mice were an average of 35 days old, and they were quarantined for 20 days prior to exposure. Before the beginning of the studies, five male and five female mice were randomly selected for parasite evaluation and gross observation for evidence of disease.
Mice were housed 5 per cage, individuals were identified by ear punch/notch and toe clip. Feed (NIH-07 open formula meal rat and mouse diet, Ziegler Brothers, Inc.) and water were available ad libitum. The mice were housed in polycarbonate cages (Lab Products, Inc.) on stainless steel racks, with heat-treated hardwood chips as bedding.
The temperature of the animal room was 23.3±2°C, the relative humidity was 40-80%. Fluorescent lighting was provided for 12 hours/day, and there were aproximately 12 air changes per hour.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A premix with manganese (II) sulfate monohydrate and feed was prepared by blending with a spatula; premix and remainder of feed was layered in a
Patterson-Kelley twin-shell blender and mixed for 15 minutes with an intensifier bar on for the first 5 minutes. Dose formulations were prepared once.
Groups of five male and five female mice were fed diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. The level of manganese in the diet received by controls was approximately 92 ppm. The appropriate feed was supplied twice weekly and was available ad libitum

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability analyses of the dose formulations were conducted by the analytical chemistry laboratory using a spectrophotometric method. Homogeneity was confirmed; stability of the dose formulations was established for 2 weeks in the dark at room temperature and for 1 week exposed to air and light. A subsequent study confirmed the stability of the dose formulations for 3 weeks under the conditions listed above. No direct speciation was performed. However, complete recovery from dose formulations was achieved and other likely species are not soluble in dilute acid which was used for extraction. These findings strongly support the conclusion that the manganese remained in the divalent state. The dose formulations were prepared once. Dose formulations were discarded 21 days after the date of preparation.
Periodic analyses of the dose formulations of manganese (II) sulfate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods. Dose formulations were analyzed once. All dose formulations were within the specified 10% of the target concentration.

Duration of treatment / exposure:

14 days

Frequency of treatment:

Daily - ad libitum in diet

Remarks:

Doses / Concentrations:
0, 3130, 6250, 12500, 25000, or 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

Five mice/sex/dose

Control animals:

yes, plain diet

yes, historical

Details on study design:

Animals were assigned to treatment groups by weight intervals. Animals from each interval were randomized and proportionately assigned to cages, then the cages were assigned to dose groups using an appropriate table of random numbers.

Positive control:

A positive control was not included.

Observations and examinations performed and frequency:

Clinical findings were recorded twice daily. Feed consumption was recorded weekly by cage. The animals were weighed at study initiation, on day 7, and at the end of the studies.
At the end of the study, blood from the vena cava of all animals was collected for haematology analyses (haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, and leukocyte count and differential).

Sacrifice and pathology:

A gross necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, left testicle, and thymus were weighed. Tissue samples of the livers from high-dose and control rats were collected for manganese concentration analyses. Histopathologic examinations were not conducted.

Other examinations:

The managanese concentration in tissue was determined.

Statistics:

Pairwise comparisons and were used to identify differences between control and treated groups. The significance of pairwise comparisons was determined according to the methods of Dunnett (1955), Williams (1971, 1972), Shirley (1977), Dunn (1964), Jonckheeres test (1954) or the Mann-Whitney U test.

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

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

One female mouse in the 25000 ppm group died of unknown causes on day 1; all other mice survived to the end of the study (Table 1). No significant evidence of toxicity was observed except possible body weight effects in both sexes (Table 1). However, the report stated that no conclusions could be made regarding the body weight data because of poor randomization of animals at study initiation. No organ weight differences were attributed to manganese (II) sulfate monohydrate exposure. Absolute or relative organ weight differences in some of the exposure groups were probably related to body weight differences between exposed and control groups. No chemical-related differences in haematology parameters were observed. Manganese concentrations in the livers of 50000 ppm mice were 8 to 15 times higher than those found in controls (males: control, 0.966 µg/g; 50000 ppm, 8.020 μg/g; females: 0.708 µg/g; 10.300 µg/g).

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Sex:

male/female

Critical effects observed:

not specified

Table 1. Survival, body weights and feed consumption.

Concentration (ppm)	Survival^a	Mean body weight and Weight Changes^b(g)			Final Weight Relative to Controls (%)	Feed Consumption^c
		Initial	Final	Change		Week 1	Week 2
Male
0	5/5	21.4±0.6	25.6±1.2	4.2±0.8		4.2	4.2
3130	5/5	23.8±0.4*	26.8±0.7	3.0±0.5	105	2.8	3.2
6250	5/5	24.4±0.5**	26.0±1.0	1.6±0.5**	102	3.0	3.5
12500	5/5	24.6±0.7**	24.0±0.7	0.6±0.5**	94	3.7	4.3
25000	5/5	24.8±0.4**	24.4±0.2	0.4±0.2**	95	5.1	4.6
50000	5/5	19.2±0.4*	21.8±0.7*	2.6±0.5**	85	3.2	4.9
Female
0	5/5	15.6±0.6	21.0±1.0	5.4±0.8		3.3	4.2
3130	5/5	18.4±0.2**	18.0±0.3**	0.4±0.2**	86	3.8	4.8
6250	5/5	17.8±0.2**	17.2±0.4**	0.6±0.4**	82	4.1	4.3
12500	5/5	18.6±0.7**	16.8±0.6**	1.8±0.4**	80	4.1	5.2
25000	4/5^d	18.2±0.4**	17.0±0.4**	1.3±0.3**	81	4.8	6.0
50000	5/5	18.6±0.4**	15.2±0.5**	3.4±0.2**	72	3.5	3.69

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

** P ≤0.01

aNumber of animals surviving at 14 days/number initially in group

bWeights given as mean ± standard error.

cFeed consumption is expressed as grams per animal per day.

dDay of death: 1

Conclusions:

The 14 day NOAEL was considered to be 50000 ppm.

Executive summary:

Groups of five male and five female mice received diets containing 0, 3130, 6250, 12500, 25000, or 50000 ppm manganese (II) sulfate monohydrate for 14 days. One female mouse in the 25,000 ppm group died on day 1 of unknown causes; all other mice survived to the end of the study. Differences in body weights between exposed and control mice could not be attributed to chemical adminsitration. Therefore the NOAEL can be considered to be 50000 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Read across from a single read across substance.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

The substance is considered to be corrosive, therefore inhalation exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the inhalation route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

The substance is considered to be corrosive, therefore inhalation exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the inhalation route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

The substance is considered to be corrosive, therefore dermal exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the dermal route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

The substance is considered to be corrosive, therefore dermal exposure must be minimised by the use of suitable engineering controls and/or PPE. The repeated dose toxicity of the substance is adequately addressed by the results of a 28-day oral study. Further testing by the dermal route is not justified on scientific grounds as local effects will predominate, for reasons of exposure and additionally for reasons of animal welfare.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Key Short-Term Repeated Dose Oral Toxicity: Read-Across Source MnSO4 – NTP (1993)

Groups of five male and five female rats received diets containing 0, 3 130, 6 250, 12 500, 25 000, or 50 000 ppm manganese (II) sulfate monohydrate for 14 days. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

All rats survived to the end of the study. Male rats exposed to 50 000 ppm had a mean body weight gain 57 % lower and a final mean body weight 13 % lower than those of the controls. The mean body weight gain of 50 000 ppm females was 20 % lower and the final mean body weight was 7 % lower than those of the controls. During the second week, 50 000 ppm males and females exhibited diarrhoea. Manganese concentrations in the livers of 50 000 ppm males and females were more than twice those of controls (males: control, 2.80 µg/g; 50 000 ppm, 5.92 µg/g; females: 2.40 µg/g, 6.82 µg/g).

The 14-day NOAEL was considered to be 25 000 ppm.

 

The NOAEL of 25000 ppm for MnSO4 is equivalent to 9124 ppm Mn.

 

Supporting Short-Term Repeated Dose Oral Toxicity in Mice: Read-Across Source MnSO4 – NTP (1993)

Groups of five male and five female mice received diets containing 0, 3 130, 6 250, 12 500, 25 000, or 50 000 ppm manganese (II) sulfate monohydrate for 14 days. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

One female mouse in the 25 000 ppm group died on day 1 of unknown causes; all other mice survived to the end of the study. Differences in body weights between exposed and control mice could not be attributed to chemical adminsitration. Therefore, the NOAEL can be considered to be 50 000 ppm.

 

The NOAEL of 50000 ppm for MnSO4 is equivalent to 47170 ppm NaMnO4 and 18248 ppm Mn.

 

Key Sub-Chronic Repeated Dose Oral Toxicity in Rats: Read-Across Source MnSO4 – NTP (1993)

Groups of 10 male and 10 female rats received diets containing 0, 1 600, 3 130, 6 250, 12 500, or 25 000 ppm manganese (II) sulfate monohydrate for 90 days. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1 700 mg/kg body weight in males and 115 to 2 000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3 130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6 250, 12 500, or 25 000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6250, 12 500, and 25 000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6 250, 12 500, and 25 000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent haematocrit and erythrocyte count in the 6 250, 12 500, and 25 000 ppm groups. No clinical or histopathologic findings in rats were chemical related.

No NOAEL could be identified for male rats on the basis of liver weight differences. A NOAEL of 3 130 ppm for female rats can be assigned on the basis of reduced body weight gain at doses of 6 250 ppm and higher.

 

The NOAEL of 3130 ppm for MnSO4 is equivalent to 2942 ppm NaMnO4 and 1142 ppm Mn.

 

Supporting Sub-Chronic Repeated Dose Oral Toxicity in Mice: Read-Across Source MnSO4 – NTP (1993)

Groups of 10 male and 10 female mice received diets containing 0, 3 130, 6 250, 12 500, 25 000, or 50 000 ppm manganese (II) sulfate monohydrate for 90 days. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7 400 mg/kg body weight in males and 390 to 6 900 mg/kg body weight in females. No deaths were chemical related. The mean body weight gains of exposed male mice and of 50 000 ppm female mice were significantly lower than those of controls. The absolute and relative liver weights of 50 000 ppm males were significantly lower than those of controls. The percent haematocrit and haemoglobin concentration of males and females exposed to 50 000 ppm were lower than those of the controls, and the mean erythrocyte volumes were significantly lower than those of the controls. The total leukocyte counts of males in the 25 000 and 50 000 ppm groups were significantly lower than that of the controls. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Epithelial hyperplasia and hyperkeratosis of the forestomach occurred in three 50 000 ppm males.

Justification for classification or non-classification

The registered substance uses repeated dose toxicity data read-across from manganese sulphate, which has a harmonised classification as STOT RE 2. This classification has been read-across.