Dimanganese trioxide

Endpoint summary

Description of key information

Relevant data for repeated toxicity was not available for the target substance. Thus, data from an appropriate read-across partner (manganese sulphate) was used to assess the specific target organ toxicity of dimanganese trioxide (target substance). Sub-chronic and chronic oral repeated dose toxicity studies are available, which were conducted within the US NTP programme for manganese sulphate. Moreover, a sub-chronic inhalation toxicity study in rhesus monkeys is available. Based on the results from the read-across partner, no classfication for specific target organ toxicity of the target substance is warranted.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across statement in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical findings were attributed to the administration of the test item.

Mortality:

no mortality observed

Description (incidence):

Survival of exposed males and females was similar to that of the control groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weights of exposed males were similar to those of the control group.
After week 37, mean body weights of all exposed groups of females were lower than that of the controls. The final mean body weights for the 1 500, 5 000, and 15 000 ppm groups were 6%, 9%, and 13% lower than that of the control group.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by exposed male and female mice was similar to that of the control groups.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Percent hematocrit, hemoglobin concentrations, and erythrocyte counts in 15 000 ppm male mice at the 15-month interim evaluation were greater than those of the controls but the significance of these slight increases is uncertain.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No test item-related effects were observed at the 9-or 15-month interim evaluations.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Liver: At the 9-month interim evaluation, absolute liver weights of 15 000 ppm males and of 5 000 and 15 000 ppm females were significantly lower than those of controls. Since these groups also had lower mean body weights, and relative liver weights were similar to controls, the lower absolute liver weights are not considered chemical related. At the 15-month interim evaluation, absolute and relative liver weights of exposed mice were similar to controls.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Thyroid Gland: At the 9- and 15-month interim evaluations, thyroid follicle dilatation was present in 15 000 ppm males and females but not in the controls. At the end of the 2-year study, the incidence of follicular dilatation increased significantly in 15 000 ppm males and 5 000 and 15 000 ppm females. A significantly increased incidence of focal hyperplasia of follicular epithelium also occurred in 15 000 ppm males and in all exposed females.

Forestomach: A statistically significant increased incidence of focal squamous hyperplasia of the forestomach occurred in the 15 000 ppm males and females, accompanied by ulceration/erosion and inflammation. Hyperplasia of the squamous epithelium occurred focally at various sites of the forestomach mucosa. The lesion was characterized by broad-based areas of either proliferative epithelial thickening and hyperkeratosis or by polypoid projections of thickened epithelium protruding directly from the mucosa into the lumen of the stomach. Inflammation of the lamina propria and submucosa subjacent to the ulcerative lesions consisted of a mixture of infiltrating neutrophils and mononuclear leukocytes.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Thyroid gland: Follicular cell adenomas were found in three (6%) 15 000 ppm males. This rate is marginally higher than the average rate of 2% and just within the range of 0% - 6% for historical control male mice. The incidence of this neoplasm was 10% in 15 000 ppm females, which is slightly above the average of 3% and range of 0%-9% for historical control female mice. The incidences of adenoma in 15 000 ppm males and females were not significantly greater than those of the controls.

Liver: One male in the 15 000 ppm group and two females in the 5 000 ppm group had hepatocellular adenomas at the 15-month interim evaluation. At the end of the 2-year study, hepatocellular adenomas occurred with a statistically significant negative trend in males (30/50, 29/49, 19/51, 20/50) that was also significant by pairwise comparison in the 5 000 and 15 000 ppm groups. Hepatocellular foci did not occur in an exposure-related pattern (foci of any type, males: 4/50, 16/49, 9/51, 1/50). The incidences of adenoma or foci in exposed females were similar to those of the controls.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Tissue metal concentration analyses: At the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of the 5 000 and 15 000 ppm groups. Hepatic iron levels were significantly lower in exposed females at the 9- and 15-month interim evaluations and in 5 000 and 15 000 males at the 15-month interim evaluation. Tissue concentrations of manganese in the brain (except 1 500 and 5 000 ppm females at 15 months), kidney, and pancreas (except 1 500 males at 9 months and 1 500 ppm females at 15 months) of exposed groups were significantly greater those of controls.

Details on results:

The study suggests equivocal evidence of carcinogenicity in male and female mice based on marginally increased incidences of thyroid gland follicular cell adenoma and significantly increased incidences of follicular cell hyperplasia.

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Effect level:

540 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Effect level:

700 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Effect level:

540 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Conclusions:

In this study equivalent to OECD 453, a NOAEL of 5 000 ppm can be considered for males, which is equal to approx. 540 mg/kg body weight. Subsequently, the LOAEL for males is determined to be 15 000 ppm which is equal to 1800 mg/kg body weight. For females, a NOAEL of 1 500 ppm can be considered, which is equal to 200 mg/kg body weight.

Executive summary:

In a chronic toxicity study similar to guideline OECD 453, manganese sulphate monohydrate (97% purity) was administered to young adult B6C3F1 mice (70/sex/dose) in diet at dose levels of 0, 1 500, 5 000 and 15 000 ppm for 103 weeks.

Lower mean body weights were observed in female mice (6% at 1 500 ppm; 9% at 5 000 ppm and 13% at 15 000 ppm. Furthermore, focal squamous hyperplasia of the forestomach in male and female mice at 15 000 ppm was observed. In the thyroid gland, the incidence of follicular dilatation increased significantly in 15 000 ppm males and 5 000 and 15 000 ppm females. There was equivocal evidence of carcinogenic activity of the test item in male and female mice, based on a marginally increased incidence of thyroid gland follicular cell adenoma and a significantly increased incidence of follicular cell hyperplasia.

Based on the results the oral NOAEL was determined with 200 mg/kg body weight for the females and 540 mg/kg body weight for males.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across statement (see IUCLID section 13).

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across statement in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

mortality observed, treatment-related

Description (incidence):

Survival of 15 000 ppm male rats was significantly lower than that of the controls. Survival of 1 500 and 5 000 ppm males and all exposed groups of females was similar to that of controls. The significant reduction in survival of 15 000 ppm males was attributed to increased severity of nephropathy and renal failure. The decreased survival did not occur until approximately week 93 of the study.

For survival rates see Table 1 in box 'Any other information on results incl. tables'.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weights of 1 500 and 5 000 ppm male rats exposed to the test item were similar to those of controls. The mean body weights of 15 000 male rats were within 5% of that of controls until week 89. From week 89, the mean body weights ranged from 8% to 13% lower than that of controls. At the end of the 2-year study, the final mean body weight of 15 000 ppm males was 10% lower than that of controls. Mean body weights of exposed females were similar to that of controls throughout the 2-year study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by exposed groups was similar to that by control groups. Rats exposed to 1 500, 5 000, or 15 000 ppm manganese (II) sulfate monohydrate received approximate daily doses of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg (females).

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Values for hematology were generally similar among exposed and control groups at the 9- and 15-month interim evaluations. Slight differences in some parameters between exposed and control groups were not considered related to the ingestion of the test item.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Values for clinical chemistry parameters were generally similar among exposed and control groups at the 9- and 15-month interim evaluations. Slight differences in some parameters between exposed and control groups were not considered related to the ingestion of the test item.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

No test item-related lesions were observed at the 9-or 15-month interim evaluations

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Chronic nephropathy occurred in all male rats examined at both interim evaluations and most of the control and exposed males at the end of the study. The average severity of nephropathy was slightly greater in the high-dose group, but the difference was not statistically significant. Because of the subjective nature of the severity grading, an additional evaluation of the kidney of high-dose and control male rats was performed without knowledge of the previous diagnoses. The result of the additional evaluation confirmed the presence of a marginally increased severity of nephropathy in the high-dose group, and the difference was significant (P=0.04) by a two-sided MannWhitney U test. The severity of nephropathy varied from minimal to marked. Minimal nephropathy was characterized by a few sparsely scattered cortical foci of regenerating tubules with increased epithelial cytoplasmic basophilia and slightly thickened glomerular basement membranes. Nephropathy of mild severity had similar morphologic features, but these features occurred with greater frequency. Also present were occasional dilated tubules filled with homogenous hyaline material and lined by flattened epithelial cells. Nephropathy of moderate to marked severity had similar but more severe and extensive tubule lesions. In addition, variable interstitial fibrosis and mineralization with mononuclear leukocyte infiltration, variable tubule loss and atrophy, and degenerative glomerular changes occurred. In the most severe cases, cystic tubules lined by cuboidal or attenuated epithelial cells were present.
The incidences of several lesions commonly associated ¬with advanced nephropathy and renal failure were significantly increased in 15 000 ppm male rats. These lesions included mineralization of blood vessels (4/52, 10/51, 6/51, 17/52), mineralization of the glandular stomach (8/52, 13/51, 9/51, 23/52), fibrous osteodystrophy of the femur (12/52, 14/51, 12/51,24/52), and parathyroid gland hyperplasia (14/41, 14/46, 12/49, 23/50).

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Pancreas: Hyperplasia or adenoma of the pancreatic islets occurred in a few males in each of the exposure groups but not in the control group (hyperplasia: control, 0/52; 1,500 ppm, 2/50; 5,000 ppm, 2/51; 15,000 ppm, 3/51; adenoma: 0/52, 3/50, 4/51, 3/51; Tables A5 and A1). In addition, a carcinoma of the pancreatic islets was found in one 15,000 ppm male. However, neither the trend test nor pairwise comparisons were significant, and the incidences in each of the dose groups were within the range of NTP historical control groups (adenoma, 0% to 12%; carcinoma, 0% to 6%).
Adrenal Gland: In females, medullary hyperplasia occurred with a significant negative trend and a significantly decreased incidence in the 15 000 ppm group (control 12/50, 1 500 ppm 11/50, 5 000 ppm 6/51, and 15 000 ppm 1/48). Benign pheochromocytomas of the adrenal medulla in males occurred with a significant negative trend, but the decreases were not significant by pairwise comparison (14/52, 17/51, 14/51, and 6/52); the incidence of medullary hyperplasia in exposed males was similar to that of the controls.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Tissue metal concentration analyses: The hepatic iron concentrations for these exposure groups were lower than for controls. 15,000 ppm males had a significantly higher concentration of manganese in the brain and kidney at the 9-month interim evaluation and in the brain, kidney, and pancreas at the 15-month interim evaluation. Copper levels in the kidney of 15,000 ppm males at 9 months and in 15,000 ppm females at 9 and 15 months were significantly greater than those of the controls.

Dose descriptor:

NOAEL

Effect level:

715 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Remarks on result:

other: No adverse effects notified

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

mortality

Dose descriptor:

LOAEL

Effect level:

615 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

mortality

Critical effects observed:

not specified

Table 1: Survival of Rats in the 2 -Year Feed Study

	Control	1 500 ppm	5 000 ppm	15 000 ppm
Males
Animals initially in study	70	70	70	70
9-Month interim evaluation(a)	8	10	10	10
15-Month interim evaluation (a)	10	9	9	8
Moribund	21	24	24	38
Natural deaths	6	10	5	7
Animals surviving t study termination	25	17	22(b)	7
Percent probability of survival at end of study (c)	49	34	43	14
Mean survival (days) (d)	581	573	579	571
Survival analyses (e)	P=0.004	P=0.381	P=0.872	P=0.006
Females
Animals initially in study	70	70	70	70
9-Month interim evaluation(a)	10	10	10	10
15-Month interim evaluation (a)	10	10	9	10
Accidental deaths (a)	0	0	1	0
Moribund	6	11	6	11
Natural deaths	7	2	2	1
Missexed (a)	0	0	0	2
Animals surviving t study termination	37	37	42	36
Percent probability of survival at end of study (c)	74	74	85	75
Mean survival (days) (d)	608	594	596	607
Survival analyses (e)	P=0.004	P=0.381	P=0.872	P=0.006

(a)   Censored from survival analyses

(b)   Includes one animal that died the last week of study

(c)    Kaplan-Meier determinations

(d)   Mean of all deaths (uncensored, censored, and terminal sacrifice)

(e)   The result of the life table trend test (Tarone, 1975) is in the control column, and the results of the life table pairwise comparisons (Cox, 1972) with the controls are in the exposed columns. A negative trend or lower mortality in an exposure group is indicated by N.

Conclusions:

In this study equivalent to OECD 421, a NOAEL of 5 000 ppm can be considered for males, which is equal to approx. 200 mg/kg body weight. Subsequently, the LOAEL for male rats is determined to be 15 000 ppm which is equal to 615 mg/kg body weight. For females, a NOAEL of 15 000 ppm can be considered due to absence of adverse effects, which is equal to 715 mg/kg body weight.

Executive summary:

In a chronic toxicity study similar to guideline OECD 453, manganese sulphate monohydrate (97% purity) was administered to young adult Fischer 344 rats (70/sex/dose) in diet at dose levels of 0, 1 500, 5 000 and 15 000 ppm for 103 weeks.

Mortality occurred at the high dose in males, which was attributed to increased severity of nephropathy and renal failure. Further, lower mean body weights were observed in the high dose in males. No adverse effects were observed in female rats. Based on the results the oral NOAEL was determined with 715 mg/kg body weight for the females and 200 mg/kg body weight for males.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across statement (see IUCLID section 13).

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across statement in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

A few mice in the male and female exposure groups exhibited fight wounds.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One control male mouse and one female mouse receiving 3 130 ppm died of unknown causes during this study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

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 50 000 ppm group was 13% lower than that of the controls. The mean body weight gain of 50 000 ppm females was significantly lower than that of the controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by exposed male and female mice was similar to that by the controls. 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 ppm in females.

Food efficiency:

not examined

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):

The percent hematocrit, hemoglobin concentrations, and mean erythrocyte volumes of 50 000 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.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

The absolute and relative liver weights of 50 000 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.

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Three 50 000 ppm males had mild epithelial hyperplasia and hyperkeratosis of the forestomach.

Histopathological findings: neoplastic:

not specified

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effect

Critical effects observed:

not specified

Conclusions:

In this study, under the given conditions, a NOAEL of 50 000 ppm for females and 25 000 ppm for males can be considered.

Executive summary:

In a sub-chronic toxicity study, manganese sulphate monohydrate (97% purity) was administered to young adult B6C3F1 mice (10/sex/dose) in diet at dose levels of 0, 3 130, 6 250, 12 500, 25 000, and 50 000 ppm for 13 weeks. The absolute and relative liver weights of 50 000 ppm males were significantly lower than those of controls. Three 50 000 ppm males had mild epithelial hyperplasia and hyperkeratosis of the forestomach.

Based on the results the oral NOAEL was determined with 50 000 ppm for the females and 25 000 ppm for males.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across statement (see IUCLID section 13).

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across statement in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

No test item related effects observed.

Mortality:

no mortality observed

Description (incidence):

No rats died during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weight gain in males receiving 3 130 ppm was marginally lower than that of the controls and was significantly lower in the three highest female dose groups (11% at 6 250 ppm; 13% at 12 500 ppm and 17% at 25 000 ppm) than the controls. Final mean body weights of all exposed animals were within 5% of those of the controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by exposed rats was similar to that by the controls. 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. Females ingested an average of 20% more manganese (II) sulfate monohydrate than males in the corresponding exposure groups.

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

Description (incidence and severity):

Neutrophil counts were significantly higher in all exposed male groups, whereas lymphocyte counts were significantly lower in the 6 250, 12 500, and 25 000 ppm groups. In contrast, the total leukocyte counts of 6 250, 12 500, and 25 000 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 6 250, 12 500, or 25 000 ppm. The relationship between these differences and the ingestion of manganese (II) sulfate monohydrate is not clear.

Clinical biochemistry findings:

not examined

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):

Absolute and relative liver weights of all exposed males and of the female 25 000 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.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No test item related effects observed.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Critical effects observed:

not specified

Conclusions:

In this study, under the given conditions, a NOAEL of 12 500 ppm can be considered for female and male rats.

Executive summary:

In a sub-chronic toxicity study, manganese sulphate monohydrate (97% purity) was administered to young adult F344 rats (10/sex/dose) in diet at dose levels of 0, 1 600, 3 130, 6 250, 12 500 and 25 000 for 13 weeks. No rats died during 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 25 000 ppm female rats were significantly lower than those of controls.

Based on the results the oral NOAEL was determined with 12 500 ppm for females and males.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across statement (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

93 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

similar to guideline study, GLP study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2.16 mg/m³

Study duration:

subchronic

Species:

monkey

Quality of whole database:

Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Relevant data for repeated toxicity was not available for the target substance. Thus, data from an appropriate read-across partner (manganese sulphate monohydrate) was used to assess the specific target organ toxicity of dimanganese trioxide (target substance). For further details on read-across justification please refer to IUCLID section 13.

Sub-chronic and chronic oral repeated dose toxicity studies are available, which were conducted within the US NTP programme for manganese sulphate. They do not fully comply with the current respective guidelines due to the lack of e.g. urinalysis data. Instead, clinical signs, body weight development and gross and histopathology examinations were performed. The studies were assessed as of high quality, since they were peer-reviewed by a panel nominated by the US NTP.

In a sub-chronic toxicity study, manganese sulphate monohydrate (97% purity) was administered to young adult B6C3F1 mice (10/sex/dose) in diet at dose levels of 0, 3130, 6250, 12500, 25000, and 50000 ppm for 13 weeks. The absolute and relative liver weights of 50000 ppm males were significantly lower than those of controls. Three 50000 ppm males had mild epithelial hyperplasia and hyperkeratosis of the forestomach. Based on the results, the oral NOAEL was determined to be 50000 ppm for the females and 25000 ppm for males. In a sub-chronic toxicity study in rats, manganese sulphate monohydrate (97% purity) was administered to young adult F344 rats (10/sex/dose) in diet at dose levels of 0, 1600, 3130, 6250, 12500 and 25000 for 13 weeks. No rats died during 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. Based on the results the oral NOAEL was determined with 12500 ppm for females and males.

In a chronic toxicity study conducted similar to guideline OECD 453, manganese sulphate monohydrate (97% purity) was administered to young adult Fischer 344 rats (70/sex/dose) in diet at dose levels of 0, 1500, 5000 and 15000 ppm for 103 weeks. Mortality occurred at the high dose in males, which was attributed to increased severity of nephropathy and renal failure. Further, lower mean body weights were observed in the high dose in males. No adverse effects were observed in female rats. Based on the results, the oral NOAEL was determined to be 15000 ppm in diet (equivalent to 715 mg/kg bw/day) for the females and 5000 ppm in diet (equivalent to 200 mg/kg bw/day) for males (re-calculated values of 334 and 93 mg/kg bw/day dimanganese trioxide).

In a chronic toxicity study conducted similar to guideline OECD 453, manganese sulphate monohydrate (97% purity) was administered to young adult B6C3F1 mice (70/sex/dose) in diet at dose levels of 0, 1 500, 5000 and 15000 ppm for 103 weeks. Lower mean body weights were observed in female mice (6% at 1500 ppm; 9% at 5000 ppm and 13% at 15000 ppm. Furthermore, focal squamous hyperplasia of the forestomach in male and female mice at 15000 ppm was observed. In the thyroid gland, the incidence of follicular dilatation increased significantly in 15000 ppm males and 5 000 and 15000 ppm females. There was equivocal evidence of carcinogenic activity of the test item in male and female mice, based on a marginally increased incidence of thyroid gland follicular cell adenoma and a significantly increased incidence of follicular cell hyperplasia. Based on the results, the oral NOAEL was determined to be 1500 ppm in diet (equivalent to 200 mg/kg bw/day) for the females and 5000 ppm in diet (equivalent to 540 mg/kg bw) for males (re-calculated values of 93 and 252 mg/kg bw/day dimanganese trioxide).

In a sub-chronic inhalation toxicity study, the source substance was administered to 4 – 6 male Rhesus monkeys at concentrations of 0.18, 0.92 and 4.62 mg/m³ via aerosol inhalation for 6 h a day, 5 days a week for 65 exposure days. Detailed clinical observations, body weight, organ weight, hematology and clinical chemistry examinations were conducted. No treatment related toxic effects for clinical observations, body weight, organ weight, hematology or clinical chemistry were observed. Based on the results, the NOAEC can be considered to be 4.62 mg/m³ (re-calculated value of 2.16 mg/m³ dimanganese trioxide).

 

Justification for classification or non-classification

Based on the available data from the read-across partner, the target substance dimanganese trioxide does not warrant classification for specific target organ toxicity in accordance to CLP as no severe toxic effects were observed.