Manganese dichloride

Carcinogenicity

Description of key information

An extensive review of literature (Assessment of Genotoxicity and Carcinogenicity of inorganic-forms of Manganese, MHRP 2009) concluded through weight-of-evidence that  there is insufficient evidence to suggest that inorganic manganese induces cancer in humans. This is further supported by the UK HSE report Manganese and its inorganic compounds (EH64 1999), which concludes that there is no evidence linking Manganese and its inorganic compounds to carcinogenicity in humans. The Scientific Committee on Occupational Exposure Limits (SCOEL 2009) states “data on carcinogenicity mutagenicity and genotoxicity are inconclusive and inadequate to establish a definitive position on the carcinogenicity on manganese and its compounds".

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

well-documented guideline study under GLP. The justification for read-across from manganese sulphate to manganese dichloride is based on the fact that both substances are soluble and both substances, in their solubilised form will contain Mn2+ cations which is the constituent part of both substances which is expected to be the entity more likely to cause an effect than the accompanying anions which is not likely to play any part in the toxicity. Mn2+ cations in this case are likely to enter the cells in equal amounts in both cases.

Justification for type of information:

See the read-across report attached in Section 13.

Reason / purpose for cross-reference:

other: read-across target

Principles of method if other than guideline:

Groups of 70 male and 70 female mice were fed diets containing 0, 1, 500, 5,000, or 15,000 ppm manganese (II) sulphate monohydrate for 103 weeks. The level of manganese in the diet received by controls was approximately 92 ppm. As many as 10 rats per group were evaluated after 9 months and 15 months of chemical exposure.

GLP compliance:

yes

Remarks:

FDA GLP( 21 CFR, Part 58)

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Frederick Cancer Research Facility (Frederick, MD).
- Age at study initiation: approximately 41 days
- Housing: Polycarbonate cage (Lab products, Inc., Garfield, NJ). Cages were rotated every 2 weeks. Bedding: Heat-treated hardwood chips (PWI, Inc., Loweville, NY
- Diet : NIH-07 open formula meal rat diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum. (NIH-07 diet contains 60 g manganous oxide per
- Water :Automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6 - 23.9 °C
- Humidity (%): 35 - 65 %
- Air changes (per hr): minimum of 10 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours/day

Route of administration:

oral: feed

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dose formulations were prepared by mixing manganese (II) sulphate monohydrate with feed. A premix with manganese (II) sulphate 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.

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Storage temperature of food:Stored in plastic buckets with lids in the dark at 25°C

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulations were analysed every month. All dose formulations were within the specified 10% of the target concentrations throughout the studies. Periodic analyses of the dose formulations of manganese (II) sulphate monohydrate were conducted at the study laboratory and at the analytical chemistry laboratory using spectrophotometric methods.

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

Daily

Dose / conc.:

1 ppm (nominal)

Remarks:

Nominal in diet (Based on average daily feed consumption Males -160, 540, or 1,800 mg/kg bw. Females- 200, 700, or 2,250 mg/kg)

Dose / conc.:

500 ppm (nominal)

Remarks:

Nominal in diet (Based on average daily feed consumption Males -160, 540, or 1,800 mg/kg bw. Females- 200, 700, or 2,250 mg/kg)

Dose / conc.:

5 000 ppm (nominal)

Remarks:

Nominal in diet (Based on average daily feed consumption Males -160, 540, or 1,800 mg/kg bw. Females- 200, 700, or 2,250 mg/kg)

Dose / conc.:

15 000 ppm (nominal)

Remarks:

Nominal in diet (Based on average daily feed consumption Males -160, 540, or 1,800 mg/kg bw. Females- 200, 700, or 2,250 mg/kg)

No. of animals per sex per dose:

70 males and 70 females per dose

Control animals:

other: Yes. The level of manganese in the diet received by controls was approximately 92 ppm.

Details on study design:

- Dose selection rationale: The dose selected for the 2-year NTP study in mice were 1, 500, 5,00, and 15,000 ppm manganese (II) sulphate monohydrate in feed. Dose selection for mice was based on significantly lower body weight gains in exposed males and in 50, 000 ppm females and on significantly lower absolute and relative liver weights in 50,000 ppm males in the 13-week studies.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Initially, weekly during first 13 weeks of study, monthly thereafter, and at interim evaluation.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Initially, weekly during first 13 weeks of study, monthly thereafter, and at interim evaluation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected at the 9- and 15-month interim evaluation for haematology
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals per group
- Parameters examined: Haematology: Erythrocytes, haemoglobin, haematocrit, platelets, mean erythrocyte volume, mean erythrocyte haemoglobin, mean erythrocyte haemoglobin concentration, reticulocytes, nucleated erythrocytes, and leukocyte count and differential.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:Blood was collected at the 9- and 15-month interim evaluation for clinical chemistry
- Animals fasted: No data
- How many animals: 10 animals per group
- Parameters examined: Alanine aminotranferase, aspartate aminotransferase, sorbitol dehydrogenase, blood urea nitrogen, and creatinine.

OTHER: Tissue metal concentration analyses: manganese, iron, copper, and zinc concentration

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes.
Complete histopathology examinations were performed on all 0 and 15,000 animals at the 9- and 15- month interim evaluations and gross lesions examined for the 1,500 and 5,000 ppm groups. Complete histopathologic examinations were performed on all animals at the end of the studies and on all animals that died or were killed moribund during the studies. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone, bone marrow, brain, cecum , colon, and rectum, oesophagus, gallbladder (mice), heart, kidney, liver, lung, mandibular, and mesenteric lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, prostate gland, salivary gland, skin, small intestine, spleen, stomach (forestomach and glandular), testes/epididymis, thymus, thyroid gland, trachea, uterus, and urinary bladder.

Statistics:

See any other information on materials and methods incl. tables

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):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

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:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
Survival of exposed males and females was similar to that of the control groups. No clinical findings were attributed to the administration of manganese (II) sulphate monohydrate.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of exposed males were similar to those of the control group. After week 37, mean body weight 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)
Feed consumption by exposed males and females mice was similar to that of the control groups.

HAEMATOLOGY
Percent haematocrit, haemoglobin concentrations, and erythrocyte counts in 15,000 ppm male mice at the 15 month interim evaluation were greater than those of the control. These slight increases were not consistent with the finding in the 13-week and their significance is uncertain.

CLINICAL CHEMISTRY
No notable differences were observed in the clinical chemistry parameters.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Other than the forestomach effects, the principal lesions in mice associated with ingestion of manganese (II) sulphate monohydrate were found in the thyroid gland. Significant increased incidences of follicular dilatation and focal hyperplasia of the follicular epithelium were found in 15,000 ppm males and exposed females.
In male mice, follicular cell adenomas occurred only in the 15,000 ppm group and at a rate of 6%, as compared to the average rate of 2% and range of 0% to 4% for historical control groups. Furthermore, the incidence of follicular cell adenomas of 10% in 15,000 ppm females was also slightly above the range of 0% to 9% for historical controls. Whilst the incidence of follicular cell adenomas in exposed mice were not significantly greater than those of the controls, the slight increase in incidence relative to the historical control range and supported by the increased incidence of follicular cell hyperplasia was considered equivocal evidence of carcinogenic activity.

OTHER FINDINGS: Tissue metal concentration analyses: At the 9-month and 15-month interim evaluation, tissue concentrations of manganese were significantly elevated in the livers of the 5,000 and 15,000 ppm groups. Hepatic iron level 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 concentration 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 significant greater those of control.

Dose descriptor:

NOAEL

Effect level:

540 other: mg/kg bw

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effects up to the top dose tested.

Remarks on result:

other:

Remarks:

Effect type: other: toxicity and carcinogenicity

Dose descriptor:

NOAEL

Effect level:

700 other: mg/kg bw

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects upto the top dose tested.

Remarks on result:

other:

Remarks:

Effect type: other: toxicity and carcinogenicity

Dose descriptor:

NOAEL

Effect level:

176 other: mg Mn/kg bw/day

Based on:

element

Sex:

male

Basis for effect level:

other: as above

Remarks on result:

other:

Remarks:

Effect type: other: toxicity and carcinogenicity

Dose descriptor:

NOAEL

Effect level:

227.5 other: mg Mn/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

other: as above

Remarks on result:

other:

Remarks:

Effect type: other: toxicity and carcinogencitiy

Conclusions:

There was equivocal evidence of carcinogenic activity of MnSO4 in male and female B6C3F1 mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia. The ingestion of diets containing MnSO4 was associated with focal squamous hyperplasia of the forestomach in male and female mice, and ulcers and inflammation of the forestomach in male mice. The results are not considered sufficient to classify MnSO4 as carcinogenic, especially considering no evidence in the analogous rat study.

Executive summary:

The carcinogenic potential of manganese sulphate monohydrate was investigated by the National Toxicology Program (NTP) in a study which can be regarded a fully reliable guideline compliant GLP study on chronic toxicity.

During the study, groups of 70 male and 70 female mice were fed diets containing 0, 1500, 5000 or 15000 ppm manganese sulphate for 2 years. Animals were sacrificed after 9, 15 and 24 months for full histopathological evaluation.

Under the conditions of the study survival rates of exposed male and female mice in the 2-year study were similar to those of the control groups. The mean body weights of exposed male mice were similar to that of the control group. Compared to controls, female mice had exposure-related lower mean body weights after week 37, and 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. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to the administration of manganese (II) sulphate monohydrate.

No chemical-related differences between exposed and control groups occurred in haematology or clinical chemistry parameters. 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-month interim evaluation and in 5,000 and 15,000 males and all exposed females at the 15-month interim evaluation.

Incidences of thyroid follicular dilatation and hyperplasia were significantly greater in 15,000 ppm male and female mice than in controls. Follicular cell adenomas occurred in one 15,000 ppm male at the 15-month interim evaluation and in three 15,000 ppm males at the end of the study but not in the lower exposure groups or the control group. Follicular cell adenomas also occurred in two control, one 1,500, and five 15,000 ppm female mice at the end of the study. It is uncertain if the slightly increased incidence of follicular cell adenoma is related to the ingestion of manganese (II) sulphate monohydrate.

The incidences of focal hyperplasia of the forestomach epithelium were significantly greater in the 15,000 ppm male and exposed female groups. The hyperplasia was associated with ulcers and inflammation in some mice, particularly males.

Finding from the study show equivocal evidence of carcinogenic activity of manganese (II) sulphatemonohydrate in male and female mice, based onthe marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

176 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

GLP and Guideline compliant carcinogencity studies avaialable on the read across substance..

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

On review of the information on the carcinogenic potential of inorganic manganese it is concluded that there is insufficient evidence to warrent classification of the substance as a carcinogen, therefore, in accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the substance does not require classification with respect to carcinogenicity.

In accordance with the criteria for classification as defined in Regulation 1272/2008, the substance does not require classification with respect to carcinogenicity.

Additional information

An extensive review of literature was conducted to analyse the carcinogenic potential of manganese and its inorganic compounds (Assem et al. 2011)

The most robust and relevant study identified was a 2 year NTP carcinogenicity study, meeting the OECD 451 guidelines, (NTP 1993) in which Fischer 344 rats and B6C3F1 mice were fed diets containing MnSO₄.H₂O at 0, 1500, 5000, or 15,000 mg/kg of diet. Overall, dietary intakes were 60, 200, or 615 mg/kg bw/d and 70, 230, or 715 mg/kg bw/d in male and female rats, respectively, and 160, 540, or 1800 mg/kg bw/d and 200, 700, or 2250 mg/kg bw/d in male and female mice, respectively. Male rats in the highest dose group developed a higher incidence of advanced renal disease resulting in significantly lower survival, attributed to ingestion of MnSO4.H2O. No treatment-related increase in the incidence of any neoplasm was reported in rats of either gender. However, an increase in thyroid gland follicular dilatation and hyperplasia and a marginal increase in follicular-cell adenomas (males: 3/50, 6%; females: 5/51, 10%) were reported in mice at the highest dose, compared with concurrent controls (males: 0%, females: 4%) and historical controls (males: 0–6%, females: 0–9%). An increased incidence of focal hyperplasia of the forestomach epithelium was also observed in exposed mice.

The study found equivocal evidence in mice of a possible carcinogenic effect on the thyroid in the form of a marginal increase in the incidence of thyroid-gland follicular-cell adenoma and significant increases in the incidence of follicular-cell hyperplasia and follicular dilation at the highest dose (achieved dosage of 1800 and 2250 mg/kg bw/d, in males and females respectively). The incidence of thyroid adenoma in the mice was at the upper limit of the historic control range in males and marginally above the historic control range in females. Focal hyperplasia of the forestomach was also noted in the treated mice, although this was associated with ulcerative and inflammatory changes. In contrast, no evidence of any treatment-related neoplastic or preneoplastic effects were noted in the thyroid or other organs of rats at the somewhat lower achieved dosages of up to 615 and 715 mg/kg bw/d in males and females, respectively.

Given the current data on Mn, it is not possible to postulate with any degree of confidence either the mechanism of thyroid neoplasia in mice or the basis for the difference in response noted between rats and mice. However, it is of interest to note that there is evidence that exposure to inorganic Mn compounds produce changes in the metabolic profile of a number of organs (including liver, adrenals, and brain) in various animal species (IEH 2004). For example, changes in hepatic cytochrome P-450, cytochromeb5, NADPH cytochromecreductase (Deimling and Schnell 1984), monoamine oxidase, adenosine deaminase (Nishiyama et al. 1977), tyrosine aminotransferase, and tryptophan oxygenase activities (Shukla et al. 1980) were all identified as being modified by Mn in various experiments. Thus, it is possible that a species-specific effect on thyroid hormone metabolism may exist, possibly involving changes in liver enzyme profile. Bearing in mind that the significance of rodent thyroid cancers to human risk assessment has also been widely questioned (Hill et al. 1998; Poirier et al. 1999; IARC 2001; Lewandowski et al. 2004) and in this case the thyroid effect was observed in only one rodent species, the significance to humans is uncertain.

A number of additional experimental studies in animals have also investigated the carcinogenic potential of Mn compounds or the interaction of these compounds with other (carcinogenic) compounds. However, the majority of these studies employed parenteral injection routes and all are considered to be of limited quality and robustness. These studies are outlined below for the purpose of completeness.

In a study by Furst (1978), groups of male and female F344 rats (25 of each gender per group) were given oral doses of Mn powder (10 mg/rat given twice a month for 24 treatments) or intramuscular (im) injections of MnO₂ (10 mL MnO₂ in trioctanoin/rat/month for 9 months) and members of groups of female Swiss albino mice (n=25) were given a single im injection of Mn powder (10 mg) or 6 im injections of MnO2 at a total dose of 15 mg or 30 mg. No treatment-related increase in tumors was reported, although the study was poorly documented and full details of treatment regimes and study durations were not presented. Furthermore, pathology was performed on only a limited number of tissues and clinical signs were not reported. The findings from this study are therefore considered to be of limited value.

In one other study, strain A mice were given ip injections of MnSO₄ up to 3 times a week for 30 weeks to give total doses of 0, 132, 330, or 660 mg/kg bw for each group (Stoner 1976). Animals were sacrificed after 30 weeks and the lungs were assessed for the presence of tumors. A significant increase in the number of lung tumors was reported at the highest dose (1.20 tumors/animal) compared with controls saline (0.42 tumors/animal). However, subsequent studies have questioned the validity of this short-term test design and choice of animal model. For example, in a study by Smith and Witschi (1984), only 5 out of a total of 18 known human carcinogens were unequivocally positive in a Strain A mouse lung tumor assay.

Two studies (Sunderman 1976; Sunderman et al. 1980) investigated the potential protective action of Mn against some chemically induced tumors. The earlier study investigated effects on Fischer 344 rats of Mn dust upon the incidence of sarcomas induced at the injection site by a single injection of 1 mg nickel subsulfide (αNiS2). Injection-site sarcomas were identified 2 years after injection in 77% (23/30) of rats given a single im injection of αNiS2 (1.2 mg). However, co-administration of αNiS2 with Mn dust (median particle diameter 1.6 μm) containing 94% Mn resulted in a reduction in the incidence of sarcomas to only 7% after 2 years. Importantly, no sarcomas occurred in the group given Mn dust alone. The underlying mechanism of action of this protective effect is unclear, but isotopic experiments suggest that Mn dust may affect the subcellular distribution of Ni without affecting its kinetics (Sunderman 1976). In the second study, Sunderman et al. (1980) showed that the incidence of injection site sarcomas was 17/20 in each group of Fischer 344 rats given 0.6 or 1.2 mg benzo[a]pyrene (BaP) alone. However the number of tumors was reduced to 5/17 in rats given combined doses of 0.6 mg BaP with 4.4 mg Mn dust, and 10/19 in rats given 1.2 mg BaP with 4.4 mg Mn dust; treatment with Mn dust alone did not elicit development of any tumors. In contrast to this evidence for an apparently protective effect of Mn co-administration against the tumorogenic effect of BaP, a further experiment reported in this paper showed that Mn exerted no effect on the induction of local sarcomas by 7,12-dimethylbenz[a]anthracene (0.6 mg) or BaP when the Mn was injected at a different site from the co-injectant. Given the limitations in the experimental designs and the route of administration by im injection, these studies are not considered relevant to the assessment of Mn carcinogenesis.

While some of these additionalin vitro, in vivo, and human volunteer studies suggest that Mn can induce inflammatory responses in the lung, epidemiological studies have not indicated an increased risk of lung cancer among workers occupationally exposed to Mn; this is in contrast to certain other metals, such as Cr and Ni (IARC 1990). The available limited epidemiological studies do not provide any clear evidence that either occupational or environmental exposure to inorganic Mn is associated with an increased cancer risk.

In conclusion,there is insufficient evidence to indicate that inorganic Mn exposure produces cancer in animals or humans.

 

References:

Deimling, M. J., and Schnell, R. C. 1984. Effect of manganese on the hepatic microsomal mixed function oxidase enzyme system in the rat.Fundam. Appl. Toxicol.4: 1009–1018

 

Furst, A. 1978. Tumorigenic effect of an organomanganese compound on F344 rats and Swiss albino mice.J. Natl. Cancer Inst.60: 1171–1173

 

Hill, R. N., Crisp, T. M., Hurley, P. M., Rosenthal, S. L., and Singh, D. V. 1998. Risk assessment of thyroid follicular cell tumors.Environ. Health Perspect.106: 447–57

 

IARC. 2001.Some thyrotropic agents.IARC monographs on the evaluation of carcinogenic risks to humans, Vol. 79. Lyon, France.

 

IARC. 1990.Chromium, nickel and welding.IARC monographs on the evaluation of carcinogenicrisks to humans, Vol. 49. Lyon,France.

 

IEH. 2004.Occupational exposure limits: Criteria document for manganese and inorganic manganese compounds.Available at:http://www.cranfield.ac.uk/health/researchareas/environmenthealth/ieh/ieh%20publications/w17.pdf

 

Lewandowski, T. A., Seeley, M. R., and Beck, B. D. 2004. Interspecies differences in susceptibility to perturbation of thyroid homeostasis: A case study with perchlorate.Regul.Toxicol. Pharmacol.39: 348–62

 

National Toxicology Program. 1993.Toxicology and carcinogenesis studies of manganese (ii) sulfate monohydrate (CAS no. 10034-96-5) in F344/N rats and B6C3F1 mice (Feed studies).Available at: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr428.pdf

 

Nishiyama, K., Suzuki, Y., Fujii, N., Yano, H., Ohnishi, K., and Miyai, T. 1977. Biochemical changes and manganese distribution in monkeys exposed to manganese dioxide dust.Tokushima J. Exp. Med.24: 137–45

 

Smith, L. H., and Witschi, H. P. 1984. Studies on the mouse lung tumour assay as a screen for carcinogens.Toxicologist4: 37

 

Stoner, G. D. 1976. Test for carcinogenicity of metallic compounds by the pulmonary tumor response in strain A mice.Cancer Res.36: 1744–47

 

Sunderman, F. W., Jr. 1976. Effects of manganese on carcinogenicity and metabolism of nickel subsulfide.Cancer Res.36: 1790–1800

 

Sunderman, F.W., Jr., McCully, K. S., Taubman, S. B., Allpass, P. R., Reid, M. C., and Rinehimer, L. A. 1980. Manganese inhibition of sarcoma induction by benzo[a]pyrene in rats.Carcinogenesis1: 613–20

Justification for selection of carcinogenicity via oral route endpoint:
Read-across is to the substance MnSO4, chloride ions are not intrinsically more toxic than sulphate ions or vice versa, and in the milleu in the stomach the anion takes on little importantance, paticularly give the excess of chloride. Therefore in accordance with Annex XI section 1.1, because existing data can be used, a new study specifically with MgCl2 is not scientifically necessary.