Manganese dinitrate

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 the registered substance, manganese dichloride, is not carcinogenic. 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”.

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 Annex VI, Directive 67/548/EEC (DSD), 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