Magnesium hydroxide

Carcinogenicity

Description of key information

There is no toxicological data available to assess the carcinogenic potential of the target substance magnesium hydroxide. The carcinogenic potential is assessed by a read-across approach considering information from studies conducted with magnesium chloride hexahydrate and magnesium sulphate. For more details on the read-across justification, please refer to IUCLID section 13.

Based on the available data from the source substances, the target substance magnesium hydroxide can be considered as non-carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

No abnormal clinical signs were observed throughout the test period. Treatment with magnesium chloride had no effect on survival rate.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

Treatment with magnesium chloride had no effect on survival rate.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of females from week 8 until end of study were lower in group fed 2 % magnesium chloride than in the control group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intake of females in the high-dose group were higher than that in the male group.

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):

No treatment-related changes were noted.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

In females of the high-dose group, a significant increase was observed in the level of serum albumin.

Endocrine findings:

not specified

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related changes were noted.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In females of the high-dose group, significant increases were observed in the absolute and relative weights of the brain and in the relative weights of the heart and kidneys. In the same group, a significant decrease was noted in the absolute liver weights. The other sporadic effects were not dose related and were therefore not regarded as being of biological significance.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The highest incidence of non-neoplastic lesions was observed for cystic endometrial hyperplasla, which occurred in about 59, 38 and 34% of female in the control and low- and high-dose groups, respectively. Other lesions seen in mice of both sexes occurred in the lymph nodes, spleen, thyroid, lung, forestomach, kidney and ovary. However, the development of biologically significant lesions attributable to the treatment was not observed.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The only tumour that showed an increased incidence, although not strictly in a dose-related manner, was a malignant lymphoma/leukaemla in females and to a lesser extent in males. In male mice, a dose-related decrease in the incidence of hepatocellular carcinoma was observed. A decrease in the incidence of hyperplastlc (neoplastic) nodules in the liver was also noted in males of treated groups but the differences from the control value were not significant.

Two cases of bone osteosarcomas were noted in females of the high-dose group, and sarcomas of the uterus were observed in both control and treated groups. These tumours sometimes metastasized to the lung, liver and a number of other organs.

Relevance of carcinogenic effects / potential:

With the exception of a significant decrease in the incidence of liver tumours among males in the high-dose group, no differences were noted in the tumour incidence between the treated and control animals. Therefore magnesium chloride is not carcinogenic to mice and may also decrease tumour incidence.

Key result

Dose descriptor:

NOAEL

Effect level:

2 810 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

3 930 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Table 1: Food, water and magnesium chloride intake in B6C3F1 mice

		Average daily intake			Total intake
Sex	Dose (%)	Food (g/mouse/day)	Water (g/mouse/day)	MgCl2 6H2O (g/kg body weight/day)	MgCl2 6H2O (g/kg body weight)
Males	0	5.3	6.4	-	-
	0.5	5.1	5.9	0.57	453
	2.0	5.1	6.2	2.81	1894
Females	0	5.3	4.9	-	-
	0.5	5.4	4.9	0.73	496
	2.0	5.9	5.5	3.93	2646

Conclusions:

Magnesium chloride hexahydrate is not carcinogenic to mice when administered in the diet.

Executive summary:

In a carcinogenicity study, groups of 50 male and 50 female B6C3F1 mice were given magnesium chloride hexahydrate (98% purity) at dose levels of 0 (control), 0.5 and 2% in the diet for 96 weeks, after which all animals received the control diet for 8 weeks and were then necropsied. In females of the high-dose group, a decrease in body weight was observed. However, survival rates did not differ between the treatment and control groups for males or females and clinical signs and urinary, hematological or serum clinical chemistry parameters showed no treatment-related effects. Therefore, this change was considered not to be of biological significance.

On histological examination, tumors were mainly found in the skin/subcutis, liver and lymphatic system. However, with the exception of a significant decrease in the incidence of liver tumors among males of the high-dose group, no differences were noted in the tumor incidence between the treated and control animals Thus, the study described here clearly shows a lack of carcinogenicity of magnesium chloride given to B6C3F1 mice in the diet.

Under the condition of the study, the NOAEL for female and male mice was, respectively 3930 mg/kg bw/day (2% in feed) and 2810 mg/kg bw/day (2% in feed) which is equal to 1127 mg/kw bw/day and 806 mg/kg bw/day magnesium hydroxide.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

806 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Mass median aerodynamic diameter (MMAD):

>= <= µm

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

48% (10/21), 41% (9/22) and 30% (6/20) of rats died within 1 year after end of exposure in the controls, the short whisker, and long whisker groups, respectively.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The growth curves of the groups were almost identical during all observed periods.

Food consumption and compound intake (if feeding study):

not examined

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

Endocrine 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):

No significant differences were found among the groups

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the rats with four-week exposure and a one-year clearance period, one pulmonary adenoma was found, in the short whisker exposure group. Segmental calcifications of the pulmonary artery were found more often in the short whisker and long whisker exposure groups than in the control group, although the difference was not significant (p < 02). In the rats with one year clearance after the one-year exposure, several neoplastic lesions were found in both experimental and control groups. Two, two, and one pulmonary adenoma occurred in the short whisker, long whisker, and the control groups, respectively. One of them showed a pronounced epithelial atypia, but this was not conclusive of carcinoma. The number of adenomas in the exposure groups was not significantly greater than that of the control group. Hepatocellular adenoma and carcinoma occurred somewhat more often in the long whisker group than in the control groups.

Details on results:

In the rats examined one year after exposure, neoplastic lesions were found in both experimental and control groups. Two were found in the short whisker group, two in the long whisker group and one in the control group. The number of adenomas was not significantly greater in the exposure groups than in the control group.

Relevance of carcinogenic effects / potential:

The incidence of hepatocellular adenoma and carcinoma in the long whisker group tended to be higher than in the control group. But the differences were not significant. The major cause may be age because these rats were more than two years old at the end of the experiments.
The main reason why the histopathological findings were not significantly different between the control and exposure groups may be because the magnesium hydroxide is so soluble, as confirmed by the intratracheal study. If no whiskers exist in the body, there should be no effects. When large amounts of the whiskers are present at one time, however, some biological effects may be possible. In the inhalation study, the incidence of tumors in the exposure group was larger but not significantly so than that in the controls. The experimental data could not be compared directly with theirs because the experimental conditions-namely, exposure methods, dose, and animals-were different. In work environments, however, inhalation is the major route of exposure, so the results are relevant to the understanding of the health effects of magnesium sulphate whiskers.

Dose descriptor:

NOAEC

Remarks on result:

not determinable because of methodological limitations

Conclusions:

Chronic inhalation exposure of rats to the test material (long or short magnesium sulphate whiskers) did not reduce the survival rate. There were no differences in growth curves, organ weights or histopathological findings in lungs between treated and control animals. The occurrence of adenoma and carcinoma a year after chronic exposure to magnesium sulphate whiskers was not significant between exposed and control rats.

Executive summary:

In a study from Hori et al., male Wistar rats were exposed to magnesium sulphate whiskers by inhalation for six hours a day, five days a week, for four weeks (sub-chronic study), or for one year (chronic study) to clarify the biological effects of the whiskers. There were few whiskers detected in the rat lungs even at one day after the exposure, suggesting that they are dissolved and eliminated rapidly from the lungs. To measure the clearance rate of the whiskers from the lungs, an intratracheal instillation was performed in golden hamsters. The half-life of the whiskers in the lung was determined as 17-6 minutes by temporally measuring the magnesium concentration up to 80 minutes after the instillation. There were no differences in survival rate, growth curves, organ weights or histopathological findings in lungs between treated and control animals. A histopathological examination indicated a frequent occurrence of adenoma and carcinoma in the year after chronic exposure, but it was not significantly different between exposed and control rats.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data, Magnesium hydroxide does not warrant classification for carcinogenicity.

Additional information

A valid carcinogenicity study has been conducted in B6C3F1 mice with the analogous substance magnesium chloride hexahydrate via the dietary route. This study is regarded as relevant for magnesium hydroxide as well, as the toxicity is expected to result from the magnesium ion and oral absorption of both salts is considered comparable as magnesium hydroxide will be converted at the pH of the stomach to magnesium chloride (magnesium ions) as well. The study revealed no test substance related increase in tumor incidence compared to controls and concluded that the test substance was not carcinogenic under the testing conditions. No other toxicologically relevant findings apart from reduced body weight in females of the high dose group were observed in this study up to the highest dose level of 2810 mg/kg bw per day in males and 3930 mg/kg bw in females corresponding to 1127 mg/kw bw/day and 806 mg/kg bw/day of magnesium hydroxide.

In a chronic inhalation study with male Wistar rats, biological effects of magnesium sulphate as the occurrence of adenoma and carcinoma were investigated. No significant difference between exposed and control rats was observed.

From these observations it can be concluded that magnesium hydroxide is not considered to have a carcinogenic potential.