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Toxicological information

Carcinogenicity

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Description of key information

A key 24-month carcinogenicity study was available in rats for ferric chloride by drink water administration at concentrations of 0.25 and 0.5%, corresponding with mean dose levels of 170 and 320 mg/kg bw in males and 188 and 336 mg/kg bw in females. NOAEL for systemic toxicity was 170/188 mg/kg in males/females, whereas NOAEL for carcinogenicity was 320/336 mg/kg bw in males/females. For iron sulfide, similar NOAEL values are assumed.

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
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The cumulative mortality at termination in males of the 0.5% group was significantly decreased compared with the control value
Mortality:
mortality observed, treatment-related
Description (incidence):
The cumulative mortality at termination in males of the 0.5% group was significantly decreased compared with the control value
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
significantly lower than those of the corresponding control groups, especially at highest dose
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
significantly lower than those of the control groups
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no specific lesions considered to be attributable to ferric chloride treatment
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no statistically significant differences in the overall tumor incidence between control and treated groups of either sex
Details on results:
CLINICAL SIGNS AND MORTALITY
The cumulative mortality at termination in males of the 0.5% group was significantly decreased compared with the control value.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of the treated males and females were significantly lower than those of the
corresponding control groups.
The final body weight of the treated groups were significantly lower than those of the control groups.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
The mean daily water intake of the treated groups was significantly lower than those of the control groups. The mean daily ferric chloride intakes in the 0.25 and 0.5% groups calculated from the water intake were, respectively, 169.7 and 319.7 mg/kg body weight/day in males, and 187.9 and 336.0 mg/kg body weight/day in females.

HISTOPATHOLOGY: NON-NEOPLASTIC
Various types of non-neoplastic lesions were observed in each group. Age-related chronic nephropathy was present in all groups. Testicular atrophy, accompanied by oligospermia or aspermia, was seen in almost all male rats of all groups. Ductular proliferation and altered cell foci, which are known to be common in ageing F344 rats (Burek, 1978; Eustis et al., 1990), were observed in the livers of both control and treated rats. In sections stained with Berlin blue, although slight staining was seen in various organs/tissues from treated and control rats, no marked increase in pigment deposition was observed in any organ or tissue of the 0.5% group. There were no specific lesions considered to be attributable to ferric chloride treatment.


HISTOPATHOLOGY: NEOPLASTIC (if applicable)
The first autopsy was performed at wk 49, when a female rat in the 0.5% group was killed in extremis because of a malignant fibrous histiocytoma. This rat and all of the animals that survived beyond this week were included in the effective numbers, with the exception of rats for which histopathological examinations could not be performed owing to advanced autolysis.
There were no statistically significant differences in the overall tumor incidence between control and treated groups of either sex. Tumors were found in many organs or tissues in all groups, including the control group. In males of all groups, tumours of the testis were most frequent, followed by neoplasms of the haematopoietic organs, adrenal gland, mammary gland, thyroid, pituitary and pancreas. In females, tumors of the uterus, pituitary, haematopoietic organs, mammary gland, adrenal gland and thyroid were common. Tumors were also detected in the other organs or tissues in all groups of both sexes, but the incidence was very low. None of the treated groups demonstrated a significant increase in the incidence of any specific tumor over that in the corresponding control group. All tumors observed in this study were similar to those that are known to occur spontaneously in this strain of rats (Goodman et al., 1979; Haseman et al., 1990; Solleveld et aL,1984).

References:
Burek J. D. (1978) Pathology of Aging Rats. Edited by J. D. Burek. pp. 58-70. CRC Press, Boca Raton, FL. Cerutti P. A. (1985) Prooxidant states and tumor promotion. Science 227, 375-381.
Eustis S. L., Boorman G. A., Harada T. and Popp J. A. (1990) Liver. In Pathology of the Fischer Rat. Edited by G. A. Boorman, S. L. Eustis, M. R. Elwell, C. A.
Montgomery, Jr and W. F. MacKenzie. pp. 71-94. Academic Press, San Diego, CA
Goodman D. G., Ward J. M., Squire R. A., Chu K. C. and Linhart M. S. (1979) Neoplastic and non-neoplastic lesions in aging F344 rats. Toxicology and Applied Pharmacology 48, 237-248.
Haseman J. K., Arnold J. and Eustis S. L. (1990) Tumor incidences in Fischer 344 Rats: NTP historical data. In Pathology of the Fischer Rat. Edited by G. A. Boorman, S. L. Eustis, M. R. Elwell, C. A. Montgomery, Jr and W. F. MacKenzie. pp. 555-564. Academic Press, San Diego, CA.
Solleveld H.A., Haseman J. K. and McConnel E. E. (1984) Natural history of body weight gain, survival, and neoplasia in the F344 rat. Journal of the National Cancer Institute 72, 929-940.

Relevance of carcinogenic effects / potential:
The design and conduct of the present ferric chloride bioassay was in accordance with guidelines for carcinogenicity tests and the evaluation of resultant data (National Cancer Institute, 1976; National Toxicology Program, 1984; Odashima, 1980). The highest dose currently recommended is that which, when given for the duration of the chronic study, is just high enough to elicit signs of minimal toxicity without significantly altering the normal lifespan of the animal through toxic effects other than carcinogenicity. In this study, the maximal tolerated dose was based on the weight-gain decrement observed in the subchronic study: since the highest dose in carcinogenicity studies should not cause more than a 10% reduction in weight gain, a dose level of 0.5% was selected as the maximal tolerated dose. Body weigths at the end of the study in 0.25 and 0.5% treated animals were 94 and 94% in males and 90.5 and 85.4% in females. However during the 3rd part of the study, body weigths were more prominently decreased at the highest groups compared to the control group, therefore the MTD was reached at the highest dose level.
From the above results, it was concluded that ferric chloride exerts no carcinogenic activity in F344 rats when administered as a 0.25 or 0.5% solution continuously in the drinking water for up to 2 year.
Key result
Dose descriptor:
NOAEL
Effect level:
0.5 other: 0.5% in drinking water
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: carcinogenicity
Key result
Dose descriptor:
NOAEL
Effect level:
320 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: carcinogenicity
Key result
Dose descriptor:
NOAEL
Effect level:
336 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: carcinogenicity
Dose descriptor:
NOAEL
Effect level:
170 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: systemic toxicity
Dose descriptor:
NOAEL
Effect level:
188 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: systemic toxicity
Conclusions:
It is concluded that under the conditions of this experiment, read-across substance ferric chloride exerts no carcinogenic potential in F344 rats.
Executive summary:

The carcinogenicity of read-across substance ferric chloride, a compound that is used as a food additive, a haemostatic or treatment for hypochromic anaemia, was examined in F344 rats of both sexes. It was dissolved in distilled water at levels of 0, 0.25 or 0.5%, and groups of 50 male and 50 female rats were given one of these solutions ad libitum as their drinking water for up to 2 year. The dose levels corresponded with a mean test article intake of 170 and 320 mg/kg bw in males and 188 and 336 mg/kg bw in females. The mean body weights of the treated rats were lower than control group values for both males and females, especially at the highest dose level where maximum tolerated dose level was reached. A variety of tumors developed in all groups, including the control group, but all these neoplasms were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumor was found in the treated groups of either sex, up to systemic mean dose level of 320/336 mg/kg bw in males/females. Thus it is concluded that under the conditions of this experiment, read-across substance ferric chloride exerts no carcinogenic potential in F344 rats. The mean dose level of 170/188 mg/kg bw in males/females was considered NOAEL for systemic toxicity.

 

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
170 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
High quality study

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The carcinogenicity of ferric chloride, a compound that is used as a food additive, a haemostatic or treatment for hypochromic anaemia, was examined in F344 rats of both sexes. It was dissolved in distilled water at levels of 0, 0.25 or 0.5%, and groups of 50 male and 50 female rats were given one of these solutions ad libitum as their drinking water for up to 2 year. The dose levels corresponded with a mean test article intake of 170 and 320 mg/kg bw in males and 188 and 336 mg/kg bw in females. The mean body weights of the treated rats were lower than control group values for both males and females, especially at the highest dose level where maximum tolerated dose level was reached. A variety of tumors developed in all groups, including the control group, but all these neoplasms were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumor was found in the treated groups of either sex, up to systemic mean dose level of 320/336 mg/kg bw in males/females. Thus it is concluded that under the conditions of this experiment, ferric chloride

exerts no carcinogenic potential in F344 rats. The mean dose level of 170/188 mg/kg bw in males/females was considered NOAEL for systemic toxicity.

 

From a systemic viewpoint, iron trichloride can also be considered to be a (worst case) read across source chemical for iron sulfide. In contrast to iron dichloride, there is no direct toxicological comparison for the acute toxicity between iron trichloride and iron sulfde. Therefore a benefit factor for iron sulfide is not discussed in this case. Therefore, the systemic NOAEL for chronic toxicity of iron sulfide is assumed to be similar, i.e. 170/188 mg/kg bw for males/females respectively.

Justification for classification or non-classification

Iron sulfide does not have to be classified for carcinogenicity according theCLP Regulation No. 1272/2008 of 16 December 2008.