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Carcinogenicity

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Description of key information

The critical component melamine was administered to rats and mice in a daily diet over a period of 103 weeks (NTP, 1983b, Melnick R.L. et al. 1984a). Due to melamine induced formation of bladder stones leading to bladder tumours, the NOAEL is considered to be 2250 ppm for males (150 mg/kg bw/day) and 4500 ppm for females (300 mg/kg bw/day).

Key value for chemical safety assessment

Additional information

Reasons for read across

Melamine phosphate was not tested for carcinogenicity. It is acceptable to derive the systemic toxicity from experimental data of melamine since both melamine and its phosphate salt have a high solubility in water and a log POWof less than 1 and phosphate is an abundant in cells and body fluids. Melamine and melamine phosphate have a similar solubility in water (3.5 – 3.9 g/L at 20°C). In addition, the higher molecular weight of melamine phosphate compared to melamine gives a safety margin.

 

Effects of melamine to urinary bladder

A carcinogenesis bioassay of melamine (NTP, 1983b) was conducted by feeding diets containing 2250 or 4500 ppm melamine to groups of 50 male F344/ N rats and 50 B6C3F, mice of each sex for 103 weeks. Groups of 50 female rats were fed diets containing 4500 or 9000 ppm melamine. Groups of 49 male rats, 50 female rats, 49 male mice, and 50 female mice served as controls.

The predominant effect of melamine in rats was formation of urinary bladder stones in association with bladder tumours in male rats. Moreover, chronic inflammation was significantly increased in the kidney of dosed female rats and is attributed to the administration of melamine.

Acute and chronic inflammation and epithelial hyperplasia of the urinary bladder were found in increased incidence in dosed male mice. However, there was no evidence of bladder tumour development in this species.

 

In another study (Melnick R.L. et al. 1984a) melamine was administered in the diet to F344 rats or B6C3Fj mice for 103 weeks to determine carcinogenic potential. The dose levels of melamine were 2250 or 4500 ppm for male rats and mice of each sex, and 4500 or 9000 ppm for female rats.

Transitional-cell carcinomas in the urinary bladder of male rats occurred at a significantly higher incidence in the high dose group than in the controls. Seven of the eight male rats with transitional-cell carcinomas of the urinary bladder also had bladder stones. There was a significant association between bladder stones and bladder tumours in male rats fed with high doses of melamine. Urinary bladder tumours were not observed in the low-dose male rat group, while bladder stones were observed in one rat in this group. In female rats, chronic inflammation of the kidney was observed at an increased incidence in both the low and high dose groups.

 

Discussion

The primary toxicity of melamine is based on the formation of bladder stones. This is also the primary toxic effect for other substances, e.g dimethyl terephthalate and terephthalic acid. In several studies (especially related to melamine and also for the other compounds) it was shown that the irritative stimulation by calculi leads to proliferative lesions in the urinary tract which can result in the formation of tumours in the urinary bladder. As no genotoxic properties were shown for melamine, it can be assumed that the formation of bladder calculi is the only effect which leads to the formation of bladder calculi.

The production of calculi is a high-dose-only phenomenon. Therefore, the extrapolation to humans from the rodent bioassay should be dependent on dose requirements for formation of calculi rather than any type of statistical extrapolation to lower doses.

However, it must be presumed that calculus formation poses some carcinogenic risk to humans. However, the doses frequently required to form calculi are several orders of magnitude greater than the doses expected for human exposure.

 

Conclusion

Due to melamine induced formation of bladder stones leading to bladder tumours, the NOAEL is considered to be 2250 ppm for males (150 mg/kg bw/day) and 4500 ppm for females (300 mg/kg bw/day).

 

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for carcinogenicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for carcinogenicity under Regulation (EC) No. 1272/2008.