Registration Dossier

Administrative data

Description of key information

Melamine was administered to rats and mice in a daily diet over a period of 103 weeks (NTP, 1983b) and 13 weeks (Melnick R.L. et al. 1984a), respectively. Due to melamine induced formation of urany bladder stones, the NOAEL is considered to be 750 ppm for males (72 mg/kg bw/day) and 15000 ppm for females (1400 mg/kg bw/day).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
72 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reasons for read across

Melamine phosphate was not tested for repeated dose toxicity. 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 very low log POW . In addition, the toxicity of melamine is higher than the toxicity of phosphate. Whereas the high dose effect of phosphates are related to a disturbance in calcium homeostasis, the target organ of melamine is the kidney. The acidic environment of the stomach increases dissociation into melamine and phosphate. Phosphate is an abundant in cells and body fluids and is part of natural food. Excessive oral doses of phosphate are known to interfere with calcium homeostasis, the maximum tolerable daily intake of phosphates was set at 70 mg/kg bw and represents the amounts present in natural food and food additives (WHO Food Additives Series No. 17 - Phosphoric acid and phosphate salts). Overall, the no-observed effect level for melamine is consideered adequate for melamine phosphate. 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 13 weeks to determine its toxicological profile. The dose levels of melamine in the subchronic studies ranged from 750 to 18,000 ppm for rats, and 6000 to 18,000 pprn for mice.

Increased incidences of urinary bladder stones and hyperplasia of the bladder epithelium were observed in male rats fed diets containing melamine. Ulceration of the bladder epithelium was observed in mice of both sexes. The distribution of these toxic lesions was not correlated statistically with the distribution of urinary bladder stones.

An four-week feeding study with male weanling rats showed a NOAEL of 2000 ppm (ca 240 mg/kg bw) (Heck et al 1985).

 

Discussion

The primary toxicity of melamine is based on the formation of bladder stones. In several studies (especially related to melamine and also for the other compounds) it was shown that the irritating stimulation of calculi leads to proliferative lesions in the urinary tract which can result in the formation of tumours in the urinary bladder.

The circumferential relationship of the prostate gland to the urethra in males may increase the tendency for obstruction of the urethra and thereby account for the apparent difference in susceptibility between male and female rats in developing bladder stones.

Hyperplasia of the transitional epithelium is a common response to mechanical irritation from a foreign body in the urinary bladder of rats or mice. When male F344 rats were fed diets containing terephthalic acid or dimethyl terephthalate, extensive hyperplasia of the transitional epithelium occurred only in the urinary bladders that contained bladder stones (Chin et al., 1981).

 

Conclusion

For melamine, studies ranging from 14-day to chronic studies, with rats and mice were reported. The NTP-studies confirmed that the main effects of melamine are urinary bladder stones and hyperplasia of the transitional epithelium of the bladder, in case uroliths were present. These effects occurred in male rats, starting in the 13 weeks study above a dose of 750 mg/kg feed (equivalent to 72 mg/kg bw/day), in a dose dependent way. Other effects (lower body weight gain, kidney lesions) were observed only at ca. 10 times higher doses and above.

The NOAEL in rats of 72 mg/kg bw/day, based on urinary stones in male rats, is not a clear NOAEL, as there was 1/10 stone in the control group, which is strange, as urinary bladder stones in rats are seldom, and 2/10 stones in the lowest dose of 750 ppm. The difference between control and lowest dose is not statistically significant, but as there is a clear dose response relation, some doubts remain, first on the reliability of the results and second, on the NOAEL.Notably, the NOAEL of the chronic rat study is126 mg/kg bw/day and this study was also performed by NTP.

The US FDA has calculated from the results of the NTP-study a NOAELrat,13w, oral of 63 mg/kg bw/day. No data as to how FDA derived this value is available, but a NOAEL of 63 mg/kg/day seems more appropriate than 72 mg/kg/day.

NOAELs in relation to the exposure duration for rats are:

14 days: 417 mg/kg bw/day

28 days. 240 mg/kg bw/day

13 weeks: 72 respectively 63 mg/kg bw/day

2 Years: 126 mg/kg bw/day

TheNOAELrat,13w, oral of 63 mg/kg bw/daywas taken as - worst case - basis for the calculation of the long-term DNEL of melamine phosphate.

 

No experimental data is available for repeated dermal or inhalation exposure. As neither melamine nor phosphate undergo metabolism, no route-specific toxicity profile is expected.

 

 


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: urinary bladder

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 repeated dose toxicity 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 repeated dose toxicity under Regulation (EC) No. 1272/2008.