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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Reasons for read across

Melamine phosphate was not tested for toxicity to reproduction. 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. In addition, the higher molecular weight of melamine phosphate compared to melamine gives a safety margin.

 

Effects of melamine to reproduction

In the 13 week repeated dose toxicity studies conducted with rats and mice and in the carcinogenicity/repeated dose toxicity study in rats (NTP 1983 and American Cyanamid Company 1983) a pathological and histopathological examination of the reproductive organs (testes, prostate, seminal vesicles uterus and ovaries) was done. In the carcinogenicity /repeated dose toxicity study also the organ weights of the testes and the ovaries were taken.

 

In none of these studies an effect on these organs was observed. Regarding the effect of the test substance on weanling and developing animals it was shown that weanlings are more susceptible to melamine with regard to the formation of bladder calculi.

 

Discussion

The results of these studies indicate that melamine causes no toxicity to reproduction. But it is assumed that the mating behaviour of the animals might be affected by the formation of bladder stones.

The main factor for the higher susceptibility of melamine in weanlings is the dose received by the animals (this was also shown at the investigation of other bladder calculi forming substances e.g. dimethyl terephthalate, terephthtalic acid and diethylene glycol). When ingesting a test chemical at fixed concentration in the diet, weanling rats receive a higher dose of the agent than do adult rats, owing to their greater food intake per unit of body weight.

Regarding these information it is assumed that the main effect of melamine is the bladder stone formation. As already discussed in section 7.7 this is a high-dose only effect and the calculation of a DNEL for humans should be based on the dose necessary for the formation of bladder stones in humans.

Due to these reasons in context with reasons for animal welfare, the need of a two-generation toxicity study seems not to be justified.


Short description of key information:
The assessment of fertility is based on the histopathological examination of the reproductive organs in rats from a carcinogenicity study and a repeated dose study performed with melamine (NTP 1983). In none of these studies an effect on these organs was observed. Therefore, the NOAEL for fertility is considered to be 1700 mg/kg bw/day (highest dose tested).

Effects on developmental toxicity

Description of key information
The effects of melamine on development were tested in a prenatal toxicity study (BASF 1996). There were no effects on the gestational parameters and no signs of developmental toxicity up to and including 15,000 ppm (highest dose). Especially no indications of teratogenicity were found. Therefore, the NOAEL for maternal toxicity is considered to be 400 mg/kg body weight/day, for teratogenicity 1060 mg/kg bw/day. This is considered representative of melamine phosphate.
Additional information

Reasons for read across

Melamine phosphate was not tested for 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 a log POWof less than 1 and phosphate is an abundant in cells and body fluids. In addition, the higher molecular weight of melamine phosphate compared to melamine gives a safety margin.

 

Effects of melamine on development

Melamine was tested for its prenatal toxicity in Wistar rats (BASF 1996). The test substance was administered as a constant homogeneous addition to the food to 23 – 24 pregnant female rats/group at concentrations of 1,500; 4,500 and 15,000 ppm (136; 400; 1060 mg/kg bw/day) on day 6 through day 16 post coitum. The study was performed following OECD testing guideline 414 and the principles of GLP.

 

Under the conditions of this study, the administration of melamine to pregnant female rats during organogenesis elicited signs of maternal toxicity at 15,000 ppm. Maternal toxicity was substantiated by reduced food consumption, impairments in body weight/body weight gain, decreased corrected body weight gain and clinical symptoms like haematuria, indrawn flanks and piloerection.Nearly all signs of maternal toxicity proved to be fully reversible after cessation of the test substance administration. The carcass weight and the corrected body weight gain, however, showed still some impairment at terminal sacrifice.

There were no substances related findings on the gestational parameters and no signs of developmental toxicity up to and including 15,000 ppm (ca, 1060 mg/kg bw/day, highest dose). Especially no indications of teratogenicity were found.

 

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 reproductive 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 reproductive toxicity under Regulation (EC) No. 1272/2008. No experimental data is available for effects via lactation.