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EC number: 255-449-7
CAS number: 41583-09-9
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).
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
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).
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
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).
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
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.
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
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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