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EC number: 255-449-7
CAS number: 41583-09-9
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).
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
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.
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
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.
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
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.
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).
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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