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EC number: 255-449-7 | CAS number: 41583-09-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- no examination of blood (hematology and clinical biochemistry), no ophthalmological examinations were performed, no information about the determination of organ weights is given
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Reference Type:
- publication
- Title:
- Urolithiasis and bladder carcinogenicity of melamine in rodents
- Author:
- Melnick R.L. et al.
- Year:
- 1 984
- Bibliographic source:
- Toxicol. Appl. Pharmacol., 72, 292-303
- Reference Type:
- secondary source
- Title:
- Joint Assessment of Commodity Chemicals, No. 1 Melamine CAS: 108-78-1
- Author:
- unknown
- Year:
- 1 983
- Bibliographic source:
- ECETOC
- Reference Type:
- secondary source
- Title:
- Melamine
- Author:
- Trochimowicz H. J. et al.
- Year:
- 2 001
- Bibliographic source:
- Patty´s Toxicology, 5th Edition, Vol.4
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- NTP Thirteen-Week toxicity study.
Two studies using different dose levels were described. The second study was conducted to determine a no effect level for the formation of bladder stones. - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Melamine
- EC Number:
- 203-615-4
- EC Name:
- Melamine
- Cas Number:
- 108-78-1
- Molecular formula:
- C3H6N6
- IUPAC Name:
- 1,3,5-triazine-2,4,6-triamine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Frederick Cancer Research Center
- Age at study initiation: 5-6 weeks
- Weight at study initiation: Animals assigned to cages such that the average cage weights were approximately the same
- Housing: 4 rats/cage
- Water (e.g. ad libitum): ad libitum (acidified with hydrochloric acid to pH 2.5)
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 -26 °C
- Humidity (%): 30 - 70%
Administration / exposure
- Route of administration:
- oral: feed
- Details on oral exposure:
- DIET PREPARATION
Test diets were prepared by first mixing a small amount of PurinaB Lab Chow and the required amount of melamine with a mortar and pestle and then adding this premix to the required amount of animal meal and mixing for 10 to 30 minutes in a Patterson-Kelly@ twinshell blender equipped with an intensifier bar.
Test diets were stored in the freezer for no longer than 3 weeks.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prepared diets containing 100 000 ppm melamine were found to be stable for 2 weeks at temperatures up to 45°C; samples were extraceted with boiling water and analyzed by HPLC
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- continuously
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- estimated melamine consumption, 1 st study
- Dose / conc.:
- 6 000 ppm
- Remarks:
- estimated melamine consumption, 1 st study
males/females: 560 mg/kg bw/day
- Dose / conc.:
- 9 000 ppm
- Remarks:
- estimated melamine consumption, 1 st study
males: 850 mg/kg bw/day
females: 880 mg/kg bw/day
- Dose / conc.:
- 12 000 ppm
- Remarks:
- estimated melamine consumption, 1 st study
males: 1100 mg/kg bw/day
females: 1200 mg/kg bw/day
- Dose / conc.:
- 15 000 ppm
- Remarks:
- estimated melamine consumption, 1 st study
females: 1400 mg/kg bw/day
- Dose / conc.:
- 18 000 ppm
- Remarks:
- estimated melamine consumption, 1 st study
males: 1700 mg/kg bw/day
females: 1600 mg/kg bw/day
- Dose / conc.:
- 0 ppm
- Remarks:
- estimated melamine consumption, 2nd study
- Dose / conc.:
- 750 ppm
- Remarks:
- estimated melamine consumption, 2nd study
males: 72 mg/kg bw/day
females: 84 mg/kg bw/day
- Dose / conc.:
- 1 500 ppm
- Remarks:
- estimated melamine consumption, 2nd study
males/females: 150 mg/kg bw/day
- Dose / conc.:
- 3 000 ppm
- Remarks:
- estimated melamine consumption, 2nd study
males/females: 300 mg/kg bw/day
- Dose / conc.:
- 6 000 ppm
- Remarks:
- estimated melamine consumption, 2nd study
males: 590 mg/kg bw/day
females: 600 mg/kg bw/day
- Dose / conc.:
- 12 000 ppm
- Remarks:
- estimated melamine consumption, 2nd study
males/females: 1300 mg/kg bw/day
- No. of animals per sex per dose:
- 1st study: 12
2nd study: 10 - Control animals:
- yes, concurrent no treatment
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes (weekly)
2nd study only: Urine samples collected from each cage were centrifuged and the sediment fractions were examined microscopically.
(At day 65, 5 rats of either sex fed 750 ppm melamine and two control rats of each sex were placed in metabolism cages and fasted overnight. Urine samples collected from each cage were cetnrifuged and the dediment fractions were examined microscopically) - Sacrifice and pathology:
- GROSS PATHOLOGY/HISTOPATHOLOGY:
1st study:
necropsies performed on all animals;
following tissues examined histologically in controls and animals in highest dosed groups:
gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary glands. salivary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction (rib), thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach,
duodenum, jejenum, ileum, colon, mesenteric lymph nodes, liver, gallbladder (mice), pancreas, spleen, kidneys, adrenals, bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, nasal cavity, brain, and pituitary. For lowest dose group, only kidney and urinary bladder examined.
2nd study:
necropsoies performed on all animals;
Kidney and urinary bladder of all animals examined microscopically
Results and discussion
Results of examinations
- Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 1st study: One male rat receiving 18,000 ppm and two males receiving 6,000 ppm died (cf. Table 1)
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 1st study: Mean body weight gain in males and females receiving 12,000 ppm or more was depressed by more than 8% when compared with controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 1st study: Feed consumption by rats receiving 18,000 ppm was approximately 80%-90% that of controls.
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1st study: Stones were found in the urinary bladders of most dosed male rats, and the incidence was dose related (cf. Table 2). Twenty-five percent (3/ 12) or more females in the two highest dosed groups had stones.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 1st study: Histopathologic evaluations were performed on 10 animals of either sex from the high-dose (18,000 ppm), low-dose (6,000 ppm), and control groups.
18,000 ppm: Diffuse epithelial hyperplasia of the urinary bladder was found in 8/ 10 males and 2/ 10 females
6,000 ppm: focal epithelial hyperplasia was observed in only 1 / 10 males and in none of the females. The urinary bladders of animals from other dosed groups were not examined microscopically. No other compound-related histopathologic effects were observed. - Histopathological findings: neoplastic:
- not examined
- Details on results:
- Results for the 2nd Study:
CLINICAL SIGNS AND MORTALITY
None of the rats died
BODY WEIGHT AND WEIGHT GAIN
Mean body weight gain was depressed by more than 10% when compared with controls for male rats receiving 6,000 and 12,000 ppm, but no depression was observed in any group of dosed females (Table 3).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Feed consumption was not affected by incorporation of melamine in the feed.
GROSS PATHOLOGY/HISTOPATHOLOGY
Other than stones in the bladder of dosed male rats, no compound-related effects were observed at necropsy. The incidence of stones in the urinary bladder of male rats was dose related (Table 4). Stones were present even in the male group receiving 750 ppm.
Males:
750 ppm: Bladder stones
1,500 ppm: Bladder stones
3,000 ppm: Bladder stones, Hyperplasia of the transitional epithelium of the bladder was present in 1/10 male rats
6,000 ppm: Bladder stones, Hyperplasia of the transitional epithelium of the bladder was present in 3/10 male rats
12,000 ppm: Bladder stones, Hyperplasia of the transitional epithelium of the bladder was present in 9/9 male rats
The hyperplastic epithelial changes, which were found only in male rats that had bladder stones, were accompanied by prominent capillaries and occasional edema and scattered mast cells in the submucosa.
Kidney changes in male rats were minimal.
Females:
There was no evidence of urinary bladder stones or hyperplasia of the bladder epithelium in any groups of dosed female rats, but dose-related calcareous deposits were observed in the straight segments of the proximal tubules in female rats:
0 ppm: 2/10
750 ppm: 3/ 10
1,500 ppm: 4/ 10
12,000 ppm: l0/ 10
URINANALYSIS:
Urine samples were analyzed from male and female rats receiving 750 ppm melamine and compared with urine samples from control rats (Table 5).
There were no differences in the urine samples that could be attributed to the presence of melamine in the feed. Microscopic examination of the urine did not provide any evidence of melamine crystalluria.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 72 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: urinary bladder stones/Hyperplasia of bladder epithelium in males
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 400 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: based on the formation of urinary bladder stones and reduced body weights observed in the first study (refers to 15000 ppm)
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 500 ppm
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 1: 1st study: Survival, mean body weights and feed consumption of rats
Mean Body Weights (g) |
||||||
Dose (ppm) |
Survival (a) (Week of death) |
Initial |
Final |
Gain |
Weight Change relative to controls (%) (b) |
Feed consumption (% of control) |
Males |
||||||
0 |
12/12 |
88 |
297 |
209 |
||
6,000 |
10/12 (8, 10) |
87 |
287 |
200 |
-4 |
96 |
9,000 |
12/12 |
90 |
288 |
198 |
-5 |
92 |
12,000 |
12/12 |
91 |
276 |
185 |
-11 |
94 |
15,000 |
12/12 |
92 |
259 |
167 |
-20 |
0 |
18,000 |
11/12 (7) |
87 |
255 |
168 |
-20 |
88 |
Females |
||||||
0 |
12/12 |
87 |
191 |
104 |
||
6,000 |
12/12 |
79 |
181 |
102 |
-2 |
87 |
9,000 |
12/12 |
83 |
187 |
104 |
0 |
94 |
12,000 |
12/12 |
83 |
179 |
96 |
-8 |
94 |
15,000 |
12/12 |
82 |
174 |
92 |
-12 |
84 |
18,000 |
12/12 |
81 |
165 |
84 |
-19 |
78 |
(a) Number surviving/number per group
(b) ((Weight change dosed group – weight change control group)/weight change control group) X 100
Table 2: 1st study: Incidence of rats with urinary bladder stones or granular material
Dose (ppm) |
No of rats with urinary bladder stones |
|
Males |
||
0 |
0/12 |
|
6,000 |
6/12 |
|
9,000 |
8/12 |
|
12,000 |
12/12 |
|
15,000 |
10/12 |
|
18,000 |
12/12 |
|
Females |
||
0 |
0/12 |
|
6,000 |
0/12 |
|
9,000 |
0/12 |
|
12,000 |
0/12 |
|
15,000 |
3/12 |
|
18,000 |
5/12 |
Table 3: 2nd study: Survival, mean body weights and feed consumption of rats
Mean Body Weights (g) |
||||||
Dose (ppm) |
Survival (a) (Week of death) |
Initial |
Final (b) |
Gain |
Weight Change relative to controls (%) (c) |
Feed consumption (% of control) |
Males |
||||||
0 |
10/10 |
120 |
312 |
192 |
||
750 |
10/10 |
120 |
302 |
182 |
-5 |
86 |
1,500 |
10/10 |
119 |
302 |
183 |
-5 |
87 |
3,000 |
10/10 |
120 |
299 |
179 |
-7 |
89 |
6,000 |
10/10 |
119 |
290 |
171 |
-11 |
84 |
12,000 |
10/10 |
119 |
276 |
157 |
-18 |
86 |
Females |
||||||
0 |
10/10 |
95 |
176 |
81 |
||
750 |
10/10 |
94 |
179 |
85 |
+5 |
100 |
1,500 |
10/10 |
95 |
179 |
84 |
+4 |
91 |
3,000 |
10/10 |
93 |
175 |
82 |
+1 |
87 |
6,000 |
10/10 |
95 |
176 |
81 |
0 |
89 |
12,000 |
10/10 |
93 |
173 |
80 |
-1 |
92 |
(a) Number surviving/number per group
(b) Weight at day 84
(c) ((Weight change dosed group – weight change control group)/weight change control group) X 100
Table 4: 2nd study: Incidence of rats with urinary bladder stones and hyperplasia of the bladder epithelium
Dose (ppm) |
No of rats with urinary bladder stones Dose (ppm) |
Hyperplasia of the Bladder Epithelium |
Males |
||
0 |
1/10 |
0/10 |
750 |
2/10 |
0/10 |
1,500 |
5/10 |
0/10 |
3,000 |
7/10 |
1/10 |
6,000 |
9/10 |
3/10 |
12,000 |
9/9 |
9/9 |
Females |
||
0 |
0/10 |
0/10 |
750 |
0/10 |
0/10 |
1,500 |
0/10 |
0/10 |
3,000 |
0/10 |
0/10 |
6,000 |
0/10 |
0/10 |
12,000 |
0/10 |
0/10 |
Applicant's summary and conclusion
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.
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