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EC number: 442-080-3 | CAS number: -
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Test procedure is not following a guideline, nevertheless the report is scientifically acceptable. Justification for read across approach is explained in the endpoint summary.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 984
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 983
Materials and methods
- Principles of method if other than guideline:
- Two separate 13 -week studies were conducted in male and female F344 rats: the first study included 12 animals in male and female, while the second included 10 animals per group. The dose levels ranged from 6000 to 18000 ppm in the first study and from 750 to 12000 ppm in the second one. Animals were observed daily for mortality and signs of morbidity. Body weights and feed consumption data were collected weekly. Necropsies were performed on all animals.
- GLP compliance:
- not specified
Test material
Reference
- Name:
- Unnamed
- Type:
- Constituent
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 (Frederick, MD).
- Age at study initiation: 5-6 weeks old.
- Housing: four per Polycarbonate cage, changed twice per week.
- Bedding: Absorb-Dri@ heat- treated hardwood chips (Lab Products, Inc.).
- Diet: ad libitum, Purina Laboratory Chow.
- Water: ad libitum, acidified with hydrochloric acid to pH 2.5.
- Acclimation period: approximately 2 weeks before the test began.
ENVIRONMENTAL CONDITIONS
- Temperature: 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@ twin- shell blender equipped with an intensifier bar. Prepared diets containing 100000 ppm melamine were analyzed at Midwest Research Institute and were found to be stable for 2 weeks at temperatures up to 45 °C.
Test diets were stored in the freezer for no longer than 3 weeks. - Duration of treatment / exposure:
- 91 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
First Study: 0, 6000, 9000, 12000, 15000 and 18000 ppm (0, 560, 850, 1100, 1400 and 1700 mg/kg/day for male rats; 0, 560, 880, 1200, 1400 and 1600 mg/kg/day for female rats)
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
Second Study: 0, 750, 1500, 3000, 6000 and 12000 ppm (0, 72, 150, 300, 590 and 1300 mg/kg/day for male rats and 0, 84, 150, 300, 600 and 1300 mg/kg/day for female rats)
Basis:
nominal in diet
- No. of animals per sex per dose:
- First Study: 12 male and 12 female rats
Second Study: 10 male and 10 female rats - Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATION
Observed daily for mortality and signs of morbidity.
BODY WEIGHT
Body weight data collected weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE
Feed consumption data collected weekly. - Sacrifice and pathology:
- Those animals that were judged moribund were killed and necropsied.
At the end of the 91-day studies, survivors were killed with carbon dioxide, and necropsies were performed on animals that survived to the end of the studies and on all animals found dead, unless precluded in whole or in part by autolysis or cannibalization.
GROSS PATHOLOGY: Yes.
In the first 13-week study, the following tissues were examined for control and high-dose groups: gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction (rib), thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, oesophagus, stomach, duodenum, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder (mice), pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, nasal cavity, brain, and pituitary gland.
In the second study, the kidneys and urinary bladders of all animals were examined microscopically.
Tissues were preserved in 10 % neutral buffered formalin, embedded in paraffin, sectioned, and stained with haematoxylin and eosin. Only the kidney and urinary bladder of lowest-dose animals were examined microscopically.
HISTOPATHOLOGY: Yes
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- first suty: one male at 18000 ppm and two males at 6000 ppm died. Second study: none of the rats died
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- first suty: one male at 18000 ppm and two males at 6000 ppm died. Second study: none of the rats died
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- first study: depressed by more than 8 % in males and females at 12000 ppm. Second study: depressed by more than 10 % at 6000 and 12000 ppm
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- first study: at 18000 ppm 80-90 % that of the control. Second study: not affected
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- examined only in the second study
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- both first and second studies stones found in the urinary bladders
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- both first and second studies epithelial hyperplasia of the urinary bladder
- Details on results:
- CLINICAL SIGNS AND MORTALITY
_First study: one male receiving 18000 ppm and two males receiving 6000 ppm died.
_Second study: none of the rats died
BODY WEIGHT AND WEIGHT GAIN
_First study: mean body weight gain in males and females receiving 12000 ppm or more was depressed by more than 8 % when compared with controls.
_Second study: mean body weight gain was depressed by more than 10 % when compared with controls for male rats receiving 6000 and 12000 ppm, but no depression was observed in any group of dosed females.
FOOD CONSUMPTION AND COMPOUND INTAKE
_First study: feed consumption by rats receiving 18000 ppm was approximately 80 - 90 % that of controls.
_Second study: feed consumption was not affected by incorporation of melamine in the feed.
GROSS PATHOLOGY
_First study: stones were found in the urinary bladders of most dosed male rats, and the incidence was dose related; 25 % or more in the two highest dosed groups has stones.
_Second study: 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. Stones were present even in the male group receiving 750 ppm.
HISTOPATHOLOGY
_First study: histopathologic evaluations were performed on 10 animals of either sex from the high-dose (18000 ppm), low-dose(6000 ppm) and control groups. Diffuse epithelial hyperplasia of the urinary bladder was found in 8/ 10 females receiving 18000 ppm melamine, while in animals receiving 6000 ppm melamine, focal ppm 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.
_Second study: hyperplasia of the transitional epithelium of the bladder was present in 1/10 male rats receiving 3000 ppm, in 3/10 receiving 6000 ppm, and in 9/9 receiving 12000 ppm melamine. The hyperplastic epithelial changes, which were found only in male rats that had bladder stones, were accompanied by prominent capillaries and occasional oedema and scattered mast cells in the submucosa. Kidney changes in male rats were minimal. 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 (2/10 controls, 3/ 10 receiving 750 ppm, 4/ 10 receiving 1500 ppm, 10/10 receiving 3000 ppm, 8/10 receiving 6000 ppm and 10/10 receiving 12000 ppm).
URINALYSIS
_Second study: rine samples were analyzed from male and female rats receiving 750 ppm melamine and compared with urine samples from control rats. 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
- Dose descriptor:
- NOAEL
- Effect level:
- 750 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: (estimated melamine consumption for each animal was 72 mg/kg/day)
- Dose descriptor:
- NOAEL
- Effect level:
- 12 000 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: (estimated melamine consumption for each animal was 1200 mg/kg/day)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
FIRST STUDY RESULTS
Survival, mean body weight and feed consumption of rats in the first study
Dpse (ppm) |
Survival* (week of death) | Mean Body Weights [g] | Weight Change relative to respective controls** [%] | Feed consumption (% of control) | ||
Initial | Final | Gain | ||||
Males | ||||||
0 | 12/12 | 88 | 297 | 209 | ||
6000 | 10/12 (8, 10) | 87 | 287 | 200 | -4 | 96 |
9000 | 12/12 | 90 | 288 | 198 | -5 | 92 |
12000 | 12/12 | 81 | 276 | 185 | -11 | 94 |
15000 | 12/12 | 92 | 259 | 167 | -20 | 90 |
18000 | 11/12 (7) | 87 | 255 | 168 | -20 | 88 |
Females | ||||||
0 | 12/12 | 87 | 191 | 104 | ||
6000 | 12/12 | 79 | 181 | 102 | -2 | 87 |
9000 | 12/12 | 83 | 187 | 104 | 0 | 94 |
12000 | 12/12 | 83 | 179 | 96 | -8 | 94 |
15000 | 12/12 | 82 | 174 | 92 | -12 | 84 |
18000 | 12/12 | 81 | 165 | 84 | -19 | 78 |
* Number surviving/number per group
** Weight Change Relative to Controls = [(Weight Change (Dosed Group) -Weight Change (Control Group)) / Weight Change (Control Group)] * 100
Incidence of rats with urinary bladder stones or granular material
Dpse (ppm) | Number of Rats with Urinary Bladder Stones |
Males |
|
0 | 0/12 |
6000 | 6/12 |
9000 | 8/12 |
12000 | 12/12 |
15000 | 10/12 |
18000 | 12/12 |
Females |
|
0 | 0/12 |
6000 | 0/12 |
9000 | 0/12 |
12000 | 0/12 |
15000 | 3/12 |
18000 | 5/12 |
SECOND STUDY RESULTS
Survival, mean body weight and feed consumption of rats in the second study
Dpse (ppm) |
Survival* (week of death) |
Mean Body Weights [g] |
Weight Change relative to respective controls*** [%] |
Feed consumption (% of control) |
||
Initial |
Final ** |
Gain |
||||
Males |
||||||
0 |
10/10 |
120 |
312 |
192 |
||
750 |
10/10 |
120 |
302 |
182 |
-5 |
96 |
1500 |
10/10 |
119 |
302 |
183 |
-5 |
92 |
3000 |
10/10 |
120 |
299 |
179 |
-7 |
94 |
6000 |
10/10 |
119 |
290 |
171 |
-11 |
90 |
12000 |
10/10 |
119 |
276 |
157 |
-18 |
88 |
Females |
||||||
0 |
10/10 |
95 |
176 |
81 |
||
750 |
10/10 |
94 |
179 |
85 |
+5 |
100 |
1500 |
10/10 |
95 |
179 |
84 |
+4 |
91 |
3000 |
10/10 |
93 |
175 |
82 |
+1 |
87 |
6000 |
10/10 |
95 |
176 |
81 |
0 |
89 |
12000 |
10/10 |
93 |
173 |
80 |
1 |
92 |
* Number surviving/number per group
**Weight on day 84
*** Weight Change Relative to Controls = [(Weight Change (Dosed Group) -Weight Change (Control Group)) / Weight Change (Control Group)] * 100
Incidence of rats with urinary bladder stones or granular material
Dpse (ppm) | Number of Rats with Urinary Bladder Stones | Hyperplasia of the Bladder Epithelium |
Males |
||
0 | 1/10 | 0/10 |
750 | 2/10 | 0/10 |
1500 | 5/10 | 0/10 |
3000 | 7/10 | 1/10 |
6000 | 9/10 | 3/10 |
12000 | 9/9 | 9/9 |
Females |
||
0 | 0/10 | 0/10 |
750 | 0/10 | 0/10 |
1500 | 0/10 | 0/10 |
3000 | 0/10 | 0/10 |
6000 | 0/10 | 0/10 |
12000 | 0/10 | 0/10 |
Applicant's summary and conclusion
- Conclusions:
- NOAEL male: 750 ppm
NOAEL female: 12000 ppm - Executive summary:
test item was administered in the diet to F344 rats for 13 weeks (subchronic) to determine its toxicological profile.
Two separate 13 -week studies were conducted in male and female F344 rats: the first study included 12 animals in male and female, while the second included 10 animals per group. The dose levels ranged from 6000 to 18000 ppm in the first study and from 750 to 12000 ppm in the second one.
Animals were observed daily for mortality and signs of morbidity. Body weights and feed consumption data were collected weekly. Moribund animals and animals that survived to the end of the 13-week study were killed by CO2 asphyxiation. Necropsies were performed on all animals, unless precluded by autolysis or cannibalization.
Compound-related lesions were observed in the urinary tract. Most noticeable was the development of uroliths (urinary bladder stones), which occurred at a greater frequency in males than females. Increased incidences of urinary bladder stones and hyperplasia of the bladder epithelium were observed.
Conclusion
NOAEL male: 750 ppm
NOAEL female: 12000 ppm
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