Registration Dossier
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 253-575-7 | CAS number: 37640-57-6
- 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

Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attachment
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attachment
3. ANALOGUE APPROACH JUSTIFICATION
see attachment
4. DATA MATRIX
see attachment
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- three-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: summarized iinformation from reliable sources
- Principles of method if other than guideline:
- Three-generation-study in rats
- GLP compliance:
- not specified
- Remarks:
- indicated in OECD SIDS to be GLP-compliant
- Limit test:
- no
- Species:
- rat
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- no data
- Route of administration:
- oral: drinking water
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- P0: A minimum of 100 days from 36 days of age to mating
F1 and F2: 120 days after weaning
F3: 4 weeks - Details on mating procedure:
- premating procedure: A minimum of 100 days
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Treatment was initiated at 36 days of age for parents and continued for a minimum of 100 days before mating.
- Frequency of treatment:
- daily
- Details on study schedule:
- Parents were mated to produce two litters (Fia, Flb).
Weanlings from the Flb litter were randomly selected as parents for the next generation and continued on treatment for an additional
120 days. These animals were subsequently mated to produce 2 litters (F2a, F2b).
Weanlings from the F2b litter were randomly selected as parents for the last generation. These animals were also administered
sodium cyanurate for 120 days and mated to produce one litter (F3a).
Randomly selected F3a progeny continued on cyanurate treatment for an additional 4 weeks and were then sacrificed. - Dose / conc.:
- 400 mg/L drinking water
- Dose / conc.:
- 1 200 mg/L drinking water
- Dose / conc.:
- 5 375 mg/L drinking water
- Remarks:
- highest soluble concentration, ca. 370 mg/kg/day for males and 634 mg/kg/day
for females - No. of animals per sex per dose:
- 12 males
24 females - Control animals:
- yes, concurrent vehicle
- other: sodium hippurate
- Details on study design:
- Where possible, all progeny from various matings were given a post mortem examination.
Organ weight measurements and microscopic examination of tissues (including gonads and gross lesions) were carried out for all parental animals
i.e., selected Fib and F2b progeny and F3a offspring that were sacrificed 4 weeks after weaning. - Parental animals: Observations and examinations:
- mortality, body weight, food consumption, and gestation length.
- Sperm parameters (parental animals):
- no data
- Litter observations:
- mortality, body weights, food consumption litter size, pup survival to weaning, sex ratio, and pup weight.
- Postmortem examinations (parental animals):
- gross pathology and histopathology
- Postmortem examinations (offspring):
- gross pathology and histopathology
- Statistics:
- no data
- Dose descriptor:
- NOAEL
- Effect level:
- >= 5 375 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see remarks on results
- Remarks on result:
- other: A few high-dose cyanurate males did exhibit calculi in the urinary bladder accompanied by microscopic evidence of epithelial hyperplasia or chronic cystitis. These histologic changes were attributed to chronic irritation by the calculi.
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Effect level:
- 5 375 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: See P0 generation
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 5 375 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: See P0
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 5 375 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see P0 generation
- Reproductive effects observed:
- no
Sodium hippurate was provided an equivalent amount of sodium administered to high-dose sodium isocyanurate animals as second control. Weanlings from the F1 and F2 litters were randomly selected as parents for the next generation and continued on treatment. Related litters and F3 offsprings were sacrificed 4 weeks after weaning and organ weight measurements and microscopic examination of tissues were carried out.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- according to guideline
- Guideline:
- OECD Combined Repeated Dose and Reproductive / Developmental Toxicity Screening Test (Precursor Protocol of GL 422)
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- purity 99.8%
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- other: sesame oil
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- females: 14 days before mating to day 3 of lactation
males: 44 days - Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
10, 40, 150 and 600 mg/kg/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Reproductive indices:
- copulation index, fertility index, implantation, implantation index, gestation index, delivery index
- Offspring viability indices:
- live birth index, viability index, sex ratio
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: kidney toxicity
- Remarks on result:
- other: effects on kidneys at 600 mg/kg bw
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- >= 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects
- Critical effects observed:
- no
- Reproductive effects observed:
- no
The parental animals exhibited no alteration in reproductive parameters including the copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation. There were no significant differences in offspring parameters including number of offspring or live offspring, the sex ratio, live birth index, viability index and body weight. No external or visceral abnormalities related to the test substance were detected in any of the offspring. Therefore, NOAEL for parental fertility and offsprings was considered to be 600 mg/kg/day. Parental animals sufferend from adverse effects on kidney at 600 mg/kg bw/d.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: repeated dose toxicity study (13 weeks and carcinogenicity study)
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well-performed investigation with melamine, adresses effects on reproductive organs
- Principles of method if other than guideline:
- repeated dose toxicity study (13 weeks and carcinogenicity study) with examination of reproductive organs
- GLP compliance:
- not specified
- 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.
- Housing: Rats were housed four per cage in polycarbonate cages covered with nonwoven polyester filter sheets. Racks and filters were changed once every 2 weeks. Cages, bedding, and glass water bottles (equipped with stainless steel sipper tubes) were replaced twice per week.
- Diet: Purina Laboratory Chow. Ralston Purina Co. Stainless steel feed containers were changed once per week.
- Water:
First and second studies: Tap water (acidified with hydrochloric acid to pH 2.5).
Third study: ± 1 % ammonium chloride in drinking water.
Test diets, control diets, and tap water were available ad libitum.
- Bedding: Absorb-Dri heat-treated hardwood chips, changed twice per week.
- Acclimation: 2 weeks
- Randomization: Animals assigned to cages by species and sex such that the cage weighs were approximately the same.
ENVIRONMENTAL CONDITIONS
- Temperature, humidity: The temperature in the animal rooms was 22 °- 26 °C and the relative humidity was 30 %-70 %. - Route of administration:
- oral: feed
- Details on exposure:
- DIET PREPARATION
- Mixing appropriate amounts with: Test diets were prepared by first mixing a small amount of Purina B 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.
- Storage temperature of food: Test diets were stored at 4 °C for no longer than 2 weeks. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Prepared diets containing 100 000 ppm melamine were analyzed and were found to be stable for 2 weeks at temperatures up to 45 °C.
Control animals were fed Purina Lab Chow. - Duration of treatment / exposure:
- cf. 7.5.1 and 7.7
- Frequency of treatment:
- cf. 7.5.1 and 7.7
- Remarks:
- Doses / Concentrations:
0, 6000, 9000, 12000, 15000 or 18000 ppm
Basis:
nominal in diet
first study - Remarks:
- Doses / Concentrations:
0, 750, 1500, 3000, 6000 or 12000 ppm
Basis:
nominal in diet
second study - Remarks:
- Doses / Concentrations:
0, 10000 or 18000 ppm
Basis:
nominal in diet
third study - No. of animals per sex per dose:
- FIRST STUDY
- 12 males/12 females
SECOND STUDY
- 10 males/10 females
THIRD STUDY
- 10 males/10 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for mortality and signs of morbidity.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: weekly.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
URINALYSIS: Yes (only study No. 2)
-control animals: 1 male, 2 females.
- low dosed animals (750 ppm): all animals.
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Postmortem examinations (parental animals):
- GROSS PATHOLOGY (study No. 1 - 3): Yes (all animals)
HISTOPATHOLOGY (study No. 1): Yes (all animals control group (0 ppm) and highest dosed group (18000 ppm).
-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
-oesophagus
-stomach
-duodenum
-jejunum
-colon
-mesenteric lymph nodes
-liver
-pancreas
-spleen
-kidneys
-adrenals
-urinary bladder
-seminal vesicles
-prostate
-testes
-ovaries
-uterus
-nasal cavity
-brain
-pituitary
all animals low dose (6000 ppm) group:
-kidney
-urinary bladder
HISTOPATHOLOGY (study No. 2): Yes (all animals)
-kidney
-urinary bladder
HISTOPATHOLOGY (study No. 3): No - Dose descriptor:
- NOAEL
- Effect level:
- >= 18 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects on reproductive organs. Animals suffered from urinary bladder stones and associated systemic toxicity with a LOAEL of 750 ppm (ca 72 mg/kg bw).
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 18 000 ppm
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Remarks on result:
- other: No F1 generation was produced.
- Reproductive effects observed:
- no
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Study period:
- 2016-2017
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: 31 Mar 2017 is scheduled experimental completion date (draft report to QAU)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 28 Jul 2015
- Deviations:
- yes
- Remarks:
- additional investigations for kidney toxicity
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Test substance: white solid
Date of manufacture: 28 Oct 2015
Batch no. 52334524U0
Validity: 15 Sep 2020 - Species:
- rat
- Strain:
- other: Crl:Wl(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: males 10-11 weeks, females 9 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study: no
- Housing: single caging (except for mating; then 1 female with one male; except for rearing dams, then one dam with up to 13 pups)
- Diet ad libitum
- Water ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):20-24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 05-July 2016 To: 30-Aug-2016 (males) and 29-Sept-1016 (females) - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food): Ground Kliba Maintenance diet (Provimi Kliba SA, Switzerland)
- Storage temperature of food: room temperature
The stability of the substance in the diet for at least four days was shown experimentally prior to the beginning ot the study.- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: up to 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individual cages - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Doses were selected based on the results of a 7-day and a 28-day feeding study with melamine cyanurate in rats.
- Duration of treatment / exposure:
- 28 days (males)
58 days (females) - Frequency of treatment:
- daily
- Dose / conc.:
- 660 ppm (analytical)
- Dose / conc.:
- 200 ppm (analytical)
- Dose / conc.:
- 66 ppm (analytical)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- Determination of estrous cycle was done during 14 days after the acclimatization period and prior to the first dosing.
On postnatal day 4, culling will be done so that per litter 4 female and 4 male pups remain until scheduled sacrifice on postnatal day 14. - Positive control:
- not required
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on working days, once daily on weekends and public holidays
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Once a week, and for females on GD 7, 14 and 20, and on PND 4, 7,10 and 13
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Once a week, and for females on GD 7, 14 and 20, and on PND 4, 7,10 and 13
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
OTHER:
Blood is taken from all males at the end of the in-life phase (day 28). Clinical Chemistry values are determined.
Histopathology of kidneys is included and kidney weights are determined.
WATER CONSUMPTION: Once a week, and for females on GD 7, 14 and 20, and on PND 4, 7,10 and 13 - Oestrous cyclicity (parental animals):
- yes
- Reproductive effects observed:
- not specified
Results are not yet available.
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: NTP studies are considered as high quality studies, even if GLP was formally not stated and some standard methods were not applied. The studies are peer reviewed.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: NTP standards
- Deviations:
- yes
- Remarks:
- No haematology and clinical chemistry investigations were performed. No statistical analysis was reported or performed.
- Principles of method if other than guideline:
- Three 13 weeks toxicity studies were performed:
In the first 13-week study, diets containing 0, 6,000, 9,000, 12,000, 15,000, or 18,000 ppm melamine were fed to groups of 12 male and 12 female rats and to groups of 10 male and 10 female mice for 13 weeks.
Two additional 13-week studies were conducted to find a no-effect level for urinary bladder stone formation and to determine the effect of ammonium chloride in the drinking water on stone formation.
In the second 13-week study, groups of 10 rats of either sex were fed diets containing 0, 750, 1,500,3,000,6,000, or 12,000 ppm melamine for 13 weeks. At day 65, five 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 centrifuged and the sediment fractions were examined microscopically.
In a third 13-week study, groups of 10 rats of either sex were fed diets containing 0, 10,000, or 18,000 ppm melamine in the presence and absence of 1% ammonium chloride in the drinking water.
Three 13-weeks toxicity studies were performed.
- GLP compliance:
- not specified
- Limit test:
- no
- 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.
- Housing: Rats were housed four per cage in polycarbonate cages covered with nonwoven polyester filter sheets. Racks and filters were changed once every 2 weeks. Cages, bedding, and glass water bottles (equipped with stainless steel sipper tubes) were replaced twice per week.
- Diet: Purina Laboratory Chow. Ralston Purina Co. Stainless steel feed containers were changed once per week.
- Water:
First and second studies: Tap water (acidified with hydrochloric acid to pH 2.5).
Third study: ± 1 % ammonium chloride in drinking water.
Test diets, control diets, and tap water were available ad libitum.
- Bedding: Absorb-Dri heat-treated hardwood chips, changed twice per week.
- Acclimation: 2 weeks
- Randomization: Animals assigned to cages by species and sex such that the cage weighs were approximately the same.
ENVIRONMENTAL CONDITIONS
- Temperature, humidity: The temperature in the animal rooms was 22 °- 26 °C and the relative humidity was 30 %-70 %. - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Mixing appropriate amounts with: Test diets were prepared by first mixing a small amount of Purina B 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.
- Storage temperature of food: Test diets were stored at 4 °C for no longer than 2 weeks. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Prepared diets containing 100 000 ppm melamine were analyzed and were found to be stable for 2 weeks at temperatures up to 45 °C.
Control animals were fed Purina Lab Chow. - Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- continuously
- Remarks:
- Doses / Concentrations:
First study: 0, 6000, 9000, 12000, 15000 or 18000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
Second study: 0, 750, 1500, 3000, 6000 or 12000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
Third study: 0, 10000 or 18000 ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- FIRST STUDY
- 12 males/12 females
SECOND STUDY
- 10 males/10 females
THIRD STUDY
- 10 males/10 females - Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for mortality and signs of morbidity.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: weekly.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
URINALYSIS: Yes (only study No. 2)
-control animals: 1 male, 2 females.
- low dosed animals (750 ppm): all animals.
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY (study No. 1 - 3): Yes (all animals)
HISTOPATHOLOGY (study No. 1): Yes (all animals control group (0 ppm) and highest dosed group (18000 ppm).
-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
-oesophagus
-stomach
-duodenum
-jejunum
-colon
-mesenteric lymph nodes
-liver
-pancreas
-spleen
-kidneys
-adrenals
-urinary bladder
-seminal vesicles
-prostate
-testes
-ovaries
-uterus
-nasal cavity
-brain
-pituitary
all animals low dose (6000 ppm) group:
-kidney
-urinary bladder
HISTOPATHOLOGY (study No. 2): Yes (all animals)
-kidney
-urinary bladder
HISTOPATHOLOGY (study No. 3): No - Statistics:
- not reported.
- Details on results:
- STUDY No. 1:
CLINICAL SIGNS AND MORTALITY
One male rat receiving 18,000 ppm and two males receiving 6,000 ppm died .
(See Table 4)
BODY WEIGHT AND WEIGHT GAIN
Mean body weight gain in males and females receiving 12,000 ppm or more was depressed by more than 8% when compared with controls.
(See Table 4)
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Feed consumption by rats receiving 18,000 ppm was approximately 80%-90% that of controls.
GROSS PATHOLOGY
Stones were found in the urinary bladders of most dosed male rats, and the incidence was dose related. Twenty-five percent (3/ 12) or more females in the two highest dosed groups had stones.
HISTOPATHOLOGY: NON-NEOPLASTIC
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. Diffuse epithelial hyperplasia of the urinary bladder was found in 8/ 10 males and 2/ 10 females receiving 18,000 ppm melamine, while in animals receiving 6,000 ppm melamine, 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.
STUDY No. 2:
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.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Feed consumption was not affected by incorporation of melamine in the feed.
URINALYSIS
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.
GROSS PATHOLOGY
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.
HISTOPATHOLOGY: NON-NEOPLASTIC
Stones were present even in the male group receiving 750 ppm. Hyperplasia of the transitional epithelium of the bladder was present in 1/10 male rats receiving 3,000 ppm, in 3/10 receiving 6,000 ppm, and in 919 receiving 12,000 ppm melamine. 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. 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 1,500 ppm, 10/ 10 receiving 3,000 ppm, 8/ 10 receiving 6,000 ppm, and 10/ 10 receiving 12,000 ppm melamine).
STUDY No. 3:
CLINICAL SIGNS AND MORTALITY
None of the rats died.
BODY WEIGHT AND WEIGHT GAIN
Rats fed diets containing 18,000 ppm melamine plus 1% ammonium chloride in the drinking water had decreased weight gains relative to groups receiving drinking water acidified with hydrochloric acid.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no effects.
GROSS PATHOLOGY
The addition of ammonium chloride in the drinking water had no apparent effect on the incidence of urinary bladder stones in male or female rats. Urinary bladder stones were seen in 8/8 males and 3/9 females in the group that received 18,000 ppm melamine in feed plus 1% ammonium chloride in drinking water, compared with 10/ 10 males and 3/10 females in the groups administered 18,000 ppm melamine in feed without 1% ammonium chloride in the water. No other compound-related effects were observed at necropsy. - Dose descriptor:
- LOAEL
- Effect level:
- 750 ppm
- Sex:
- male
- Basis for effect level:
- other: urinary bladder stones
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 72 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: urinary bladder stones
- Dose descriptor:
- NOAEL
- Effect level:
- 6 000 ppm
- Sex:
- female
- Basis for effect level:
- other: body weight
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 600 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: body weight
- Critical effects observed:
- not specified
- Conclusions:
- Most noticeable was the development of uroliths (urinary bladder stones) at 750 ppm and higher doses, mainly in males.
- Executive summary:
Melamine (2,4,6-triamino-s-triazine) was administered in the diet to F344 rats or B6C3F1 mice for 13 weeks (subchronic) to determine its toxicologic profile. The dose levels of melamine in the subchronic studies ranged from 750 to 18000 ppm for rats, and 6000 to 18000 ppm for mice. In these studies, 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 of either species. Increased incidences of urinary bladder stones and hyperplasia of the bladder epithelium were observed at 13 weeks in male rats fed diets containing melamine.
Data source
Materials and methods
Test material
- Reference substance name:
- 1,3,5-triazine-2,4,6(1H,3H,5H)-trione, compound with 1,3,5-triazine-2,4,6-triamine (1:1)
- EC Number:
- 253-575-7
- EC Name:
- 1,3,5-triazine-2,4,6(1H,3H,5H)-trione, compound with 1,3,5-triazine-2,4,6-triamine (1:1)
- Cas Number:
- 37640-57-6
- Molecular formula:
- C3H6N6.C3H3N3O3
- IUPAC Name:
- 1,3,5-triazinane-2,4,6-trione; 1,3,5-triazine-2,4,6-triamine
- Test material form:
- solid: particulate/powder
Constituent 1
Results and discussion
Results: P0 (first parental generation)
Effect levels (P0)
- Dose descriptor:
- NOEL
- Effect level:
- 450 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity (P0)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 660 ppm
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Results: F1 generation
Effect levels (F1)
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 450 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: Derived from NOEL for kidney toxicity in the 28-day study
Target system / organ toxicity (F1)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 660 ppm
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOEL
- Generation:
- F2
- Effect level:
- 450 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity (F2)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 660 ppm
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Melamine canurate does not cause adverse effects on fertility or reproduction.
Melamine cyanurate shows significant general toxicity related to kidney failure after accumulation of melamine cyanurate crystals in the kidney.
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.

Route: .live2