Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
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: 227-645-2 | CAS number: 5921-65-3
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Data are included to support toxicokinetik assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Metabolism of Hexamethylmelamine-Ring-14C in Rats and Man
- Author:
- Worzalla JF et al.
- Year:
- 1 974
- Bibliographic source:
- CANCER RESEARCH 34, 2669-2674, October 1974
Materials and methods
- Objective of study:
- excretion
- metabolism
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The metabolism of hexamethylmelamine (HMM), an antineoplastic drug, was studied in man and rats.
- GLP compliance:
- no
Test material
- Reference substance name:
- Altretamine
- EC Number:
- 211-428-4
- EC Name:
- Altretamine
- Cas Number:
- 645-05-6
- IUPAC Name:
- N,N,N',N',N'',N''-hexamethyl-1,3,5-triazine-2,4,6-triamine
- Reference substance name:
- 2-N,2-N,4-N,4-N,6-N,6-N-hexamethyl-1,3,5-triazine-2,4,6-triamine
- IUPAC Name:
- 2-N,2-N,4-N,4-N,6-N,6-N-hexamethyl-1,3,5-triazine-2,4,6-triamine
- Reference substance name:
- Hexamethylmelamine
- IUPAC Name:
- Hexamethylmelamine
- Details on test material:
- - Name of test material (as cited in study report): hexamethylmelamine (HMM)
- Radiochemical purity (if radiolabelling): >98.5% (determined by TLC)
- Specific activity (if radiolabelling): 26.0 µCi/mg
- Locations of the label (if radiolabelling): HMM-ring-14C
Constituent 1
Constituent 2
Constituent 3
- Radiolabelling:
- yes
- Remarks:
- 14C
Test animals
- Species:
- other: human / rat (Sprague-Dawley)
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- PATIENTS
Patients selected for study were those accepted for Phase II or Phase III clinical cancer chemotherapy trials with HMM utilizing study protocols approved by the University of Wisconsin Center for Health Sciences Committee for Review of Clinical Research and Investigation Involving Human Subjects. Patient A. G. was a 62-year-old male with squamous cell tumor of the tonsil; Patient A. H. was a 51-year-old male with squamous cell lung carcinoma.
TEST ANIMALS
- Source: Sprague-Dawley, Inc., Madison, Wis.
- Weight at study initiation: 180 to 220 g
- Housing: in glass metabolism cages
- Individual metabolism cages: no data
Administration / exposure
- Route of administration:
- other: human: oral, added to orange juice / rat: i.p.
- Vehicle:
- other: HCl
- Duration and frequency of treatment / exposure:
- single dose
Doses / concentrations
- Remarks:
- Doses / Concentrations:
human: 4 mg/kg HMM (clinical dose) (A. G., 200 mg; A. H., 350 mg) together with HMM-ring-14C, 100 µCi, at 7 a.m. on the day of the experiment, followed by another dose of unlabeled HMM, 4 mg/kg, at 7 p.m.
rat: 5 mg of HMM dissolved in a minimum of HCl containing 19.1 mCi of HMM-ring-14C
- No. of animals per sex per dose / concentration:
- 2 male patients
4 male rats - Control animals:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Metabolism)
HUMAN:
- Tissues and body fluids sampled: expired breath, urine, and feces, whole blood, hemolyzed erythrocytes, plasma proteins
- Time and frequency of sampling:
Plasma: 11 samples up to 24 hours, 1 sample after 48 hours p.a. (recognizably only from a diagram)
CO2, urine, feces: 24 hr, 48 hr, 72 hr p.a.
RAT:
- Tissues and body fluids sampled: CO2 , urine, feces
- Time and frequency of sampling: 24, 48, 72 h p.a.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Method type(s) for identification: gas chromatography and mass spectrometry, thin-layer chromatography, liquid scintillation counting
Results and discussion
Main ADME resultsopen allclose all
- Type:
- metabolism
- Results:
- The s-triazine ring is very stable and does not undergo cleavage. The rat urinary metabolites were the same as those observed in humans.
- Type:
- excretion
- Results:
- mainly in urine (human: 86 and 91%, respectively; rat: average 79%)
Toxicokinetic / pharmacokinetic studies
- Details on distribution in tissues:
- Plasma levels of radioactivity reached a maximum of 4380 and 3270 dpm/mL of plasma 1 hr after administration to Patients A. G. and A. H., respectively. The half-life of radioactivity in these patients was 13 hr. Hemolyzed erythrocytes that had been washed 3 times contained 6 to 9% of the radioactivity in 1 mL of whole blood. Proteins that were precipitated from plasma with sulfosalicylic acid and washed 3 times contained only 1 to 2% of the activity in 1 mL of plasma.
A tissue distribution study of radioactivity after administration of HMM-ring-14C in rats revealed no unusually high localization of radioactivity in any tissues.
- Details on excretion:
- Recovery of radioactivity in urine after administration of HMM-ring-14C to 2 cancer patients was as follows: in 24 hr each patient excreted 61 % of the total dose of radioactivity; A. G. excreted 25% and A. H. excreted 21 % from 24 to 48 hr; A. G. excreted 5% and A. H. excreted 4% from 48 to 72 hr. Total urinary excretion of radioactivity was 91 % for A. G. and 86% for A. H. (a portion of the urine sample from 0 to 24 hr was accidentally lost by A. H.). The amounts of radioactivity in the feces of Patients A. G. and A. H. within 48 hr after administration were 0.2 and 0.1%, respectively. No radioactivity could be found as expired 14CO2 in the breath of the patients during the 1st 6 hr after the administration of HMM-ring-14C.
The excretion of radioactivity in rats was similar to that of humans, except that rats appeared to excrete the radioactivity more rapidly; also the amount of radioactivity observed in the feces of rats (20%) was higher than that found in human feces (0.1%).
Toxicokinetic parametersopen allclose all
- Toxicokinetic parameters:
- half-life 1st: 13 hrs in plasma (human)
- Toxicokinetic parameters:
- C(time): 1 hr in plasma (human)
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The human urinary metabolites observed were pentamethylmelamine; N2, N2, N4, N6-tetramethylmelamine; N2, N2, N4-trimethylmelamine; N2, N2, N6-trimethylmelamine; N2, N2-dimethylmelamine; N2, N4-dimethylmelamine; monomethylmelamine; and melamine. The identities of the metabolites were confirmed by mass spectrometry. The rat urinary metabolites were the same as those observed in humans.
Any other information on results incl. tables
The concentrated urine samples were also used for TLC. Assay of thin-layer chromatograms of urines on a radio-chromatogram scanner revealed the presence of 4 major radioactive metabolites in humans; the RF values of the radioactive metabolites were identical to samples of the authentic compounds indicated . Quantification of metabolites with a Disc integrator tracing of the radioactivity on the TLC plates gave the proportional amounts of the major radioactive metabolites in 24-hr urines. Multiplication of these proportions by the total percentage of radioactivity in the 24 hr urines gave estimates of the percentages of the various metabolites. The activity in the miscellaneous category includes a mixture of the other methylmelamines identified by gas chromatography and also of any possible unidentified metabolites. The percentage values of the metabolites correspond to the molar percentages of the metabolites since the specific activity per mole of melamine is identical to the specific activity of HMM-ring-14C.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): low bioaccumulation potential based on study results
The experiments indicate that the s-triazine ring is very stable and that it does not undergo cleavage. This is suggested by the fact that there is no production of 14CO2 after administration of HMM-ring-14C to either man or rats. The identification of the major urinary metabolites as methylmelamines and melamine also confirms the stability of the s-triazine ring in mammalian systems.
Excretion is mainly via the urine. The rat urinary metabolites were the same as those observed in humans. - Executive summary:
The metabolism of hexamethylmelamine (HMM), an antineoplastic drug, was studied in man and rats. After administration of HMM-ring-14C to 2 patients, peak plasma levels of radioactivity were seen 1 hr after drug administration and the plasma half-life of radioactivity was 13 hr. Patients excreted 61% of the radioactivity in the urine within 24 hr and 89% within 72 hr. No expired 14CO2 was found in the breath of patients within 6 hr of administration, and less than 0.2% of radioactivity was found in the feces in 48 hr.
Rats that were given HMM-ring-14C i.p. excreted 74% radioactivity in urine, 19% in feces, and none as 14CO2 within 24 hr.
Urinary metabolites were isolated by ion exchange methods, identified by gas chromatography-mass spectrometry, and quantitated using thin-layer chromatography with a radiochromatogram scanner. The urinary metabolites of HMM in both rats and man were N-demethylated homologs of HMM. These experiments suggest that in man and rats there is no significant metabolomic cleavage of the s-triazine ring and that methyl-melamines appear to be the only major urinary metabolites of HMM.
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.