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EC number: 248-660-0 | CAS number: 27794-93-0
- 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:
- chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 04.12.1975 to 03.12.1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline. It was not compliant with GLP. The study is read across from ATMP (CAS 6419-19-8).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 979
- Report date:
- 1979
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Version / remarks:
- Test conducted prior to adoption of OECD test guideline.
- Deviations:
- yes
- Remarks:
- No satellite group, and reduced haematology, clinical chemistry and urinalysis parameters examined.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Nitrilotrimethylenetris(phosphonic acid)
- EC Number:
- 229-146-5
- EC Name:
- Nitrilotrimethylenetris(phosphonic acid)
- Cas Number:
- 6419-19-8
- IUPAC Name:
- [nitrilotris(methylene)]tris(phosphonic acid)
- Details on test material:
- - Name of test material (as cited in study report): CP42902
- Substance type: Phosphonic acid
- Physical state: white powder
- Analytical purity: No data
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: 222638 and 1059624
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: Room temperature in locked storage cabinet.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York.
- Age at study initiation: 6-7 weeks
- Weight at study initiation: mean 212.6g (males) and 149.0g (females)
- Fasting period before study:
- Housing: Individually in elevated stainless steel cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored but no data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 17.11.1976 To: 30.11.1978
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Standard laboratory diet.
- Storage temperature of food: No data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- 50 g samples of the control feed and each dietary level were taken weekly and shipped to the sponsor. No further details.
- Duration of treatment / exposure:
- 24 months
- Frequency of treatment:
- continuous
Doses / concentrations
- Remarks:
- Doses / Concentrations:
50, 150, 500 mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- 70
- Control animals:
- yes, plain diet
- Details on study design:
- Post-exposure period: None
Satellite group: None - Positive control:
- None
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for the first two months and then twice daily until termination.
- Cage side observations: mortality, gross signs of toxicology or pharmacologic effects.
Interim necropsies were performed on 10/sex/group after 6 and 12 months, then on all surviving animals after 24 months. Animals that died spontaneously or were killed in a moribund condition were also examined.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly, for signs of local or systemic toxicity, pharmacologic effects and palpation for tissue masses.
BODY WEIGHT: Yes
- Time schedule for examinations: Twice pre-test, weekly through to week 13 of treatment, every two weeks for weeks 14 to 26, then monthly, and finally at termination.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): pretest, weekly up to week 13, every other week for weeks 14 to 26 and then monthly.
- 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
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest, then 3, 6, 12, 18 and 24 months.
- Dose groups that were examined: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Anaesthetic used for blood collection: Yes, ether.
- Animals fasted: Yes, overnight.
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Animals fasted: Yes, overnight
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12 and 24 months all groups 6/sex; 3 months: 6/group (males) and 6/control and high dose groups (females); 18 months: 6/sex for control and high dose groups.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.1] were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2) - Other examinations:
- None
- Statistics:
- Body weight, food consumption, haematology and clinical chemistry parameters, organ weights, organ/body weight ratios and organ/brain weight ratios were analysed. Mean values of all dose groups were compared to control at each time interval. Haematology and clinical chemistry: intergroup comparison v control by F-test and Student's t-test (using t-test modification if variances differed). Body weight, food consumption, organ weights and ratios by Dunnett's t-test.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: No treatment effects. Males (per 70) 18 (controls), 22 (low), 21 (medium) and 18 (high) died. Females (per 70), 23 (controls), 24 (low), 19 (medium) and 19 (high) died during study. No treatment-related clinical signs of toxicity.
BODY WEIGHT AND WEIGHT GAIN: High dose males slightly reduced (5-10%) from week 16-87, resulting in slight reduction in terminal body weight (controls - 522.2+/-61.3; low dose - 520.5+/-72.5; medium dose - 508.2 +/-75.6 and high - 510.1 +/-52.2 g) which was not statistically significant. Other groups comparable to controls.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Mean food consumption for high dose males was greater than control group by 3-17%. Other groups comparable to controls.
OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects.
HAEMATOLOGY: No statistically significant differences in any of the parameters measured for any group.
CLINICAL CHEMISTRY: No statistically significant differences for any of the parameters measured at any time point for any group.
URINALYSIS: No treatment-related effects.
ORGAN WEIGHTS (statistically significant changes only): Changes were observed in the highest dose group only. No other groups were affected at any sample time. Males: 15% reduction in absolute spleen weight at 24 months; 14% reduction in absolute and relative liver weight at 24 months; 23% increase in relative testes weight at 12 months, 14% increase in relative kidney weight at 12 months, 14% decrease in absolute liver weight at 6 months. Females: 13% decrease in absolute kidney weight at 12 months; 8% decrease in relative liver weight at 6 months.These changes were no considered adverse.
GROSS PATHOLOGY: No treatment-related findings.
HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related findings. The following were found equally in control and treated groups: cortical vacuolation and hematocysts in adrenal glands, pituitary tumours, pulmonary lesions (varying degrees of severity of chronic murine pneumonia complex, lymphoid proliferations, abscesses and pneumonitis), chronic pleuritis, often with adhesions to the heart, varying degrees of chronic nephritis commonly observed, hepatic lesions in many; also bile duct hyperplasia, testicular atrophy, mammary galactocele in both sexes, possibly related to prolactin secreting pituitary tumours.
HISTOPATHOLOGY: NEOPLASTIC (if applicable): No treatment-related findings (see Section 7.7).
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- > 500 other: mg/kg
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In a well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), CP42902 (nitrilotrimethylenetris(phosphonic acid), did not cause any toxological effects of concern, and the NOAEL was greater than the highest dose tested 500 mg/kg bw/day. The result is read across from ATMP (CAS 6419-19-8).
- Executive summary:
In a well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), CP42902 (ATMP) was administered via the diet to Long-Evans rats (70/sex/dose) at dose levels of 50, 150 or 500 mg/kg bw/day (groups II to IV) for 24 months. Control animals received untreated diet (Group I). Animals were regularly observed for clinical signs of toxicity, and body weights and food consumption were measured. Interim necropsies were performed at six and 12 months (10/sex/dose). Ophthalmoscopic examination, haematology, clinical chemistry and urinalysis were performed at 3, 6, 12, 18 and 24 months. Histopathological examinations were conducted on all animals that died or had to be killed in extremis, and also for 10 animals/sex for groups I and IV at six months and for all survivors in Groups I and IV at 24 months. Mean body weight values for the high dose males were slightly reduced (5-10%) from week 16 to 87. Mean food consumption values for the high dose males were generally comparable to or greater than those of the control group (3-17%) during most weeks. In the high dose group there were statistically significant changes to organ weights (adrenal glands, spleen, liver, pituitary). There were no treatment-related gross lesions or histopathological findings in any of the groups. The NOAEL for carcinogenicity and general toxicity was greater than the highest dose tested (500 mg/kg bw/day).
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