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EC number: 700-903-6 | CAS number: 255830-15-0
- 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
Carcinogenicity
Administrative data
Description of key information
In accordance with Column 2 of REACH Annex X, the carcinogenicity study (required in Section 8.9.1) does not need to be conducted as the substance is not classified as a mutagen Category 3, and there is no evidence from repeated dose toxicity studies that it has any potential to cause hyperplasia or pre-neoplastic lesions.
There are no carcinogenicity test data available for ATMP-N-Oxide-5K, however, read-across data on ATMP-H (CAS 641-19-8) are available.
In the carcinogenicity study, conducted according to OECD Test Guideline 453 but pre-GLP, the read-across substance, ATMP-H, was concluded to have no carcinogenic potential up to a dietary dose of 500 mg/kg bw/day. No other toxicological effects of concern were observed.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 04.12.1975 to 03.12.1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Version / remarks:
- Study conducted prior to adoption of OECD test guideline.
- Deviations:
- yes
- Remarks:
- No satellite groups, limited blood and clinical chemistry parameters measured.
- GLP compliance:
- no
- 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 212.6 grams for males and 149.0 grams for females.
- Fasting period before study: Not specified
- Housing: Individually in elevated stainless steel cages.
- Diet: Ad libitum
- Water: 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 hours dark / 12 hours light
IN-LIFE DATES: From: 17.11.1976 To: 30.11.1978 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet: Weekly
- Mixing appropriate amounts with: 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 grams 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
- Post exposure period:
- None.
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 70
- Control animals:
- yes, plain diet
- Details on study design:
- Post-exposure period: none.
Satellite groups: none. - Positive control:
- None
- 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: 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.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Mortality data did not reveal a treatment-related effect. There were no physical observations that were attributed to the administration of the test substance. See section 7.5.1.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight values for the high dose males were slightly reduced (5-10%) from week 16 to 87. Values for the low and mid dose groups were comparable to the controls. See section 7.5.1.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- 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. Values for the low and mid dose groups were comparable to the controls. See section 7.5.1.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Some statistically significant organ weight changes were observed in the high dose group. See section 7.5.1 for details.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross lesions attributable to treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings. Isolated miscellaneous tumours in all groups but no evidence any were treatment related.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No neoplastic findings.
- Critical effects observed:
- no
- Conclusions:
- In a carcinogenicity study, conducted according to OECD TG 453 but pre-GLP, the read-across substance, CP42902 (nitrilotrimethylenetris(phosphonic acid)), was not evidenced to have a carcinogenic potential up to a dietary dose of 500 mg/kg bw/day. No other toxicological effects of concern were observed.
Reference
Table 3 - Summary of number of in-lfe masses observed at necropsy.
Group (mg/kg bw/day) | I (0) | II (50) | III (150) | IV (500) | ||||
Number | % | Number | % | Number | % | Number | % | |
Males | 20/70 | 28.6 | 20/70 | 28.6 | 21/70 | 30 | 15/70 | 21.4 |
Females | 22/70 | 31.4 | 23/70 | 32.9 | 17/70 | 24.3 | 20/70 | 28.6 |
Table 4 - Summary of observed tumours.
Time of examination | Type of neoplastic change | |||
Group I | Group II | Group III | Group IV | |
6 months | None | None | None | None |
12 months | Adrenal pharochonacytoma (1f) |
Pituitary |
Uterine polyp (1f) |
Pituitary |
24 months* | Osteosarcoma axilla (1m) |
*pituitary and mammary tumours common.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Klimisch score 2.
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the available read across data from the parent acid (Biodynamics Inc, 1979c; rel 2), no classification is required for carcinogenicity for ATMP-N-oxide-5K according to Regulation (EC) No 1272/2008.
Additional information
In the carcinogenicity study, conducted according to OECD Test Guideline 453 but pre-GLP, ATMP-H 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 6 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, statistically significant changes to organ weights (adrenal glands, spleen, liver and pituitary) were observed. No treatment-related gross lesions or histopathological findings occurred in any of the groups. The NOAEL for carcinogenicity was concluded to be ≥500 mg/kg bw/day (BioDynamics Inc., 1979c).
In several supporting repeated dose toxicity studies using nitrilotris(methylene)]trisphosphonic acid, sodium salt (ATMP-xNa), no treatment-related induction of hyperplasia or pre-neoplastic lesions were observed (Safepharm, 1982 and Manley, 1981, reliability 4). In addition, nitrilotris(methylene)]trisphosphonic acid, sodium salt (ATMP-H), does not have any genotoxic effects.
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