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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data. Dates of treatment were 27.12.1978 to 19.01.1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 979
- Report date:
- 1979
Materials and methods
Test guideline
- Guideline:
- other: FDA "Guidelines for reproductive studies for evaluation of drugs for human use", segment II (teratological study)
- Deviations:
- not specified
- Remarks:
- Treatment on GD 6 - 15; no record of gravid uterine weight; number corpora lutea not recorded; no analytical confirmation of exposure levels.
- Principles of method if other than guideline:
- Study was used to assess the teratogenic and/or embryotoxic potential of the test substance.
- 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
- Molecular formula:
- C3H12NO9P3
- IUPAC Name:
- [nitrilotris(methylene)]tris(phosphonic acid)
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Wilmington, Mass
- Age: 72 days at mating
- Weight at study initiation: 240 – 250 grams
- Fasting period before study: Not specified
- Housing: Individually housed in elevated stainless steel cage (however, not under the mating).
- Diet: Purina Certified Rodent Chow 5001, ad libitum
- Water: By automated water system, ad libitum
- Acclimation period: 28 November to 19 December 1978
ENVIRONMENTAL CONDITIONS
- Temperature (°C): monitored twice daily, no more details.
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
IN-LIFE DATES: From: Not specified To: 19th of January 1979
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Distilled
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance was mixed with water and administered at 10 mg/kg bw/day. Dosing solutions were prepared fresh daily. Individual doses were adjusted based on the most recent body weight data.
DIET PREPARATION
- Rate of preparation of diet: Daily
- Storage temperature of food: Room temperature
VEHICLE
- Justification for use and choice of vehicle: N/a
- Concentration in vehicle: 22.4%
- Amount of vehicle: 10 mg/kg bw/day
- Lot/batch no.: Not specified
- Purity: Not specified - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: Overnight
- Further matings after two unsuccessful attempts: No data
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- Gestation days 6 - 15
- Frequency of treatment:
- Daily as a single dose
- Duration of test:
- 21 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 24 mated females/dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included gross signs
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestation day 0, 6, 10, 15, 20 and 21 (pre-necropsy)
BODY WEIGHT: Yes
- Time schedule for examinations: Gestation day 0, 6-15, 21
FOOD CONSUMPTION AND COMPOUND INTAKE:
WATER CONSUMPTION AND COMPOUND INTAKE: No
POST-MORTEM EXAMINATIONS: Yes, all females
- Sacrifice on gestation day 21 (all surviving dams) and day 21 post-mating (all surviving non-pregnant females). - Ovaries and uterine content:
- Examinations included:
- Number of corpora lutea: Yes
- Sites of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes, approximately 50% of foetuses subject to gross dissection
- Soft tissue examinations: Yes, approximately 50% of foetuses subject to gross dissection (followed by processing / staining (Alizarin red) for skeletal abnormalities/variations)
- Skeletal examinations: Yes, approximately 50% of foetuses subject to gross dissection
Type of skeletal malformations control: angulated ribs, cervical rib, wavy rib
- Head examinations: Not specified
Other: Approximately 1/2 of the foetuses were subject to Wilson serial sectioning for neural/visceral defects (10X or 20X magnification) after fixing in Bouin's solution. Additionally, approximately 1/2 of the foetuses were examined of skeletons anomalies and ossification variation after Alizarin red staining using the method of Crary but with the following modification: eviscerated foetuses were immediately placed into an aqueous potassium hydroxide solution followed by staining. Thereafter, stained foetuses were placed in Mall's solution to remove excess stain prior to clearing and storage in benzyl alcohol-glycerine solution. Internal sex determination occurred for both the groups. - Statistics:
- Chi squared, F-test and Student's T-test (absolute data) were used to compare between control and each test substance-treated group. T-tests modified using Cochran's approximation were used when variances differed significantly. Live foetuses, resorptions, implantations and corpora lutea were compared to control by using one-tailed T-test.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- One female in the 100 mg/kg bw/day dose group was sacrificed in a moribund condition on gestation day 6 which was the first day of treatment. No other mortality occurred in any of the other dose groups or the control group.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 1000 mg/kg bw/day dose group, lower weight gain compared to the control group was observed, although not statistically significant. No other significant differences in the mean body weight between the dose groups were observed.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were observed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a statistically significant increase in the implantation efficiency in the 100 mg/kg bw/day dose group. However, this was not considered to be treatment-related.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The occurrence of ≥2 resorptions in each of the treated dose groups compared to the control group was higher. However, the values were within the historical control values and therefore, not considered as treatment-related.
- Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean number of resorption observed in the 100 and 1000 mg/kg bw/day dose groups were significantly greater than the control dose group. However, the values were within the historical control range and therefore not considered as treatment-related.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no dead foetuses in any groups.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the pregnancy rate.
- Other effects:
- no effects observed
- Description (incidence and severity):
- A statistically significant decrease in the mean number of corpora lutea were observed in the 100 mg/kg bw/day dose group, however, this was not considered as treatment-related since it was not occurring in a dose-dependent manner.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day
- Basis for effect level:
- body weight and weight gain
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The mean foetal weights were comparable between the treated animals and the control dose group.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The mean numbers of live foetuses were comparable between control and the treated groups.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex: males/litter 6.9/7.0/6.6/6.0; females 7.4/6.9/7.0/6.9 (no significant effect) Sex ratio (m:f): 92.4%/102.0%/94.6%/87.3% (no significant effect)
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 1000 kg/kg bw/day dose group, 6 of 16 foetuses in one female had defects including flexed forepaws, shortened and thickened torso, abdominal distension and exaggerated forward flexure of the head. No other significant external malformations were observed. No other dose groups had any malformations.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- In the foetal skeletal examination, variations in the ossification occurred. These variations may represent delays in the ossification process or slight ossification irregularities. However, the varation were comparable between the treated groups and the control group.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The incidence of foetuses with soft tissue malformations was considered comparable between the control group and the treatment groups. The types of soft tissue malformations, e.g. distended renal pelvis and/or distended ureter are frequently observed in the specific rat strain used. A malrotation defect of the heart was observed in two foetuses in the 1000 mg/kg bw/day. Both of these foetuses had external malformations and were from the same litter as had observed external malformations. Incidences in the 500 and 1000 mg/kg bw/day were comparable to the control group. In the 100 mg/kg bw/day, the incidence of soft tissue malformations was higher than in the control group. However, this difference was not statistically significant and there was no dose relationship. Therefore, the observed effects were not considered as treatment-related.
- Other effects:
- no effects observed
- Description (incidence and severity):
- The mean crown-rump length for both sexes was significantly greater in the 500 mg/kg bw/day compared to the control group. This difference was not considered as biologically significant and therefore, not treatment related. No other differences were observed compared to the control group.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No teratogenic effects observed.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No fetotoxic effects observed.
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In a developmental toxicity study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H was administered by oral gavage to pregnant Charles River SD rats (24/dose) on gestation days 6-15. The doses tested were 100, 500 or 1000 mg/kg bw/day. The maternal NOAEL was concluded to be 500 mg/kg bw/day and the NOAEL for fetotoxicity and teratogenicity were concluded to be ≥1000 mg/kg bw/day respectively. This was based on females exposed to 1000 mg/kg bw/day gained less weight compared to the controls during the dosing period and was considered as treatment related. No other treatment-related effects were observed.
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