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EC number: 229-146-5 | CAS number: 6419-19-8
- 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. Treatment days were 09.04.1980 to 13.05.1980
- 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:
- See attachment to Section 13 for justification of read-across for the ATMP category (relevant for read across from ATMP-xNa to ATMP-H).
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 980
- Report date:
- 1980
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:
- No analytical evaluation of exposure levels.
- Principles of method if other than guideline:
- The study was designed to evaluate the embryotoxic and/or teratogenic potential of the test substance. Dosing was on gestation days 6-15, no measurement of gravid uterine weights and copora lutea were not counted.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- [nitrilotris(methylene)]trisphosphonic acid, sodium salt
- EC Number:
- 243-900-0
- EC Name:
- [nitrilotris(methylene)]trisphosphonic acid, sodium salt
- Cas Number:
- 20592-85-2
- Molecular formula:
- General formula C3H12NO9P3.xNa where x=3-5 ATMP-3Na C3H9NNa3O9P3 ATMP-4Na C3H8NNa4O9P3 ATMP-5Na C3H7NNa5O9P3
- IUPAC Name:
- Sodium salt of [nitrilotris(methylene)]trisphosphonic acid (3-5Na:1)
- Test material form:
- liquid
- Remarks:
- aqueous solution, 20 % active acid
- Details on test material:
- in water neutralised to pH 7.0
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: Females 57 days (males stated to be sexually mature)
- Weight at study initiation: Females on gestation Day 0 were approximately 26 g.
- Fasting period before study: No data
- Housing: Individual in elevated stainless steel cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One month
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data. Monitored twice daily.
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: Day 6 of gestation: 09.04.1980 - 04.05.1980 To: Day 15 of gestation: 18.04.1980 - 13.05.1980.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Not clear, stated to be distilled water and corn oil in different parts of the report.
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of test substance were dissolved in distilled water and administered at a constant volume of 10 ml/kg bw/day. Dosing solutions were prepared fresh daily.
- 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
- 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:
- GD 6 - 15
- Frequency of treatment:
- daily
- Duration of test:
- 18 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- The dose is assumed to be as neutralised acid (ATMP-xNa) but this is not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent ATMP-xNa value would be 20 mg/kg bw/day (based on 20% neutralised acid).
- Dose / conc.:
- 500 mg/kg bw/day
- Remarks:
- The dose is assumed to be as neutralised acid (ATMP-xNa) but this is not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent ATMP-xNa value would be 100 mg/kg bw/day (based on 20% neutralised acid).
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- The dose is assumed to be as neutralised acid (ATMP-xNa) but this is not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent ATMP-xNa value would be 200 mg/kg bw/day (based on 20% neutralised acid).
- No. of animals per sex per dose:
- 35 mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes for mortality and gross signs of toxicological effects (no further details).
- Time schedule: Twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestation days 0, 6, 9, 12, 15 and 18.
BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 6, 9, 12, 15 and 18. Calculated body weight change for days 0-6, 6-15 and 15-18.
FOOD CONSUMPTION: No
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18 (all surviving dams) and Day 18 post-mating in all surviving non-pregnant females.
- Organs examined: Complete gross pathology examination. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes, and weighed, measured and sex determined.
- Other: Live and dead fetuses. Internal sex determination of fetuses. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: No data - Statistics:
- Maternal body weight and reproduction data: Bartlett's test followed by one-way ANOVA (equal variance) followed by Dunnett's test or Kruskal-Wallis test (unequal variance) and summed rank test (Dunn). Pregnancy and fetal parameters: Chi square analysis followed by Fisher Exact test with Bonferroni correction. Armitage test for linear trend.
- Indices:
- No data
- Historical control data:
- No data
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No adverse clinical effects.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no treatment-related deaths (only deaths that occurred as a result of dosing errors and one death of a control animal on gestation day 11).
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effects on body weights or body weight gains.
- 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
- 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:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related adverse findings during the macroscopic examination.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No effects on implantations.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No effects on resorptions.
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No effects on numbers of live and dead fetuses.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- No effects on pregnancy rates.
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- There were no treatment-related deaths (only deaths that occurred as a result of dosing errors and one death of a control animal on gestation day 11), no adverse clinical effects, no effects on body weights or body weight gains, and no effects on reproductive parameters (pregnancy rates, numbers of live and dead fetuses, implantations and resorptions). There were no treatment-related adverse findings during the macroscopic examination.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- Assumed to be as neutralised acid but not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent ATMP-xNa value would be 200 mg/kg bw/day (based on 20% neutralised acid).
- Basis for effect level:
- other: No adverse maternal toxicity effects observed.
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No effects on mean fetal body weights.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No effects on fetal sex distribution.
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- The incidence of fetal external malformations were comparable between control and treated groups.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- During the fetal skeletal evaluations, the incidence of fetuses with at least one ossification variation was slightly higher than the concurrent control in the mid and high dose groups. However, incidences for these groups were within the range of historical values for the laboratory and strain of mouse. The type and incidence of ossification variations during the skeletal evaluations were similar to the controls. However there was a slight increase in the incidence of fetuses with rudimentary structures observed in the mid and high dose groups.
During the skeletal evaluations the incidence of malformations was low in the low (no malformations observed) and high dose groups. The incidence of skeletal malformations in the mid-dose group was significantly increased. However, this increase was attributed to a high number of malformed fetuses from a single mid-dose litter. Six fetuses from this litter had skeletal malformations that included misshapen tibia and fibula, angulated ribs and defective sternebrae. Since these effects were not observed in the highest and lowest dose groups they were not considered to be related to treatment. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- The incidence of fetal soft tissue malformations were comparable between control and treated groups. No malformations were noted in the treated groups during the gross evisceration examinations.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No effects on crown-rump length.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks:
- Assumed to be as neutralised acid (ATMP-xNa) but not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent value would be 200 mg/kg bw/day (based on 20% neutralised acid).
- Sex:
- male/female
- Basis for effect level:
- other: No adverse teratogenic effects observed.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- Assumed to be as neutralised acid (ATMP-xNa) but not clearly specified in the study report. If the dose was in terms of solution as provided, the equivalent value would be 200 mg/kg bw/day (based on 20% neutralised acid).
- Sex:
- male/female
- Basis for effect level:
- other: No adverse fetotoxic effects were observed.
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1 Summary of Malformations found during the fetal skeletal examination.
Group (mg/kg bw/day) | Malformation | Fetuses | Litter | ||
No. with malf./total examined | % | No. with malf fetuses/total examined | % | ||
0 | None | 0/138 | 0/24 | ||
100 | Cervical vertebral defect | 1/156 | 0.6 | 1/28 | 3.6 |
500 | Tibia misshapened - alone | 1/203 | 0.5 | 1/34 | 2.9 |
- with misshapened fibula and angulated ribs | 2/203 | 1.0 | 1/34 | 2.9 | |
- with misshapened fibula, angulated ribs and sternebrae defects | 1/203 | 0.5 | 1/34 | 2.9 | |
- with angulated ribs | 1/203 | 0.5 | 1/34 | 2.9 | |
Angulated ribs and scrambled sternebrae | 1/203 | 0.5 | 1/34 | 2.9 | |
Cervical rib | 1/203 | 0.5 | 1/34 | 2.9 | |
5 lumbar vertebrae | 2/203 | 1.0 | 1/34 | 2.9 | |
Total | 9/203 | 4.4* | 3/34 | 8.8 | |
1000 | Scrambled sternebrae | 1/183 | 0.5 | 1/32 | 3.1 |
Vertebral defects | 1/183 | 0.5 | 1/32 | 3.1 |
*Difference from the control group statistically significant p<0.05 (Fisher Exact test).
Applicant's summary and conclusion
- Conclusions:
- In a well-conducted teratogenicity study (FDA segment II: teratological study; reliability 2) conducted prior to the adoption of OECD test guidelines and GLP, it was concluded that ATMP-xNa (aqueous solution containing 20% w/w neutralised acid) was not embryotoxic or teratogenic when administered to mice at 100, 500 or 1000 mg/kg bw/d ay by gavage on GD6-15. The NOAEL for maternal toxicity, fetal toxicity and teratogenicity was greater than 1000 mg/kg bw/day. The doses are assumed to be as neutralised acid but this is not clearly specified in the study report. If the doses were in terms of solution as provided, the equivalent ATMP-xNa values would be 20, 100, 200 mg/kg bw/day (based on 20% neutralised acid).
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