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EC number: 237-249-1 | CAS number: 13708-85-5
- 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:
- 1977
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Justification for the bridging concept (source Draft Assessment Report from disodium phosphonate; Disodium phosphonate_DAR_08_Vol3_B6_August09_Tox)
In the ADME (absorption, distribution, metabolism, elimination) studies with fosetyl-Al, it was shown that the phosphite ion was the major metabolite corresponding to about 76% of applied 32P-labelled dose (mean of male and female; Unsworth, 1976b). The organic part of fosetyl-Al is obviously degraded via ethanol and acetate, which is then either exhaled as CO2 or further incorporated into the physiological metablic pathway. The remainder of the fosetyl-Al appears to be excreted unchanged. Therefore, it can be considered that the phoshite ion contributed to a great extend to the relevant toxicological effects observed in the toxicological studies performed with fosetyl-Al. In addition to the phosphite moiety, the fosetyl-Al molecule contains an organic moiety and an aluminium atom (see figure 6-1); data from fosetyl-Al studies can therefore be regarded as a worst case for phosphite. Because of the rapid degradation/metabolism of fosetyl-Al to phosphite, the toxicological data generated with fosetyl-Al can be used for bridging the toxicological endpoints of phosphite and its salt, disodium phosphonate.
Since ADME studies have shown that 76% fosetyl-Al is metabolized to phosphite ion, a conversion factor of 76% will be used for bridging the NOAEL’s derived from fosetyl-Al studies to phosphite, as a conversion assumption.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 977
- Report date:
- 1977
Materials and methods
- Principles of method if other than guideline:
- test method not specified but considered to meet requirements for a teratogenicity study
- GLP compliance:
- no
- Limit test:
- yes
Test material
- Reference substance name:
- Aluminium triethyl triphosphonate
- EC Number:
- 254-320-2
- EC Name:
- Aluminium triethyl triphosphonate
- Cas Number:
- 39148-24-8
- Molecular formula:
- C6 H18 Al O9 P3
- IUPAC Name:
- Aluminium tris-O-ethyl phosphonate Ehtyl hydrogen phosphonate, aluminium salt
- Test material form:
- solid
- Details on test material:
- technical Fosetyl-Al (batch FR 794/794)
Constituent 1
- Specific details on test material used for the study:
- technical Fosetyl-Al (batch FR 794/795 FT; purity 99.8%)
Test animals
- Species:
- rat
Administration / exposure
- Route of administration:
- oral: gavage
- Details on exposure:
- groups of 20 CFY female rats (rw range at start: 180 - 250 g) were administered 0; 500; 1000; or 4000 mg/kg bw/day of technical Fosetyl-Al (purity 99.8%) in an aqueous suspension (dose volume: 2.0 ml/100g), by oral gavage once daily, on d-6 through d-15 of presumed gestation
- Duration of treatment / exposure:
- d-6 through d-15 of presumed gestation
- Frequency of treatment:
- daily
- Duration of test:
- sacrifce on d-20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 811 mg/kg bw/day disodium phosphonate
- Dose / conc.:
- 4 000 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 3244 mg/kg bw/day disodium phosphonate
- No. of animals per sex per dose:
- 20
Examinations
- Maternal examinations:
- rats were observed daily throughout the dosing period for mortality and clinical signs; bw was determined on d-1; -3; -6; -10; -14; -17; and -20 of pregnancy. All rats were sacrificed on d-20 of gestation; macroscopic examination was performed with emphasis on ovaries and the uteri; number of corpora lutea, number and distribution of life young and early and/or late embryo/foetal deaths were counted; live fetuses were counted, sexed and weighed; half of the foetuses from each litter were examined of visceral abnormalities and the other half for sex determination and skeletal abnormalities.
- Ovaries and uterine content:
- macroscopic examination was performed with emphasis on ovaries and the uteri; number of corpora lutea, number and distribution of life young and early and/or late embryo/foetal deaths were counted
- Fetal examinations:
- number of corpora lutea, number and distribution of life young and early and/or late embryo/foetal deaths were counted; live fetuses were counted, sexed and weighed; half of the foetuses from each litter were examined of visceral abnormalities and the other half for sex determination and skeletal abnormalities.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Occasional death seen in the 500 and 1000 mg(kg bw dose groups were attributable to dosing errors; 5/20 rats from the 4000 mg/kg bw group died or were sacrificed on d-9; d-10 and d-11 (all exhibited bw loss and chromodaryorrhea proir to death; post mortem examination revealed marked gastric dilatation and fluid retention)
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- dose-related reduction of bw and bw gain was seen in all groups during the 1st 4 days of dosing. Effects were still obsereved in the 4000 mg/kg bw group at the end of the dosing period.
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- the number of resporptions was slightly incrased in the 4000 mg/kg bw group
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Pregnancy rate was comparable among all groups - Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- mortality
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- litter weight and mean foetal weight was slightly reduced only in the 4000 mg/kg bw group
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): mean foetal weight was slightly reduced only in the 4000 mg/kg bw group - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- litter weight was slightly reduced only in the 4000 mg/kg bw group
- Changes in postnatal survival:
- not specified
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- foetuses from the 4000 mg/kg bw group exhibited a slightly higher incidence of major abnormalities (thoracic asymmetry, displaced kidney and testes, hydrocephaly, vein/artery transposition, intra-abdominal and subcutaneous hemorrhage) and minor abnormalities (subcutaneous edema, medial displacement of the testis)
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- A higher incidence of skeletal (sternebrae) variants was only seen in the 4000 mg/kg bw group, which would correlate with the lower mean foetal weight
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- Remarks on result:
- other: effects related to maternal toxicity
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Controls | 500 mg/kg bw/day | 1000 mg/kg bw/day | 4000 mg/kg bw/day | |
MATERNAL OBSERVATIONS | ||||
Mortality | 0/20 | 1/20 (a) | 2/20 (a) | 5/20 |
Bw gain (g) | ||||
day6 -10 | 23 | 21 | 18 | 31 |
day6 -20 | 125 | 118 | 125 | 108 |
Pregnancy rate (%) | 95 | 95 | 95 | 95 |
No. with viable young | 19 | 18 | 17 | 14 |
LITTER OBSERVATION | ||||
Live young | ||||
males | 5.4 | 5.8 | 5.1 | 5.3 |
females | 6.4 | 5.5 | 6.9 | 6.2 |
total | 12.7 | 11.3 | 13.1 | 11.5 |
Embryonic deaths | ||||
early | 0.4 | 0.6 | 0.4 | 0.5 |
late | 0.1 | 0.4 | 0.0 | 0.8 |
total | 0.54 | 0.9 | 0.4 | 1.3 |
Mean pre-implantation loss (%) | 10.3 | 12.7 | 12.1 | 12.1 |
Mean post-implantation loss (%) | 3.5 | 8.9 | 2.6 | 10.5 |
Litter weight (g) | 48.05 | 42.07 | 48.50 | 39.71* |
Mean foetal weight (g) | 3.79 | 3.74 | 3.72 | 3.46 |
Major malformations | ||||
Minor malformations | 2/242 (0.8%) | 1/204 (0.8%) | 2/222 (0.8%) | 2/161 (3.8%) |
visceral | 8/119 (6.9%) | 7/103 (6.6%) | 8/108 (7.4%) | 8/78 (13.0%) |
skeletal | 9/121 (7.0%) | 9/100 (12.6%) | 14/112 (11.8%) | 17/78 (22.4%) |
Sketetal variants | ||||
extra-ribs | 24.6% | 29.0% | 42.1% | 27.7% |
sternebra extra-ribs | 23.8% | 38.2% | 8.9% | 56.1% |
(a): dosing error; * p<0.05 |
Applicant's summary and conclusion
- Conclusions:
- Oral administration of daily dose up to 4000 mg/kg bw/day fosetyl-Al, equivalent to 3244 mg/kg bw/day disodium phosphonate, in pregnant rats induced maternal toxicity at 4000 mg/kg bw level, bw loss and mortality) and developmental toxicity including occasionally statistically significant and non-significant excess in the incidence of major and minor abnormalities and skeletal variants; such effects were related to maternal toxicity. No effects were seen in the 500 and 1000 mg/kg bw groups.
The NOAEL in this study is 1000 mg/kg bw/day fosetyl-Al, equivalent to 811 mg/kg bw/day disodium phosphonate, both for maternal and developmental toxicity.
Due to the fact that the highest dose level tested in the rat developmental toxicity study covers the limit dose of 1000 mg/kg bw/day also for phosphorous acid or disodium phosphonate, it is considered very unlikely that relevant additional information on reproductive endpoints can be achieved by repeating the study with disodium phosphonate. Therefore, due to animal welfare reasons no additional studies were performed with disodium phosphonate on this endpoint.
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