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Toxicological information

Developmental toxicity / teratogenicity

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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:
1977
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

Constituent 1
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)
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.