Disodium phosphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03/2015 to 12/2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according to OECD guideline under GLP conditions

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco, Lecco Italy
- Age at study initiation: 7-9 wks
- Weight at study initiation: (P) Males: 200-225 g; Females: 175-200 g
- Housing: polysulphone solid bottomed cages
- Diet (e.g. ad libitum): laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via
G. Galilei, 4, 20019, Settimo Milanese (MI), Italy) was offered ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 2 °C
- Humidity (%): 55 +/- 15
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: until positive identification occurs or 14 days have elapsed
- Proof of pregnancy: [vaginal plug] referred to as [day 0] of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Formulations of the test item were prepared as solutions in water. Concentration
was assessed for all levels by taking two analytical aliquots (approximately
1 mL). Each analytical aliquot was analysed separately. Concentration was
evaluated as the mean of the two determinations.

Duration of treatment / exposure:

Males:
Animals will be dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks
prior to pairing and thereafter through the day before necropsy.

Females:
Animals will be dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks
prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum or the day before sacrifice.

Frequency of treatment:

once a day

Remarks:

Doses / Concentrations:
100 mg/kg bw
Basis:
nominal in water

Remarks:

Doses / Concentrations:
300 mg/kg bw
Basis:
nominal in water

Remarks:

Doses / Concentrations:
1000 mg/kg bw
Basis:
nominal in water

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before treatment and once daily during treatment

BODY WEIGHT: Yes
- Time schedule for examinations:
Males were weighed weekly from allocation to termination. Females were
weighed weekly from allocation to positive identification of mating and on
Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4
post partum.

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abormalities

GROSS EXAMINATION OF DEAD PUPS:
yes

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY
The clinical history of the males and females of the parental generation was
studied and a detailed post mortem examination was conducted (including
examination of the external surface and orifices).


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed, respectively:

Adrenal glands
Brain (cerebrum, cerebellum, medulla/pons)
Clitoris
Epididymides
Kidneys
Liver
Ovaries with oviduct
Penis with preputial glands
Pituitary
Prostate gland
Spleen
Seminal vesicles with coagulating glands
Testes
Thymus (where present)
Thyroid
Uterus with cervix
Vagina

Postmortem examinations (offspring):

As soon as possible after parturition was considered complete (Day 0 or 1
post partum), all pups (live and dead) were counted, sexed and live pups were
identified. Live pups were individually weighed on Days 1 and 4 post partum.
Pups dying during the lactation period were weighed before the despatch to
necropsy. Observation was performed once daily for all litters.

Statistics:

Standard deviations were calculated as appropriate. For continuous variables
the significance of the differences amongst group means was assessed by
Dunnett’s test or a modified t test, depending on the homogeneity of data.
The non-parametric Kruskal-Wallis analysis of variance was used for the
other parameters. Intergroup differences between the control and treated
groups were assessed by the non-parametric version of the Williams test. The
criterion for statistical significance was p<0.05.

Reproductive indices:

Males: Copulation index and Fertility index
Females: Copulatory index and Fertility index, Pre-birth loss, Pup loss at birth, cumulative pup loss, pre-implantation loss
Males and females: Pre coital interval

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One female dosed at 1000 mg/kg/day was humanely killed on Day 24 of
the gestation period for a prolapse of the uterus. Macroscopically and
microscopically, no lesions were noted.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

1 Mortality and fate of females:
One high dose female (no. X0170069) was humanely killed on Day 24 of
gestation period for prolapse of the uterus. No clinical signs were observed
in this animal during the study. At post mortem examination, unilateral
implantation was observed. Macroscopically and microscopically, no lesions
were noted.
A total of 10 females were proved to be not pregnant at necropsy: 2 females
in the control group, 2 in the low dose group, 3 in the mid-dose group (1
of these, No. X0170059, did not mate) and 3 in the high dose group. One
female from the low dose group (no. X0170023), one from the mid-dose
group (no. X0170041) and one from the high dose group (no. X0170069)
showed unilateral implantation, while mating was not detected in 1 female
(no. X0170003) of the control group.
The number of females with live pups on Day 4 post partum was: 8 in the
control group, 7 in each of the low and mid-dose groups, 6 in the high dose
group. Total litter loss was observed in a single female (no. X0170023) from
the low dose group.


2 Clinical signs:
No signs of toxicological relevance were observed during the study.


3 Body weight and body weight gain:
No significant changes in body weight were observed in the treated animals
when compared to controls.

4 Food consumption:
Food consumption was unaffected by treatment in both sexes during the
study.

5 Oestrus cycle, reproductive parameters, pairing combination
and mating performance:
No treatment-related anomalies were noted in the oestrus cycle of the treated
females when compared to controls. The mean pre-coital interval and the
number of copulation plugs were similar between control and treated groups.

All females mated with the exception of female no. X0170059 of the middose
group. However, 2 females in the control group (nos. X0170005 and
X0170017), 2 in the low dose group (nos. X0170025 and X0170039), 3 in
the mid-dose group (nos. X0170047, X0170057 and X0170059, one of which
did not mate) and 3 in the high dose group (nos. X0170061, X0170075 and
X0170079) were found not pregnant.
The copulatory index was 100% for both sexes for Groups 1, 2 and 4 and
90% for Group 3. The fertility indices were 80% in Groups 1 and 2, 70% in
Groups 3 and 4.


6 Implantation, pre-birth loss data and gestation length of
females:
Gestation periods were similar in treated groups and controls. All dams gave
birth between Days 22 and 23 post coitum (with the exception of animal
no. X0170049 who gave birth on Day 21). Corpora lutea, implantations and
pre-implantation loss, total litter size and pre-birth loss (percentage) did not
show dose-related or treatment-related differences.

7 Litter data at birth, on Day 1 and on Day 4 post partum
of females and sex ratio of pups:
No significant differences in total litter size, live litter size, mean pup loss,
sex ratio and mean pup weights were observed among the surviving treated
dams and the controls.

8 Clinical signs of pups:
No relevant clinical signs, that could be related to treatment, were reported
at the examination of pups during the lactation period.

9 Necropsy findings in decedent pups and in pups sacrificed
on Day 4 post partum:
No relevant differences between control and treated groups were noted at
necropsy in the decedent pups. No significant abnormalities were recorded in
the pups sacrificed on Day 4 post partum or in the pup humanely killed on
Day 1 post partum (animal no. X0170049, pup no. 17) due to the absence of
skin in the neck and ventral region.

10 Terminal body weight and organ weights:
Terminal body weight was unaffected by treatment in both sexes.
No changes of toxicological significance were observed in the weight of the
organs. The statistically significant increase of the relative weight of kidneys
observed in the high dose females was not considered to be of toxicological
relevance, since it was of low magnitude and not supported by histopatological
examination.

11 Macroscopic observations:
Detailed macroscopic observations have been reported for male and female
animals from all groups.
No relevant changes were noted in treated animals. The sporadic changes
observed in few treated animals could be considered incidental.

12 Microscopic observations:
Histopathological evaluation was performed on selected tissues/organs in
control and high dose groups, as well as on all abnormalities detected during
post mortem observation.
No treatment-related changes were noted.
A limited number of lesions, reported in control and treated animals, were
considered to be an expression of spontaneous and/or incidental pathology,
seen in this species and age of untreated animals.

Spermatogenic cycle:
Seminiferous tubules were evaluated with respect to their stage in the
spermatogenic cycle and to the integrity of the various cell types within
the different stages; regular layering in the germinal epithelium was noted.

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

food efficiency

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

histopathology: neoplastic

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

No relevant differences between control and treated groups were noted at
necropsy in the decedent pups. No significant abnormalities were recorded in
the pups sacrificed on Day 4 post partum or in the pup humanely killed on
Day 1 post partum (animal no. X0170049, pup no. 17) due to the absence of
skin in the neck and ventral region.

Body weight and weight changes:

not examined

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

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Clinical signs of pups:
No relevant clinical signs, that could be related to treatment, were reported
at the examination of pups during the lactation period.

Necropsy findings in decedent pups and in pups sacrificed
on Day 4 post partum:
No relevant differences between control and treated groups were noted at
necropsy in the decedent pups. No significant abnormalities were recorded in
the pups sacrificed on Day 4 post partum or in the pup humanely killed on
Day 1 post partum (animal no. X0170049, pup no. 17) due to the absence of
skin in the neck and ventral region.

Dose descriptor:

NOEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

Reproductive effects observed:

not specified

Executive summary:

The effects of the test item, Bruggolen® H10, on fertility, pregnancy and early lactation of the offspring were investigated when administered orally to male and female Wistar Hannover rats. Groups of 10 males and 10 females received the test item by gavage at dosages of 100, 300 and 1000 mg/kg/day. One female dosed at 1000 mg/kg/day was humanely killed on Day 24 of the gestation period for a prolapse of the uterus. Macroscopically and microscopically, no lesions were noted. No treatment-related effects were detected in males and in the remaining females from the high dose and the other treated groups during the in vivo phase. No treatment-related anomalies were noted in the oestrus cycle of the treated females when compared to controls. Copulatory and fertility indices did not show any treatment-related differences among treated and control groups. Parturition, lactation, implantation, litter data and sex ratio did not show any changes of toxicological relevance. Necropsy findings in pups did not reveal any treatment-related effect. No relevant changes were detected at post mortem examination in treated animals, when compared with controls. Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages and a regular layering in the germinal epithelium was described. In conclusion, no treatment-related effects indicating systemic toxicity were observed in male or female animals at any of the dose levels investigated (100, 300 and 1000 mg/kg/day). No effects on sexual function and fertility or in developmental parameters and lactation were observed at any of the dose levels investigated. On the basis of the results obtained in this study, the NOEL (No Observed Effect Level) for general toxicity and for fertility and reproduction parameters was considered to be 1000 mg/kg/day for males and females.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

excellent

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Short description of key information:
NOEL (general toxicity and fertility) = 1000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
Study according to OECD guideline under GLP conditions

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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.

Reason / purpose for cross-reference:

read-across source

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

Specific details on test material used for the study:

technical Fosetyl-Al (batch FR 794/795 FT; purity 99.8%)

Species:

rat

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

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

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.

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

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:

no effects observed

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

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

Abnormalities:

no effects observed

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

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

Abnormalities:

no effects observed

Developmental effects observed:

no

	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

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

811 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Disodium phosphonate is considered not to be teratogenic in rats and has no adverse effects on the reproduction of rats.

Classification according to (EU) No. 1272/2008 ist not required.