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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
Toxicity to reproduction
Administrative data
- 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
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Disodium phosphonate
- EC Number:
- 237-249-1
- EC Name:
- Disodium phosphonate
- Cas Number:
- 13708-85-5
- Molecular formula:
- Na2HPO3
- IUPAC Name:
- disodium phosphonate
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): Bruggolen® H10
- Substance type: inorganic
- Physical state: solid
- Lot/batch No.: 14060611
- Expiration date of the lot/batch: 29.02.2016
- Storage condition of test material: ambient conditions
Constituent 1
Test animals
- 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
Administration / exposure
- 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
Doses / concentrationsopen allclose all
- 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
Examinations
- 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
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- 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 / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
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.
Effect levels (P0)
- 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
Results: F1 generation
General toxicity (F1)
- 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
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
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.
Effect levels (F1)
- 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
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- 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.
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