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EC number: 432-070-7 | CAS number: -
- 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:
- 08/2014 to 09/2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
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 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Test material form:
- other: microgranules
- Details on test material:
- - Name of test material (as cited in study report): BRUGGOLITE FF6 M
- Substance type: organic
- Physical state: solid
- Lot/batch No.: 11062802
- Expiration date of the lot/batch: 31.07.2021
- Storage condition of test material: room temperature
- Other: RTC numbers 12924, 14263
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Age at study initiation: 9 weeks (female rats) and 11 weeks (male rats)
- Weight at study initiation: 200-225 g (female rats) and >350 g (male rats)
- Fasting period before study: no
- Housing: limited access rodent facility
- Diet (e.g. ad libitum): laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI), Italy): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimatisation period: 18 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:
DIET PREPARATION
- Rate of preparation of diet (frequency): preparation for 3 to 6 days
- Mixing appropriate amounts with (Type of food): water
VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Concentration in vehicle: 100 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Validation of the method of analysis was carried out by the Test Site LAUS
GmbH, according to a iodometric titration method released by the Sponsor (Validation of an
Analytical Method for the determination of Bruggolite FF6 M in the matrix
demineralised water - Project No. 14041501G926). The stability was found
to be 48 hours at room temperature and 1 week at +4°C for the concentration
of 100 mg/mL.
Before treatment commenced, analysis was performed to confirm that the proposed
formulation procedure was acceptable. Samples of the formulations prepared
during Weeks 1 and 2 of treatment were also analysed to check the concentration.
At each analytical session, triplicate samples of approximately 10 mL
each (of vehicle and dose level) were taken, according to instructions from
the Test Site and sent to the attention of the Principal Investigator. The
actual date for each sample collection was documented and retained with the
study raw data. - Details on mating procedure:
- The females were paired with male rats. Females were paired one to one in
the home cage of the male and left overnight. Vaginal smears were taken
daily in the morning from the day after pairing until a positive identification
of mating was made. The day of mating, as judged by the presence of sperm
in the vaginal smear or by the presence of a copulation plug, was considered
as Day 0 of gestation (or Day 0 post coitum). Full mating records were
maintained. - Duration of treatment / exposure:
- All animals were dosed once a day, from Day 6 through Day 19 post coitum.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- control group
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 24 mated female rats per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose level of 1000 mg/kg/day was selected in agreement with the Sponsor, based on information from previous studies.
Examinations
- Maternal examinations:
- Mortality
Throughout the study, all animals were checked early in each working day and
again in the afternoon. At weekends and Public Holidays a similar procedure
was followed except that the final check was carried out at approximately
mid-day.
Clinical signs
All clinical signs were recorded for individual animals. Each animal was
observed at least once daily and any clinical signs recorded starting from
allocation until sacrifice.
Signs observed outside the scheduled time period and mass(es) are reported
only as individual data.
Body weight
All animals were weighed on Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum.
Food consumption
Food consumption was measured on Days 3, 6, 9, 12, 15, 18 and 20 post
coitum, starting from Day 0 post coitum.
The food consumption measured on Day 18 post coitum for cage no. 2
was considered unreliable, since it was more than the double of the food
consumption of the same cage and of the other cages in the same group,
during the study.
Euthanasia
The animals were killed on Day 20 post coitum and necropsied as detailed
below. All females which completed the scheduled test period were euthanised
with carbon dioxide. All foetuses were sacrificed by intraperitoneal injection
of Sodium Thiopental followed by hypothermia. All animals were subjected
to necropsy, supervised by a pathologist.
Necroscopy
The clinical history of the animals was studied and a detailed post mortem
examination was conducted (including examination of the external surface
and orifices). Changes were noted and the abnormalities preserved in 10%
neutral buffered formalin. - Ovaries and uterine content:
- The ovaries and uteri were examined to determine:
– Gravid uterine weight;
– number of corpora lutea;
– number of implantation sites;
– number, sex and weight of all live foetuses;
– number and sex of dead foetuses (foetuses at term without spontaneous
movements and breathing);
– number of intra-uterine deaths;
– gross evaluation of placentae.
Intra-uterine deaths were classified as:
– Early resorptions: only placental remnants visible.
– Late resorptions: placental and foetal remnants visible.
Uteri or individual uterine horns without visible implantations were immersed
in a 10-20% solution of ammonium sulphide to reveal evidence of embryonic
death at very early stages of implantation. - Fetal examinations:
- All live foetuses were examined externally. Approximately one-half of the
foetuses (i.e., routinely, every second live foetus) in each litter was preserved
in Bouin’s solution for subsequent fixed-visceral examination. The remaining
foetuses were eviscerated after which the carcasses were fixed in 95% (v/v)
ethanol for subsequent skeletal examination after bone staining with Alizarin
Red S. Skeletal and fixed-visceral examinations were performed in both groups.
Structural deviations were classified as follows:
Malformations
Major abnormalities that are rare and/or affect the survival or health of the
species under investigation.
Anomalies
Minor abnormalities that are detected relatively frequently.
Variants
A change that occurs within the normal population under investigation and
is unlikely to adversely affect survival or health. This might include a delay
in growth or morphogenesis that would have otherwise followed a normal
pattern of development. - Statistics:
- For continuous variables (body weight, body weight gain and food consumption),
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. Statistical analysis of litter data and sex ratio, terminal body weight,
gravid uterus weight and absolute weight gain was carried out by means of
the Kruskal-Wallis test and intergroup differences between the control and
treated groups assessed by a non-parametric version of the Williams test. - Indices:
- Pre-implantation loss was calculated as a percentage from the formula:
Pre impl: Loss% = [(no. of corpora lutea - no. of implantations)/(no. of corpora lutea)] X 100
Post-implantation loss was calculated as a percentage from the formula:
Post impl: Loss% = [(no. of implantations - no. of live foetuses)/(no. of implantations)] X 100
Total implantation loss was calculated as a percentage from the formula:
Total impl: Loss% = [(no. of corpora lutea - no. of live foetuses)/(no. of corpora lutea)] X 100
Sex ratios of the foetuses were calculated as the percentage of males per litter.
All derived values (e.g., means, percentages, ratios) were first calculated
within the litter and the group values derived as a mean of individual litter
values. Foetal structural deviations were expressed as the percentage of
affected foetuses relative to all foetuses examined per group, as well as in
terms of the mean litter percentage of affected litters.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No signs of toxicological significance were noted during the study. Salivation
on single occasions, was seen in some treated females (1000 kg/kg/day). - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No differences of toxicological relevance were noted in body weight of females
during the study, between control and 1000 mg/kg/day treated group.
Decreases in body weight gain were seen in 1000 mg/kg/day females on
Days 9, 15, 18 and 20 post coitum, statistically significant on Day 9. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Slight statistically significant reduction in food consumption was seen on Day
20 post coitum in treated females compared to controls. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Early or late resorptions:
- not specified
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No abnormalities were seen in the control group; one dead foetus and a
total of 4 small foetuses (<2.7 g) were noted in the treated group. All these
findings were considered incidental. - 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): not specified - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Litter data, mean foetal weight and sex ratios were not affected by treatment. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- Litter data, mean foetal weight and sex ratios were not affected by treatment.
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No abnormalities were seen in the control group; one dead foetus and a
total of 4 small foetuses (<2.7 g) were noted in the treated group. All these
findings were considered incidental. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related changes were seen at skeletal examination of foetuses
performed in control and treated group, since the incidences of the findings
observed were comparable to the controls.
Metacarpal of the forepaw incompletely ossified (variant) or unossified (anomaly)
were seen in treated and control foetuses with different incidences. No
toxicological importance was attributed to the higher incidence of incompletely
ossified metacarpals seen in treated foetuses, since it should be considered in
association with the higher incidence of metacarpals unossified observed in
the control.
Other changes in foetuses of treated group were: pube incompletely ossified
(anomaly), seen in one small foetus; sternebrae unossified (anomaly) seen
in few foetuses, one of which was small; sternebrae incompletely ossified
(variant) seen in some foetuses comprising the small ones.
In addition, to the experience of the testing facility, these changes can be considered as a common
spontaneous alteration in animals of this strain. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related changes were seen at visceral examination of foetuses
performed in control and treated group, since the incidences of findings
observed were comparable to the controls. No toxicological significance was
attributed to the enlarged lateral ventricles of brain and the haemorrhagic
lungs, since they were seen only in one small foetus in the treated group.
In addition, to the experience of the testing facility, the changes observed can be considered as a
common spontaneous alteration in animals of this strain. - Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The dose level of 1000 mg/kg bw/day was considered the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity.
- Executive summary:
Study design
The effects of BRUGGOLITE FF6 M were investigated after oral administration
in Wistar Hannover female rats during pregnancy and on embryo-foetal
development. The study design was as follows:
Group 1: 0 mg/kg bw/day; 24 females
Group 2: 1000 mg/kg bw/day; 24 females
All animals were administered during the gestation period, starting from
Day 6 through Day 19 post coitum at the dose volume of 10 mL/kg. Body
weight, daily clinical signs and food consumption were recorded during the
in vivo phase. All females were caesarean-sectioned on Day 20 post coitum
and subjected to post mortem examination. The number of corpora lutea,
implantations, early and late intrauterine deaths, live and dead foetuses,
uterus weight, foetal weight and sex were recorded. All foetuses were examined
for external abnormalities. Approximately one half of the foetuses in each
litter was examined for fixed-visceral and skeletal abnormalities.
Mortality and fate of females
No animals died during the study. The number of females with live foetuses
on gestation Day 20 was 24 in the control and 23 in the 1000 mg/kg/day
dose group.
Clinical signs
No signs of toxicological significance were noted during the study. Salivation
on single occasions, was seen in some treated females (1000 kg/kg/day).
Body weight and body weight gain
No differences of toxicological relevance were noted in body weight of females
during the study, between control and 1000 mg/kg/day treated group.
Decreases in body weight gain were seen in 1000 mg/kg/day females on
Days 9, 15, 18 and 20 post coitum, statistically significant on Day 9.
Food consumption
Slight statistically significant reduction in food consumption was seen on Day
20 post coitum in treated females compared to controls.
Terminal body weight, uterus weight and absolute weight gain
No significant differences in terminal body weight, gravid uterus weight and
absolute weight gain were observed in the treated group, when compared to
the control group.
Litter data and sex ratios
Litter data, mean foetal weight and sex ratios were not affected by treatment.
Macroscopic examination
No treatment-related changes were observed at post mortem examination in
treated females, when compared to the controls.
External examination of foetuses
One dead foetus was detected in one treated female and 4 small foetuses were
noted in 4 treated females. All these findings were considered incidental.
Skeletal examination of foetuses
No relevant changes were recorded at the skeletal examination of foetuses in
the treated group compared to controls.
Visceral examination of foetuses
No treatment-related differences were seen at visceral exmination of foetuses
between the control and the treated group.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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