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EC number: 609-099-0 | CAS number: 352303-67-4
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.4420 (Preliminary Developmental Toxicity Screen)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (2-fluoro-3-methoxyphenyl)boronic acid
- EC Number:
- 609-099-0
- Cas Number:
- 352303-67-4
- Molecular formula:
- FC6H3(OCH3)B(OH)2
- IUPAC Name:
- (2-fluoro-3-methoxyphenyl)boronic acid
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- CAS No.: 352303-67-4
Physical status: Off-white powder
Purity: 100.2%
Batch No.: 18051400
Expiry date: March 14, 2019
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing Vital River Laboratory animal technology Co., Ltd. with Test Animals Quality Certification in Beijing of SCXK (Jing) 2016-0006 and the certificate number of 11400700318207.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Animals were 56-62 days old on arrival
- Weight at study initiation: (P) Males: 280-330g Females: 190-230g
- Fasting period before study: not specified
- Housing: Suspension steel cages on cage racks, 2 rats per cage, during mating animal were housed in mating cages and after mating female rats were housed in plastic cages with cob bedding and prior to parturition females were housed on wood shavings
- Diet (e.g. ad libitum): During the test, all animals were provided with an unlimited supply of feed and water
- Water (e.g. ad libitum): yes
- Acclimation period: not
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- All animals were administered once daily in the morning and seven times per week. The dosing volume of each animal was adjusted based on the latest body weight.
Administration period: Animals were dosed always until the day before dissection.
During childbirth, pregnant rats could not be dosed. - Details on mating procedure:
- Animals were mated after administration for two weeks. During the mating period, female rats and male rats were put together as one to one ratio for two weeks. At the beginning, female and male rats were put into mating cages and inspected in the next morning. Then the female rats were examined for presence of the vaginal plug using vaginal smear method. The day of finding the sperm or vaginal plug was defined as day O of pregnancy (GDO).
- Analytical verification of doses or concentrations:
- no
- Remarks:
- There were no concentration, stability and homogeneity analysis in this study. So the test item was prepared daily during dosing period and mixed adequately before using
- Duration of treatment / exposure:
- All animals were dosed during two weeks prior to mating, two weeks of the mating period, and up to the day before scheduled kill.
- Frequency of treatment:
- daily seven times per week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 400 mg/kg bw/day (nominal)
- Dose / conc.:
- 160 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 4 male/ 4 female
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
During the administration, a cage-side observation was made at least once a day and could be along with administration; a detailed observation with handling was made once per week and it could be in company with the animal weighing. All animals were observed for morbidity and mortality twice daily (once daily on non working day).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily and once per week
a) Cage-side observation: observe the appearance, fur, activity, reaction, breathing, posture, excrement and urine.
b) Observation with handling: take out the animal from the cage and put on a table, observe any abnormality of neck, head (including eyes, ears, mouth and nose), back, abdomen, anus, skin color around perineum, muscle tension, any trauma and tumour.
BODY WEIGHT: Yes
Time schedule for examinations: All animals were weighed at grouping, and once per week during the premating and mating period; all pregnant rats were weighed on day 0, 7, 14, 20 during the gestation period; parental rats and pups were weighed on PNDO and PND4 of lactation. Then mother rats were weighed once per week to adjust administration. All animals were weighed on the day of scheduled kill.
Other:
All pregnant rats were observed for parturition from GD21 twice daily in the morning and afternoon respectively (once daily on non working day). Any difficulties and abnormalities occurring during parturition were recorded on that parturition is observed to finish was considered as postnatal day (PNDO). - Postmortem examinations (parental animals):
- During the study, a necropsy were performed on animal of death inter currently or morbidity and mortality, males after the end of the mating period; all mother rats and non-mated females after the day on PND4 of the last parturition pups. Animals were euthanized by C02 inhalation followed by examinations from abdominal aorta and subjected to a full necropsy and general observation. The necropsy included carefully examinations of the external features of the carcass, external body orifices, the abdominal, thoracic, and cranial cavities and their contents of all animals, and the location, size, hardness and the color of the abnormal findings were recorded. Special attention was paid to the organs of the reproductive system. For the parous females, the number of implantation sites in the uteri was recorded.
Weigh testicle and epididymis of both sides. - Offspring viability indices:
- On PNDO, the number of live births, stillbirths, grossly malformed pups and grossly puniness pups were recorded and evaluated. Observe pups whether signs and behavior disorders or not until PND4. Record the number of live births and malformed pups on PND4.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- During the study, in low-dose group one male had tumor and one male had dehairing and scab, two females in control and low-dose group separately had emaciation and soiled perinea region.
- Mortality:
- not specified
- Description (incidence):
- 0, 2, 1 and 1 males in control and low-, mid- and high-dose groups were found accidental death, 2, 0, 2 and 2 females were found accidental death. The symptom incidence rate and animal death rate had no statistically significant increase compared with the control group (p>0.05) and no dose correlation, the death and abnormality was not considered dependent of the test item toxicity.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- During premating and mating period, the mean body weight and the body weight gain of males in all dose groups had no significantly difference compared with the solvent control group (p>0.05). During premating period, no significantly difference of females for mean body weight and body weight gain were observed in all dose groups compared with the solvent control group (p>0.05). During gestation period, the body weight of pregnant rats in high-dose group during pregnant period (GD7, GD14) had a statistically significant increase compared with the control group (p>0.05), but no toxicology significance. During lactation period , there was no significantly difference of mother rats' body weight and body weight gain in all dose groups compared with the solvent control group (p>0.05).
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- During the premating period, the mean food consumption and total food consumption of males in all dose groups had no significantly difference compared with the solvent control group (p>0.05). During the premating period, the mean food consumption and total food consumption of females in high-dose group had a statistically significant increase compared with the control group (p>0.05 or p> 0.01), no significantly difference was found in low- and mid-dose groups(p>0.05); The food consumption of pregnant rats on GD14 in high-dose group had a statistically significant increase compared with the control group (> 0.01), no significantly difference was found in low- and mid-dose groups(p>0.05). There was no significantly difference on the food consumption of the dams during the lactation period in all dose groups compared with the solvent control group (p>0.05). According to the results above, the test item may activate the increase of food consumption, but males were not found similar effect, and no dose-dependent adverse effect was observed, so it was considered that the results had no correlation with the test item toxicity.
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The animal of the control and high-dose groups were preserved and examined including males' testis and epididymis, females' ovaries, among all scheduled necropsy animals, one male in mid- and high-dose groups was observed with epididyrnis inflammatory cell infiltration respectively, one female in mid-dose group was observed with ovary cyst, one female in high-dose group was observed with ovary corpora lutea degeneration; But no statistics significance (p>0.05); No toxicity histopathological abnormity of all inspected animals was observed.
Reproductive function / performance (P0)
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Weigh testicle and epididymis of both sides about all male rats, and calculate relatively viscera weight based on the terminal weight; the relatively epididymis, the testicle and terminal bodyweight in all dose group had no significantly difference compared with the solvent control group (P>0.05).
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Fourteen female rats and fourteen male rats (13 males in high-dose group) were put together as one to one ratio for mating in this study. There were 13, 14, 14 and 13 mated male rats in the solvent control groups and 60, 160, 400mg/kg/bw; there were 13, 14, 13 and 13 mated female rats which were found vaginal plug, and one female in the mid- and high-dose group each were not found accurate mated evidence but pregnant, so the successful mated females in the mid- and high-dose group were 14; and 13, 13, 12 and 14 pregnant female rats; 12, 11, 10 and 12 pregnant rats had live pups; and 1, 5, 3 and 1 pregnant rats respectively had at least one stillbirth pup, one pregnant rats in low-dose group had all pups being stillbirth; 1, 0, 1 and 2 pregnant rats died during pregnancy period which were observed fetus rats in uterus when necropsy; one dam died during lactation period in control and mid-dose groups respectively; There was no significantly difference of the results above in all dose groups compared with the solvent control group (p>0.05), so it was considered that the results had no correlation with the test item toxicity; no pregnant rats died for dystocia.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 400 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Dose descriptor:
- NOAEL
- Effect level:
- 400 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
Results: F1 generation
General toxicity (F1)
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- The live births index of pups in high-dose group had a statistically significant increase compared with the control group (p >0.05), the live births index of pups in low-dose group had a statistically significant decrease compared with the control group (p > 0.05), no significantly difference in mid-dose group was found(p>0.05), as a result of no dose correlation, so that was considered no toxicology significance.
The pup viability index in high-dose group had a statistically significant decrease compared with the control group (p > 0.01), which was considered attributing the death of all 20 pups in animal 2309, causing by individual litter data, no correlation with the test item administration, no significantly difference of pup viability index in low- and mid-dose group was found(p>0.05), The post-implantation loss in mid-dose group had a statistically significant decrease compared with the control group (p,s;0.05), but without toxicology significance, no significantly difference were observed of pups post-implantation loss in low- and high-dose group(p>0.05); The males ratio of low-dose group had a statistically significant increase compared with the control group (p ,s; 0.05), but no significantly difference were observed in mid- and high-dose groups, no dose correlation, so that was considered without correlation with the test item administration. There was no significantly difference in average implantation number, live births number, stillbirth number and live pups number on PND4 compared with the solvent control group (p>0.05). - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There was no significantly difference in average litter weight in all dose groups compared with the solvent control group (P>0.05) in PNDO and PND4
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No malformation and significantly abnormality of all live pups in all groups were observed from birth to study ending (p>0.05).
- Other effects:
- no effects observed
- Description (incidence and severity):
- No malformation and significantly abnormality of all live pups in all groups were observed from birth to study ending (p>0.05).
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 400 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- viability
- body weight and weight gain
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
- Lowest effective dose / conc.:
- 400 mg/kg bw/day (nominal)
- Treatment related:
- no
Applicant's summary and conclusion
- Conclusions:
- For fertility and development, there was no adverse effect on the fertility of males and females in 400mg/kg.bw group; there was no adverse effect on the growth and development of pups, so it was considered FMPBA had no obvious fertility and development toxicity for rats at 400mg/kg.bw dose level.
Based on the results above, it is concluded that the No Observed Adverse Effect Level (NOAEL) for general toxicity to parent rats for exposure to FMPBA by oral is 400mg/kg.bw; The NOAEL for reproduction toxicity to parent rats for exposure to the test item by oral is 400mg/kg.bw, the NOAEL for developmental toxicity to pups for exposure to the test item by oral is 400mg/kg.bw. - Executive summary:
This study was conducted to provide initial information on possible effects on reproduction/ developmental toxicity of FMPBA, following exposure by oral in rats, also to be used as a dose range finding study for other reproduction/developmental studies. The method of this test was designed to be compatible with Guidelines for the Testing of Chemicals (the second edition), No.421:Reproduction/Developmental Toxicity Screening Test, State Environmental Protection Administration (2013 ).
This study was conducted in SD rats and all animals were SPF grade. Based on the preliminary results of the preliminary test for the repeated dose oral toxicity, three doses of 400, 160 and 60mg/kg.bw were used in the study, a concurrent solvent control was included. There were fourteen male and fourteen female rats in each group. All animals were dosed during two weeks prior to mating, two weeks of the mating period, and up to the day before scheduled kill. The test was finished after four days of the last litter pups birth. The clinical observations were made daily, and body weight and food consumption were weighed weekly. The reproductive/developmental parameters were evaluated at the same time. All parental animals were macroscopically examined for any abnormalities and pathological changes. The histopathology examination was made for the reproduction organs of rats in the control group and high-dose group. During the study, no test item administration correlative abnormity symptom was found in all dose groups. 0, 2, 1 and 1 males in control and low-, mid- and high-dose groups were found accidental death, 2, 0, 2 and 2 females were found accidental death. But the animal death rate had no statistically significant increase compared with the control group (p>0.05), the death and abnormity was not considered dependent of the test item toxicity.
During the study, the body weight of males in all dose groups had no adverse effect; during gestation period, the body weight of pregnant rats in high-dose group during pregnant period (GD7, GD14) had a statistically significant increase compared with the control group (p:s;0.05), but no toxicology significance. During the premating period, the food consumption of males in all dose groups had no significantly difference compared with the solvent control group, but the mean food consumption and total food consumption of females in high-dose group had a statistically significant increase compared with the control group (p:s;0.05 or p:S0.01), and the food consumption of pregnant rats on GD14 in high-dose group had a statistically significant increase compared with the control group (p:s;0.01), it was considered the test item in this dose may activate the increase of food consumption, but males were not found similar effect, and no dose-dependent adverse effect was observed, so it was considered that the results had no correlation with the test item toxicity. There were no significantly difference of males mating index, fertility index in all dose groups compared with the solvent control group (p>0.05); There were no significantly difference of females mating index, fertility index, fecundity index and gestation index in all dose groups compared with the solvent control group (p>0.05), and there were no significantly difference of females mating time and gestation days in all dose groups compared with the solvent control group (p>0.05).
The pup viability index in high-dose group had a statistically significant decrease compared with the control group (p:s;0.01), the live births index of pups in low-dose group had a statistically significant decrease compared with the control group (p:s;0.05), but the results of above were considered attributed to the death of all pups in single litter in corresponding dose group, caused by individual difference, no correlation with the test item administration. The males ratio of low-dose group had a statistically significant increase compared with the control group (p:s;0.05), but no significant differences were observed in mid- and high-dose groups, without dose correlation, so that was considered without correlation with the test item administration. There was no significantly difference in average implantation number, live births number, stillbirth number and live pups number compared with the solvent control group (p>0.05).
The inspection of gross necropsy and histopathological examination was done to animals, no significantly difference of gross necropsy and histopathology examination were found to be related with the test item treatment. Exposure of rats to different doses of FMPBA by oral resulted that, no test item disposal correlated animal death and toxicity symptom was found in 60, 160, 400mg/kg.bw dose groups, so it was considered the test item had no obvious general toxicity to parent rats at 400mg/kg.bw dose group.
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