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EC number: 242-355-6 | CAS number: 18472-87-2
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2).
Link to relevant study records
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Data is from peer-reviewed journal.
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The study was conducted to determine the reproductive toxicity potential of 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen -9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.- 18472-87-2) when administered orally to wistar pregnant rats.
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): PHLOXINE B
- Molecular formula: C20H4Br4Cl4O5.2Na
- Molecular weight: 829.64 g/mol
- Substance type: Organic
- Physical state: Red-brown powder - Species:
- rat
- Strain:
- Wistar
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Nihon Rat Co. Ltd., Tokyo.
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation:207.1-211.3g
- Fasting period before study: No data available
- Housing: Housed individually
- Diet (e.g. ad libitum): basal laboratory chow (NMF,Oriental Yeast Co., Tokyo) ad libitum
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2 degC
- Humidity (%): 50-60 %
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To: No data available - Route of administration:
- oral: feed
- Vehicle:
- other: basal laboratory chow
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Phloxine certified for food dye was obtained as powder from Hodogaya Chem. Co. Phloxine diet was prepared to contain 0, 0.3, 1.0 and 3.0% in a basal laboratory chow.
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Basal laboratory chow
- Concentration in vehicle: 0, 0.3, 1.0 and 3.0% (0, 280, 920, 2870 mg/kg/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available - Details on mating procedure:
- - M/F ratio per cage: No data available
- Length of cohabitation: Overnight
- Proof of pregnancy: Next morning those with vaginal plug or sperm in the vaginal smear were taken to be in day zero of pregnancy.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 19 days
- Frequency of treatment:
- Daily
- Details on study schedule:
- Food dye Red No.104(phloxin) was administered to Wistar pregnant rats at levels of 0, 0.3, 1, and 3% in diet during pregnancy and teratogenic effects and fetal and maternal organ distribution was examined. Suppression in maternal body weight gain and growth retardation in foetuses was observed in the highest dose group. No evidences of increase in fetal death and malformation were obtained in all groups. The postnatal development was maintained well without any adverse effects. However all newborn from 4 out of 5 dams in 3% group was killed by cannibalism within 2 days after birth.
- Remarks:
- 0, 0.3, 1.0 and 3.0% (0, 280, 920, 2870 mg/kg/day)
- No. of animals per sex per dose:
- Total animals – females 80
0%(0 mg/kg/day): 20 female
0.3%(280 mg/kg/day): 20 female
1%(920 mg/kg/day): 20 female
3%(2870 mg/kg/day): 20 female - Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- Clinical sign, body weight and body weight gain, Food and Water Consumptions and food efficiency was examined.
- Oestrous cyclicity (parental animals):
- Any irregularity in estrous cyclicity was observed. Number of corpora lutea, inplantations and rate of nidations are also examined.
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- Fetal mortality, litter size, body weight, body length, fetal resorption, sex ratio and tail length was observed. Motor activities, righting reflex, pinna reflex, pain response and startle response were also examined.
- Postmortem examinations (parental animals):
- Organ weight and gross pathology were observed.
- Postmortem examinations (offspring):
- Organ weight, visceral and skeletal anomalies, internal organ anomalies was examined.
- Statistics:
- No data available
- Reproductive indices:
- Gestation index, total implants index, birth index, weaning index and delivery index were examined
- Offspring viability indices:
- Viability in day 0, 4 and 8 week were examined.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No toxic symptoms were observed in treated dams as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose level of 3%, a slight depression of weight gain were observed, but any other toxic symptoms were not observed throughout the period of pregnancy. No marked changes in 0.3 and 1% groups were noted.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- No effect was observed in food consumption of treated rats as compared to control.
The net amounts of phloxine ingested daily during pregnancy were 2.87g/kg for 3% group, 0.92 g/kg for 1% group and 0.28g/kg for 0.3% group, respectively. - Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose level of 3%, decrease in food efficiency were observed.
- 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:
- no effects observed
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed in the number of corpora lutea or implantations and the rate of nidation of treated female rats as compared to control.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 920 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- food consumption and compound intake
- food efficiency
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive performance
- other: No adverse effects was observed.
- Critical effects observed:
- no
- Remarks on result:
- not measured/tested
- Critical effects observed:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No evidences of increase in fetal mortality.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day dose groupe as compared to control.
- 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
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control. The observed changes were not remarkable.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross pathological anomalies and skeleton were observed in treated offsprings as compared to control.
- Histopathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No evidences of fetuses with external and internal malformations were obtained in all groups.
Prenatal development In 2870 mg/kg bw/day, slight increase in nucleus with deformed shapes and low stainability insternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning. - Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- No significant difference between the phloxine-treated and control groups was found in the mean litter size, delivering rate or body weight of newborn at birth. In 3% group, however, all newborn from 4 out of 5 dams examined were killed by cannibalism of the dams within 2 days after birth. The mean litter sizes at the 4th and 8th weeks after birth were almost same among 0.3%, 1% and control groups. With the female of 3% group, significantly low body weight was obtained, but no appreciable failures.
Body lenght: Decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control.
Tail lenght: No effect were observed on tail lenght of treated offspring as comparted to control. - Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Neurobehavioural parameters: No effect were observed on motor activities, righting reflex, pinna reflex, pain response and startle response of treated offsprings as compared to control.
- Developmental immunotoxicity:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 920 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect on survival, body weight, body lenght, tail lenght, organ weight, gross pathology and histopathology
- Critical effects observed:
- no
- Remarks on result:
- not measured/tested
- Critical effects observed:
- not specified
- Reproductive effects observed:
- no
- Conclusions:
- NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2).
- Executive summary:
In a one generation reproductive toxicity study, wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) in the concentrations of 0, 280, 920, 2870 mg/kg/day (0, 0.3, 1.0 and 3.0 %) during gestation orally by feed. No toxic symptoms were observed in treated rats. No effect on food consumption and water consumptions were observed in treated rats. Slight decrease in body weight gain and decrease in food efficiency and decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control.No significant effects were observed in number of corpora lutea or implantations and the rate of nidation, organ weights and gross pathology in treated female rats as compared to control. No effect were observed on litter size and fetal mortality. Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day. Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control.The observed change in lung weight were not remarkalbe. No effect on tail lenght and gross pathology were observed in offspring. During prenatal development , slight increase in nucleus with deformed shapes and low stainability in sternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning.Therefore, NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rat treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3- oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) orally by feed.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 920 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The data is Klimicsh 2 and from peer-reviewed journal.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Various experimental studies from peer-reviewed journals has been investigated for reproductive toxicity to a greater or lesser extent for the test chemical 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (CAS Number: 18472-87-2). The studies are summarized as below:
The one generation reproductive toxicity study was conducted by Shinsuke NAKAURA et al. (J. Food Hyg. Soc. Vol. 16, No. 1, pg 34-40, 1975). Wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) in the concentrations of 0, 280, 920, 2870 mg/kg/day (0, 0.3, 1.0 and 3.0 %) during gestation orally by feed. No toxic symptoms were observed in treated rats. No effect on food consumption and water consumptions were observed in treated rats. Slight decrease in body weight gain and decrease in food efficiency and decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control. No significant effects were observed in number of corpora lutea or implantations and the rate of nidation, organ weights and gross pathology in treated female rats as compared to control. No effect were observed on litter size and fetal mortality. Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day. Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control. The observed change in lung weight were not remarkalbe. No effect on tail lenght and gross pathology were observed in offspring. During prenatal development , slight increase in nucleus with deformed shapes and low stainability in sternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning. Therefore, NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rat treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3- oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) orally by feed.
Further, the study was published in a SCCNFP report (COLIPA n° C53, SCCNFP/0788/04, 23 April 2004), in which the reproductive toxicity potential of 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (Phloxine) (CAS No.- 18472-87-2) was determined when administered orally to HanBrl: WIST(SPF) rats. Range finding study was conducted using 5 females (mated) HanBrl: WIST(SPF) rats. No toxic effects was observed on a range-finding study. 10, 50 and 250 mg/kg bw/day were selected as dose levels for a subsequent prenatal developmental toxicity study. The female HanBrl: WIST(SPF) rats were given Phloxine at concentrations of 0, 10, 50 and 250 mg/kg bw/day from day 6 through day 20 of gestation.
In the main study 1 low- and 1 mid-dose female died due to dosing error but no test-substance related effects were observed. Reddish faeces were observed in all test groups. Transient slight reductions inbody weight gainand food intake at 250 mg/kg bw/day were observed.No treatment related effects were observed on reproductive parameters tested. Reddish stomach/ intestinal content in mid- and high-dose group was observed.No treatment related effects were observed ongeneral foetal data, foetal visceral examination and foetal skeletal examination.
The test substance 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (Phloxine) (CAS No.- 18472-87-2)elicited slight maternal toxicity at 250 mg/kg bw/day but was not embryotoxic or teratogenic at the doses tested. The NOAEL for maternal toxicity was considered to be 50 mg/kg bw/day whereas NOAEL for teratogenicity study was considered to be 250 mg/kg bw/day.
Moreover, the present study was conducted by M. SENO et al., (Fd Chem. Toxic. Vol. 22, No. 1 pp. 55-60, 1984) to determine the reproductive toxicity potential of 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (Phloxine B) (CAS No.- 18472-87-2) when administered orally to pregnant Jcl:ICR mice. Pregnant Jcl:ICR mice were given Phloxine B in the diet at concentrations of 0, 1, 3 and 5%(0, 2000, 6000 and 10000 mg/kg/day)from the morning of day 6 through day 16 of gestation. The mice were killed on day 18 and foetuses were examined for external, visceral and skeletal anomalies. A significant decrease in body-weight gain was observed in all of the treated groups. Among the dams in the high-dose group, two maternal deaths, one abortion and a significant increase in liver weight were observed; none of these effects occurred at the lower dose levels. However, the 3% group, in which maternal toxicity was found only as a decrease in maternal bodyweight gain. A dose-related incidence of splitting of the cervical vertebral arches (nos 3-6) was noted in all of the treated groups, but this anomaly was not found in the controls. The total incidence of skeletal anomalies was also dose related and was significantly increased at the 3 and 5% dose levels. Therefore, NOAEL for maternal toxicity study (F0 -generation) was considered to be 2000.0 mg/kg/day (1%) and LOAEL for F1 generation was 2000.0 mg/kg bw/day (1%) when Jcl:ICR female mice were treated with 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Phloxine B) (CAS No. 18472-87-2). orally by feed from day 6 to 16 of gestation.
So, based on the above mentioned studies for target substance 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (CAS Number: 18472-87-2), it was found that no adverse effects on sexual function and fertility was observed. Therefore, according to CLP criteria, the substance 3,4,5,6-tetrachloro-2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (CAS Number: 18472-87-2) cannot be classified as reproductive toxicant.
Effects on developmental toxicity
Description of key information
NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2).
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Data is from peer-reviewed journal
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Effects of Food Dye Red No.104 (Phloxine) on the Pre and Postnatal Development in Rats in Relation to Fetal distribution were observed.
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): PHLOXINE B
- Molecular formula: C20H4Br4Cl4O5.2Na
- Molecular weight: 829.64 g/mol
- Substance type: Organic
- Physical state: Red-brown powder - Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Nihon Rat Co. Ltd., Tokyo.
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation:207.1-211.3g
- Fasting period before study: No data available
- Housing: Housed individually
- Diet (e.g. ad libitum): Basal laboratory chow (NMF,Oriental Yeast Co., Tokyo) ad libitum
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2 degC
- Humidity (%): 50-60 %
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To: No data available - Route of administration:
- oral: feed
- Vehicle:
- other: basal laboratory chow
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Phloxine certified for food dye was obtained as powder from Hodogaya Chem. Co. Phloxine diet was prepared to contain 0, 0.3, 1.0 and 3.0% in a basal laboratory chow.
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Basal laboratory chow
- Concentration in vehicle: 0, 0.3, 1.0 and 3.0% (0, 280, 920, 2870 mg/kg/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage: No data available
- Length of cohabitation: Overnight
- Proof of pregnancy: Next morning those with vaginal plug or sperm in the vaginal smear were taken to be in day zero of pregnancy.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available - Duration of treatment / exposure:
- 19 days
- Frequency of treatment:
- Daily
- Duration of test:
- Upto day 57 after litter birth
- Remarks:
- 0, 0.3, 1.0 and 3.0% (0, 280, 920, 2870 mg/kg/day)
- No. of animals per sex per dose:
- Total animals – females 80
0%(0 mg/kg/day): 20 female
0.3%(280 mg/kg/day): 20 female
1%(920 mg/kg/day): 20 female
3%(2870 mg/kg/day): 20 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- Clinical sign, body weight and body weight gain, Food and Water Consumptions and food efficiency was examined.
- Ovaries and uterine content:
- Number of corpora lutea, inplantations and rate of nidations are also examined.
- Fetal examinations:
- Fetal mortality, litter size, body weight, body length, fetal resorption , sex ratio and tail length, Motor activities, righting reflex, pinna reflex, pain response and startle response, Organ weight, visceral, skeletal anomalies and internal organ anomalies was examined.
- Statistics:
- No data available
- Indices:
- Gestation index, total implants index, birth index, weaning index and delivery index were examined.
- Historical control data:
- No data available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No toxic symptoms were observed in treated dams as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose level of 3%, a slight depression of weight gain were observed, but any other toxic symptoms were not observed throughout the period of pregnancy. No marked changes in 0.3 and 1% groups were noted.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- No effect was observed in food consumption of treated rats as compared to control.
The net amounts of phloxine ingested daily during pregnancy were 2.87g/kg for 3% group, 0.92 g/kg for 1% group and 0.28g/kg for 0.3% group, respectively. - Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose level of 3%, decrease in food efficiency were observed.
- 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:
- no effects observed
- Description (incidence and severity):
- No significant differences between the phloxine-treated and control groups were found in the uterus and placental weight.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No significant gross pathological changes were observed in treated female rats as compared to control.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- 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:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Reproductive performance:No significant effect were observed in number of corpora lutea or implantations and the rate of nidation of treated female rats as compared to control.
- Dose descriptor:
- NOAEL
- Effect level:
- 920 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- food efficiency
- gross pathology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- other: No adverse effect on reproductive performance was observed.
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related - Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Mortality: No effect were observed on litter size and fetal mortality of treated rats as compared to control.
Body weight:Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day dose group as compared to control.
Body lenght: Decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control.
Tail lenght: No effect were observed on tail lenght of treated offspring as comparted to control.
Neurobehaveal parameters: No effect were observed on Motor activities, righting reflex, pinna reflex, pain response and startle response of treated offsprings as compared to control.
Organ weights:Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control. The observed change were not remarkalbe.
Gross pathology:No gross pathological anomalies were observed in treated offsprings as compared to control.
Histopathology:Prenatal development In 2870 mg/kg bw/day, slight increase in nucleus with deformed shapes and low stainability insternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning.
Postnatal development:No skeleton anomalies were observed in treated offsprings as compared to control. - Dose descriptor:
- NOAEL
- Effect level:
- 920 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect on survival, body weight, body lenght, tail lenght, organ weight, gross pathology and histopathology.
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rats treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2).
- Executive summary:
In a developmental toxicity study, wistar female rats treated with 3,4,5,6-tetrachloro-2 -(1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9 -yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) in the concentrations of 0, 280, 920, 2870 mg/kg/day (0, 0.3, 1.0 and 3.0 %) during gestation orally by feed. No toxic symptoms were observed in treated rats. No effect on food consumption and water consumptions were observed in treated rats. Slight decrease in body weight gain and decrease in food efficiency and decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control. No significant effects were observed in number of corpora lutea or implantations and the rate of nidation, organ weights and gross pathology in treated female rats as compared to control. No effect were observed on litter size and fetal mortality. Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day. Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control.The observed change in lung weight were not remarkalbe. No effect on tail lenght and gross pathology were observed in offspring. During prenatal development , slight increase in nucleus with deformed shapes and low stainability in sternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning.
Therefore, NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rat treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3 -oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) orally by feed.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 920 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The data is Klimicsh 2 and from peer-reviewed journal.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The effect of oral 3,4,5,6-tetrachloro-2 -(1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9 -yl)benzoic acid (CAS No.18472-87-2) exposure on mammalian development has been fully investigated. The studies are summarized as below:
In a developmental toxicity study conducted by Shinsuke NAKAURA et al. (J. Food Hyg. Soc. Vol. 16, No. 1, pg 34-40, 1975), wistar female rats treated with 3,4,5,6-tetrachloro-2 -(1,4,5,8-tetra bromo-6-hydroxy-3-oxoxanthen-9 -yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) in the concentrations of 0, 280, 920, 2870 mg/kg/day (0, 0.3, 1.0 and 3.0 %) during gestation orally by feed. No toxic symptoms were observed in treated rats. No effect on food consumption and water consumptions were observed in treated rats. Slight decrease in body weight gain and decrease in food efficiency and decrase in body lenght was observed in 2870 mg/kg/day treated offsprings as compared to control. No significant effects were observed in number of corpora lutea or implantations and the rate of nidation, organ weights and gross pathology in treated female rats as compared to control. No effect were observed on litter size and fetal mortality. Significantly decrease in body weight was observed in female offspring at 2870 mg/kg/day. Significant effect were observed in lung weight of male rats at 920 mg/kgbw/day as compared to control.The observed change in lung weight were not remarkalbe. No effect on tail lenght and gross pathology were observed in offspring. During prenatal development , slight increase in nucleus with deformed shapes and low stainability in sternebrae and decreases in the number of metacarpus and coccygeal vertebrae were observed. These findings may suggest a retardation of ossification in fetal stage, but such changes were not observed in rats examined after weaning.
Therefore, NOAEL was considered to be 920 mg/kg/day for F0 and F1 generation when Wistar female rat treated with 3,4,5,6-tetrachloro-2- (1,4,5,8-tetra bromo-6-hydroxy-3 -oxoxanthen-9-yl)benzoic acid (Food dye Red No.104 / phloxine) (CAS No.18472-87-2) orally by feed.
Moreover, the study published in a SCCNFP report (COLIPA n° C53, SCCNFP/0788/04, 23 April 2004). reveals that the developmental toxicity potential of 3,4,5,6-tetrachloro-2 -(1,4,5,8-tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (Phloxine) (CAS No.- 18472-87-2) was determined when administered orally to HanBrl: WIST(SPF) rats. Range finding study was conducted using 5 females (mated) HanBrl: WIST(SPF) rats. No toxic effects was observed on a range-finding study. 10, 50 and 250 mg/kg bw/day were selected as dose levels for a subsequent prenatal developmental toxicity study. The female HanBrl: WIST(SPF) rats were given Phloxine at concentrations of 0, 10, 50 and 250 mg/kg bw/day from day 6 through day 20 of gestation.
In the main study 1 low- and 1 mid-dose female died due to dosing error but no test-substance related effects were observed. Reddish faeces were observed in all test groups. Transient slight reductions in body weight gain and food intake at 250 mg/kg bw/day were observed. No treatment related effects were observed on reproductive parameters tested. Reddish stomach/ intestinal content in mid- and high-dose group was observed.No treatment related effects were observed ongeneral foetal data, foetal visceral examination and foetal skeletal examination. The test substance 3,4,5,6-tetrachloro-2-(1,4,5,8- tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (Phloxine) (CAS No.- 18472-87-2) elicited slight maternal toxicity at 250 mg/kg bw/day but was not embryotoxic or teratogenic at the doses tested. The NOAEL for maternal toxicity was considered to be 50 mg/kg bw/day whereas NOAEL for teratogenicity study was considered to be 250 mg/kg bw/day.
Thus, on the basis of above available studies and by comparing these with the CLP criteria, it can be concluded that no adverse effects on develop ment of the offspring was observed. Therefore the substance 3,4,5,6-tetrachloro-2 -(1,4,5,8-tetrabromo-6-hydroxy- 3-oxoxanthen-9-yl) benzoic acid (CAS No.- 18472-87-2) can be regarded as not owing a significant potential for developmental toxicity.
Justification for classification or non-classification
Based on the available data for the assessment of reproductive toxicity and following Regulation (EC) 1272/2008 no classification of 3,4,5,6- tetrachloro- 2-(1,4,5,8-tetrabromo-6-hydroxy-3-oxoxanthen-9-yl)benzoic acid (CAS Number: 18472-87-2) as reproductive toxicant is warranted.
Additional information
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