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EC number: 939-505-4 | 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
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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:
- 10 April 2003 - 2 June 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study was conducted according to GLP and an equivalent of OECD guideline 421.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of t-butylphenyldiphenyl phosphate and bis-t-butylphenylphenyl phosphate and triphenyl phosphate
- IUPAC Name:
- Reaction mass of t-butylphenyldiphenyl phosphate and bis-t-butylphenylphenyl phosphate and triphenyl phosphate
- Reference substance name:
- Phosflex 61B
- IUPAC Name:
- Phosflex 61B
- Details on test material:
- - Name of test material (as cited in study report): Phosflex 61B
- Physical state: Liquid
- Analytical purity: No data
- Storage condition of test material: At room temperature protected from light
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Age at study initiation: (P) 8 wks
- Weight at study initiation: (P) Males: 226-262 g; Females: 156-193 g
- Housing: Individually, in accordance with the Guide for the Care and Use of Laboratory Animals (1996)
- Diet (e.g. ad libitum): Ad libitum, certified rodent diet
- Water (e.g. ad libitum): Ad libitum, municipal water
- Acclimation period: approx. 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8-26.1
- Humidity (%): 30-70
- Air changes (per hr): min. of 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared approximately every 4 weeks at graded concentrations of 25, 125 and 500 mg/ml and adminstered at a dosing volume of 2 ml/kg.
VEHICLE
- Concentration in vehicle: 25, 125 and 500 mg/ml
- Amount of vehicle (if gavage): 2 ml/kg
- Lot/batch no. (if required): 062K0006 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: up to 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually in shoebox cage - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test substance in corn oil was analysed by HPLC/UV for homogenicity, stability and concentration.
- Duration of treatment / exposure:
- - Female: 2 weeks prior to mating, during mating period (up to 2 weeks) and during gestation, lactation and until post-partum day 4
- Male: 2 weeks prior to mating, during mating period (up to 2 weeks) and additionally treated for a total minimum of 35 consecutive days - Frequency of treatment:
- Daily
- Details on study schedule:
- Not relevant, as the study is a screening study (only P exposed to test article)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
50, 250, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on findings from previous toxicity studies with the test material
- Rationale for animal assignment (if not random): At random - Positive control:
- Not relevant
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily
- Cage side observations: moribundity and mortality, general appearance, overt signs of toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations:
Not measured during cohabitation
Males: prior to treatment initiation and weekly thereafter
Females: GD 0,7, 14 and 20, PD 0 and 4
Fasted body weight collected prior to terminal sacrifice, except in lactating females.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly prior to mating.Not measured during cohabitation. Females: GD 0, 4, 7, 14 and 20, PD 0 and 4. Males: weekly until sacrifice. - Oestrous cyclicity (parental animals):
- Not performed
- Sperm parameters (parental animals):
- Not performed
- 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, fetal weight (litter weight)
GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY
The following tissues were preserved: vagina, ovaries with oviducts, pituitary gland, cervix, testes, epididymides, seminal vesicles, prostate, coagulating gland and uterus.
Evaluation of histopathology and organ weights was performed for the ovaries, testes and epididymides from animals in the vehicle control and high-dose groups (10/sex/group). - Postmortem examinations (offspring):
- Not performed
- Statistics:
- - Mean and SD
- One-way ANOVA (homogeneity in variance)
- Post-hoc comparisons using Dunnett's test (when main effect differences were found)
- Chi-square test (mating performance and absolute pup survival) - Reproductive indices:
- Not calculated
- Offspring viability indices:
- Not calculated
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- not considered treatment related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- not considered treatment related
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
No mortality and no treatment related clinical signs observed.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No difference in body weight or body weight gain for treated males as compared to the control group. For treated female groups, significant increases in body weight were noted as compared to the control group (low dose: GD7 and 14, mid/high dose: GD 0, 7, 14 and at termination). Body weight gain was only significantly increased during week 1 of precohabitation. These effects were considered to be unrelated to treatment, as they were not observed in males.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment related effects on mating index and length of gestation.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects on male organ weights were noted. Only the fasted weight was significantly increased in the mid and high dose group females, but this was considered to be caused by the increase in body weight.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment related effects observed in both males and females.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment related effects observed in both males and females.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- not considered treatment related
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Details on results (F1)
The post-implantation loss was higher in the mid and high dose groups (not statistically significant). However, a statistically significant increase in the absolute number of stillbirths in the mid and high dose groups was noted. For the mid dose group this was caused by 10 deaths in one litter. The number of litter deaths between PD0-4 was significantly decreased for all treatment groups. The overall number of litter deaths was only significantly decreased for the low dose group. Due to the lack of a dose related response and similar overall deaths across the groups, the effects were considered unrelated to treatment.
BODY WEIGHT (OFFSPRING)
No effects were noted on the mean body weights of litters during PD0-4.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
RESULTS OF TEST | DOSING GROUPS | |||
Control | Low (50 mg/kg bw/day) | Medium (250 mg/kg bw/day) | High (1000 mg/kg bw/day) | |
ANALYSES | ||||
Stability | Greater than 7 weeks | |||
Concentration | Within 5% of target concentrations | |||
Homogeneity | Within 5% of target concentrations | |||
PATERNAL TOXIC EFFECTS BY DOSE LEVEL | ||||
Number of animals (M) | 12 | 12 | 12 | 12 |
Mortality | X | X | X | X |
Clinical signs | X | X | X | X |
Body weight | X | X | X | X |
Body weight gain | X | X | X | X |
Food consumption | X | X | X | Significantly increased in week 5 |
Gross necropsy | X | X | X | X |
Organ weights changes (relative and absolute) | X | X | X | X |
Histopathology | X | X | X | X |
MATERNAL TOXIC EFFECTS BY DOSE LEVEL | ||||
Number of animals (F) | 12 | 12 | 12 | 12 |
Mortality | X | X | X | X |
Clinical signs | X | X | X | X |
Body weight | X | Significantly increased on GD 7 and 14 | Significantly increased on GD 0, 7 and 14 and at termination | Significantly increased on GD 0, 7 and 14 and at termination |
Body weight gain | X | Significantly increased during week 1 of precohabitation | Significantly increased during week 1 of precohabitation (also resulting in increased total gain) | Significantly increased during week 1 of precohabitation (also resulting in increased total gain) |
Food consumption | X | Significantly increased in week 1 | X | Significantly increased on GD 14 and 20 |
Number pregnant per dose level | 11 | 12 | 11 | 12 |
Number of corpora lutea | 148 | 159 | 146 | 176 |
Pre-implantation loss | 6 | 8 | 8 | 10 |
Number of implantations | 142 | 151 | 138 | 166 |
Post-implantation loss | 12 | 8 | 30 | 20 |
Duration (days) of pregnancy (mean +/- SD) | 22.1 +/- 0.7 | 22.3 +/- 0.62 | 22.5 +/- 0.82 | 22.1 +/- 0.29 |
Number of pups born | 130 | 145 | 121 (109 after correction for 1 litter, which was excluded due to water deprivation) | 154 |
Number of stillborn fetuses | 0 | 2 | 13* (increase, but caused by 10 deaths in one litter) | 9* (increase) |
Number alive on day 0 | 130 | 143 | 108 (96 after correction for 1 litter, which was excluded due to water deprivation) | 145 |
Gross necropsy | X | X | X | X |
Organ weights changes (relative and absolute) | X | X | Significantly increased fasted weight | Significantly increased fasted weight |
Histopathology | X | X | X | X |
FETAL DATA | ||||
Number of litters | 11 | 12 | 11 | 12 |
Mean litter size | 11.8 | 12.1 | 11.0 | 12.8 |
Sex ratio (M/F) | 0.9:1 | 1.4:1 | 1.1:1 | 0.8:1 |
Body weights per litter | X | X | X | X |
Mean postnatal survival per litter (day 0-4) | 10.7 | 11.6 | 8.7 | 11.8 |
Mean postnatal deaths per litter (day 0-4) | 1.1 | 0.2 | 1.2 | 0.3 |
Absolute numbers of postnatal survival (day 0-4) | 118 | 141 | 96 (one litter excluded, due to water deprivation) | 145 |
Absolute numbers of postnatal deaths (day 0-4) | 12 | 2* (decrease) | 0* (decrease) | 4* (decrease) |
Total number of deaths | 12 | 4* (decrease) | 13 (caused by 10 deaths in 1 litter) | 13 |
X = no effects (as compared to control group) | ||||
* = significant difference (as compared to control group) |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, oral (gavage) administration of Phosflex 61B to rats did not result in overt signs of parental toxicity. This also accounts for the offspring. Therefore, the NOAEL for parental and developmental toxicity was established to be 1000 mg/kg bw/day.
- Executive summary:
Phosflex 61B was administered in doses of 0, 50, 250 or 1000 mg/kg bw/day to rats. Treatment was done 2 weeks prior to mating, during mating (male/female) and for female during gestation, lactation and post partum up to day 4. Males were treated for at least 35 consecutive days. Mortality, clinical signs, body weights, food consumption were recorded in the parental animals. Also gross necropsy and organ weights and histopathology for the reproductive organs were studied. Reproductive performance was determined as well. For the litters, viability, fetal and litter weights and gross anomalies were recorded.
No mortality or overt signs of parental toxicity were observed in the parental rats. No effect was seen on body weight and food consumption, while reproductive performance was normal. Gross necropsy and organ weight data and histopathology of the reproductive organs revealed no adverse findings.
Mean litter size and mean number of live pups was comparable between the treatment groups. Additionally, no effects on litter weights were observed. Percent post-implantation loss was higher in 250 and 1000 mg/kg groups (not statistically significant). Subsequently, a statistically significant increase in the absolute number of stillbirths in the 250 and 1000 mg/kg groups was noted. However, overall a similar number of pup deaths was observed across all groups. While the incidence was the same, the timing of the event was somewhat different. In the 250 and 1000 mg/kg groups, most of the deaths occurred on day 0, while this was after day 0 in the control group. Overall, pup survival from day 0 to 4 was lower in the 250 mg/kg group (due to 10 deaths in one litter), higher in the 50 mg/kg group and approximately the same as control in the 1000 mg/kg group.
Under the conditions of this study, oral (gavage) administration of Phosflex 61B to rats did not result in overt signs of parental toxicity. This also accounts for the offspring. Therefore, the NOAEL for parental and developmental toxicity was established to be 1000 mg/kg bw/day.
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