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EC number: 202-200-5 | CAS number: 92-88-6
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- The study was conducted in accordance with OECD Test guideline No 422 and with the principles of GLP
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- This study (OECD 422) investigates both the fertility toxicity and the developmental toxicity.
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- The study was conducted in accordance with OECD Test guideline No 422 and with the principles of GLP
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- This study (OECD 422) investigates both the fertility toxicity and the developmental toxicity.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- Study was in accordance with the range-finding assay described in OECD method 422.
Males were treated for 42 days, with a satellite high dose group retained for a further 15 days to demonstrate recovery after treatment.
The females were treated for 14 days prior to mating and then through gestation to lactation day 4. A high dose satellite recovery group of females was also retained for fifteen days following completion of treatment. - GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- - Purity: 99.96%
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Crj:CD(SD)IGS rats used but no details provided regarding supplier
- Age at study initiation: (P) x wks; (F1) x wks No data
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
IN-LIFE DATES: From: not stated To: not stated - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% sodium carboxymethylcellulose solution
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water):0.5% sodium carboxymethylcellulose solution used as suspending agent - Details on mating procedure:
- - M/F ratio per cage: 1:1.
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No information provided
- Duration of treatment / exposure:
- Males were dosed for 42 days prior to mating; the females were treated for 14 days prior to mating and then until day 4 of lactation. The female satellite animals were treated or 42 days. The recovery period for males and satellite females was 14 days. The males were terminated on day 43 of treatment (day 15 of recovery) and the females were terminated on day 5 of lactation, satellite females on day 15 of recovery and the offspring were terminated 4 days after birth.
- Frequency of treatment:
- Once daily for up to 42 days
- Details on study schedule:
- As a screening study this investigation was limited to the parental generation and F1 offspring only. The repeated adminstration phase for males (42 days) and females (14 days) prior to mating provides some subacute toxicity data and the treatment of females through gestation gives some reproductive and developmental toxicity information.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 8 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 40 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- twelve; an additional five rats per sex were allocated to the satellite groups for retention through the recovery phase.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No further details provided
- Positive control:
- Not applicable
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at weekly intervals - assessment in homecage, then in observers hands and then outside the homecage
Assessments included posture, sleeping, locomotion,vocalisations, tremors and convulsions, response to capture and handling, salivation, grading of heart beat, body temperature, exophthalmus and pupil size, exhibition of any discoloration of fur,skin or lacrimation. Outside the cage the assessment of posture, grooming, vocalisations, occurrence of straub tail, gait, tremor, convulsion pilo-erection and palpebral opening; exploration and respiratory rate and any exhibiion of stereotypy or bizarre behaviour.
BODY WEIGHT: recorded on days 1, 7, 14, 21, 28, 35 and 42 of treatment and days 1, 7, and 14 of recovery for males.
Females were weighed on days 1, 7, and 14 of treatment; days 0, 7, 14 and 20 of pregnancy and days 0 and 4 of lactation
Food consumption was recorded for the males and for the satellite females (treated at 200 mg/kg) on days 1-2, 7-8, 14-15, 29-30, 35-36 and 41-42 and then days 6-7 and 13-14 of the recovery phase.
Urinalysis was performed on Day 31 and 32 for males and females respectively
Necropsy was completed on termination of treatment or after completion of the recovery phase or day 5 of lactation
The reproductive performance of the parents was recorded for the twelve pairings per treatment group; the number of pairs copulating provided the copulation index and the number of pregnant females was used to calculate the fertility index. the mean number of days from pairing to copulation was also calculated - Oestrous cyclicity (parental animals):
- All females examined. The number of rats showing a 4 day cycle in the pre-treatment phase was recorded, together with number with 5-day cycle. Mean cycle duration was calculated
- Sperm parameters (parental animals):
- no data
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring on day 0 of lactation:
number of pups, stillbirths, live births, birth index and live birth index
Bodyweights recorded on day 0 and 4 of lactation
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Necropsy of live pups surviving to lactation day 4- examination of external and visceral changes - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals following day 42 of treatment or on day 15 of the recovery phase.
- Maternal animals: All surviving animals on day 5 of lactation or on day 15 for the satellite animals in the recovery phase.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in the attached Table were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to macroscopic postmortem examinations for external and visceral changes - Statistics:
- No data
- Reproductive indices:
- The reproductive performance of the parents was recorded for the twelve pairings per treatment group; the number of pairs copulating provided the copulation index and the number of pregnant females was used to calculate the fertility index. the mean number of days from pairing to copulation was also calculated
- Offspring viability indices:
- Number of newborn, delivery index, number of live newborn, birth index and live bith index calculated on day 0 of lactation. On day 4 of lactation the number of live pups, viability index and sex ratio were calculated.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- daily observations showed no adverse reactions; detailed clinical assessment revealed no treatment related changes
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- bodyweights for males and females showed no significant differences from controls at any timepoint. Food consumption showed no significant treatment related differences
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- bodyweights for males and females showed no significant differences from controls at any timepoint. Food consumption showed no significant treatment related differences
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- liver histopathology in males at 200 mg/kg bw.d
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No significant effects recorded
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- General toxicity
- Effect level:
- 40 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Liver effects at 200 mg/kg bw/day (urinary turbidity at 40 and 200 mg/kg bw/d is not considered to be of toxicological significance).
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- Reproductive toxicity
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No evidence of reproductive toxicity was seen in this study at the highest dose level tested of 200 mg/kg bw/d
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- Developmental toxicity
- Generation:
- F1
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No evidence of developmental toxicity was seen in this study at the highest dose level tested of 200 mg/kg bw/d
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- The treatment up to 200 mg/kg bw/d did not affect the reproductive performance of parental animals or the early development of their offspring. The no observed adverse effect dose level (NOAEL) for repeat dose toxicity of 4,4'-biphenyldiol is considered to be 40 mg/kg/day for both sexes of animals. The NOAEL for reproductive toxicity is considered to be 200 mg/kg bw/d, in the absence of any findings.
- Executive summary:
A combined repeat dose and reproductive/developmental toxicity screening test was conducted in rats according to the OECD Test Guideline 422 with 4,4'-biphenyldiol. No effects on fertillity or reproductive parameters (oestrus cyclicity, mating, implantation or lactation) were observed at any dose level. In the absence of any effects on reproductive parameters, a NOAEL for reproductive toxicity of 200 mg/kg bw/d can be determined. A NOAEL for general toxicity of 40 mg/kg bw/d can be determined based on liver effects at the highest dose level. Effects of treatment on urinalysis parameters seen at 40 and 200 mg/kg bw/d are not considered to be of toxicological significance.
No apparent changes were observed in general clinical conditions, except that urine in the 200 mg/kg-treated group became cloudy with elapse of time after excretion. Urinalysis was performed on treatment days 31 and 32 in male and female rats, respectively; calcium oxalate-like urinary crystal sediments were found in males given 200 mg/kg and in females given 40 or 200 mg/kg. Turbidity was enhanced at dose levels of 40 or 200 mg/kg, and urinary specific gravity was decreased in these females. These changes in urine parameters were not found when urinalysis was performed 11 days after cessation of the treatment (on day 11 of recovery) in either sex for the satellite animals.
Body weight, weight gain and food consumption were not affected by treatment at any dose level in either sex. No animals showed any abnormality in functional parameters after the final treatment.
At necropsy on termination of the treatment, no apparent effects of the compound were found on haematological or blood-biochemical examination at any dose level of the compound in either sex.
No effects of the compound were apparent in the female organs, including their weights or macroscopic or microscopic findings.
In contrast, 200 mg/kg of the compound exerted effects on male livers, with significant increase in relative weight, darkening or enlargement of the macroscopic appearance, development of centrilobular hepatocyte hypertrophy and reduction in occurrence of periportal fatty change. However, no animals showed any abnormality in functional observations on day 14 of the recovery period. At necropsy on day 15 of recovery, changes in the liver were not found in males given 200 mg/kg. In females given 200 mg/kg for 42 days and killed for necropsy on day 15 of recovery (satellite group), there were similarly no abnormal findings.
The treatment did not affect parameters of reproductive performance, such as the estrous cycle, ovulation, mating, implantation, delivery or lactational condition at any dose level. No adverse effects of the compound were observed on viability, morphology or growth of offspring.
The no observed adverse effect level (NOAEL) for repeat dose toxicity of 4,4'- biphenyldiol is considered to be 40 mg/kg bw/d in both sexes. The NOAEL for reproductive toxicity is considered to be 200 mg/kg bw/d, in the absence of any relevant effects.
Summary of oestrous cycle data for females treated with 4,4’-biphenyldiol
|
4,4’-biphenyldiol |
|||
0 (0.5% CMC Na solution, 5 mL/kg bw |
8 mg/kg bw/day |
40 mg/kg bw/day |
200 mg/kg bw/day |
|
Number of females examined |
12 |
12 |
12 |
12 |
Number of females with 4-day cycle in pre-treatment period |
12 |
12 |
12 |
12 |
Number of females in treatment period with 4-day cycle or |
|
|
|
|
Mean length of oestrous cycle (days) |
4.0 |
4.0 |
4.0 |
4.0 |
Number of vaginal oestrous during mating phase |
1.0 |
1.0 |
1.0 |
1.0 |
Reproductive performance of rats treated with 4,4’-biphenyldiol
|
4,4’-biphenyldiol |
|||
0 (0.5% CMC Na solution, 5 mL/kg bw |
8 mg/kg bw/day |
40 mg/kg bw/day |
200 mg/kg bw/day |
|
Number of pairs examined |
12 |
12 |
12 |
12 |
Number of pairs copulated |
11 |
11 |
12 |
12 |
Copulation index |
91.7 |
91.7 |
100 |
100 |
Number of pregnant females |
11 |
11 |
10 |
12 |
Fertility index |
100 |
100 |
83.3 |
100 |
Mean number of pairing days to copulation |
2.5 ± 1.1 |
2.6 ± 1.2 |
2.7 ± 0.8 |
2.7 ± 1.2 |
Development of pups up to day 4 of lactation
|
4,4’-biphenyldiol |
|||
0 (0.5% CMC Na solution, 5 mL/kg bw |
8 mg/kg bw/day |
40 mg/kg bw/day |
200 mg/kg bw/day |
|
Number of pregnant females |
12 |
12 |
10 |
12 |
Number of pregnant females with live newborns |
11 |
11 |
10 |
12 |
Gestation index |
100 |
100 |
100 |
100 |
Gestation length in days |
22.4 ± 0.5 |
22.4 ± 0.5 |
22.0 ± 0.0 |
22.4 ± 0.5 |
Number of corpora lutea |
15.9 ± 1.6 |
16.5 ± 1.1 |
16.2 ± 1.2 |
15.2 ± 1.5 |
Number of implantations |
15.5 ± 1.7 |
14.3 ± 3.6 |
16.0 ± 1.6 |
14.7 ± 1.72 |
Implantation index |
97.1 ± 4.3 |
86.9 ± 21.6 |
98.7 ± 4.2 |
96.7 ± 5.3 |
|
|
|
|
|
Day 0 of lactation |
|
|
|
|
Number of newborns |
14.5 ± 2.3 |
13.8 ± 4.0 |
15.1 ± 1.7 |
14.0 ± 1.8 |
Delivery index |
93.2 ± 1.1 |
94.6 ± 12.2 |
94.4 ± 4.8 |
95.5 ± 5.2 |
Number of live newborns |
14.3 ± 2.3 |
13.8 ± 4.0 |
14.6 ± 1.6 |
12.8 ± 2.9 |
Birth index |
92.0 ± 7.6 |
94.6 ± 12.2 |
91.5 ± 8.1 |
88.8 ± 20.1 |
Live birth index |
98.7 ± 3.0 |
100.0 ± 0.0 |
97.0 ± 7.5 |
93.3 ± 20.8 |
Sex ratio on Day 0 |
54.8 ± 14.5 |
49.4 ± 17.4 |
52.3 ± 15.1 |
51.6 ± 14.7 |
|
|
|
|
|
Day 4 of lactation |
|
|
|
|
Number of live pups |
13.9 ± 2.1 |
13.6 ± 4.0 |
14.5 ± 1.5 |
12.4 ± 4.2 |
Viability index |
97.7 ± 4.0 |
98.8 ± 2.6 |
99.4 ± 2.0 |
91.7 ± 28.9 |
Sex ratio on Day 4 |
54.4 ± 14.9 |
49.3 ± 17.9 |
52.1 ± 15.9 |
50.8 ± 15.2 |
Pup bodyweights up to Day 4 of lactation
|
4,4’-biphenyldiol |
|||
0 (0.5% CMC Na solution, 5 mL/kg bw |
8 mg/kg bw/day |
40 mg/kg bw/day |
200 mg/kg bw/day |
|
Day 0 of lactation |
|
|
|
|
Number of live newborns |
|
|
|
|
Male |
7.7 ± 2.1 |
6.9 ± 3.0 |
7.6 ± 2.1 |
6.5 ± 2.2 |
Female |
6.5 ± 3.0 |
6.9 ± 3.3 |
7.0 ± 2.6 |
6.3 ± 2.7 |
Bodyweight of live newborn (g) |
|
|
|
|
Male |
6.8 ± 0.8 |
6.9 ± 0.8 |
6.5 ± 0.5 |
6.6 ± 0.8 |
Female |
6.6 ± 0.6 |
6.6 ± 0.7 |
6.0 ± 0.4 |
6.2 ± 0.8 |
|
|
|
|
|
Day 4 of lactation |
|
|
|
|
Number of live pups |
|
|
|
|
Male |
7.5 ± 2.3 |
6.8± 3.1 |
7.5± 2.2 |
6.8± 2.0 |
Female |
6.4 ± 2.2 |
6.8± 3.2 |
7.0 ± 2.6 |
6.7± 2.5 |
Bodyweight of pups (g) |
|
|
|
|
Male |
10.6 ± 1.7 |
10.7 ± 1.1 |
10.2 ± 1.1 |
10.8 ± 1.0 |
Female |
10.3 ± 1.4 |
10.4 ± 1.4 |
9.8 ± 1.0 |
10.0 ± 0.9 |
Pup morphology findings
|
4,4’-biphenyldiol |
|||
0 (0.5% CMC Na solution, 5 mL/kg bw |
8 mg/kg bw/day |
40 mg/kg bw/day |
200 mg/kg bw/day |
|
Dead pups |
|
|
|
|
Number of dead pups examined |
3 |
1 |
6 |
12 |
External examinations |
3 |
1 |
6 |
12 |
Visceral examinations |
0 |
0 |
5 |
1 |
Number of pups with external changes |
0 |
0 |
0 |
0 |
Number of pups with visceral changes |
0 |
0 |
0 |
0 |
|
|
|
|
|
Live pups |
|
|
|
|
At birth (day 0) |
|
|
|
|
Number of newborns examined |
157 |
152 |
146 |
154 |
Number of newborns with |
|
|
|
|
At necropsy (day 4 of lactation) |
|
|
|
|
Number of pups examined |
153 |
150 |
145 |
149 |
Number of pups with external changes |
0 |
0 |
0 |
0 |
Number of pups with visceral changes |
0 |
0 |
0 |
0 |
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Biphenyl-4,4'-diol
- EC Number:
- 202-200-5
- EC Name:
- Biphenyl-4,4'-diol
- Cas Number:
- 92-88-6
- Molecular formula:
- C12H10O2
- IUPAC Name:
- [1,1'-biphenyl]-4,4'-diol
- Details on test material:
- No further details.
Constituent 1
- Specific details on test material used for the study:
- - Purity: 99.96%
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Crj:CD(SD)IGS rats used but no details provided regarding supplier
- Age at study initiation: (P) x wks; (F1) x wks No data
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
IN-LIFE DATES: From: not stated To: not stated
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% sodium carboxymethylcellulose solution
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water):0.5% sodium carboxymethylcellulose solution used as suspending agent - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No information provided
- Details on mating procedure:
- - M/F ratio per cage: 1:1.
- Duration of treatment / exposure:
- Males were dosed for 42 days prior to mating; the females were treated for 14 days prior to mating and then until day 4 of lactation. The female satellite animals were treated or 42 days. The recovery period for males and satellite females was 14 days. The males were terminated on day 43 of treatment (day 15 of recovery) and the females were terminated on day 5 of lactation, satellite females on day 15 of recovery and the offspring were terminated 4 days after birth.
- Frequency of treatment:
- Once daily for up to 42 days
- Duration of test:
- 6 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 8 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 40 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- twelve; an additional five rats per sex were allocated to the satellite groups for retention through the recovery phase.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No further details provided.
As a screening study this investigation was limited to the parental generation and F1 offspring only. The repeated adminstration phase for males (42 days) and females (14 days) prior to mating provides some subacute toxicity data and the treatment of females through gestation gives some reproductive and developmental toxicity information.
The males and females were dosed for up to 42 days by oral gavage and this subacute exposure was used to address the short-term toxicology endpoints. Clinical signs, bodyweight gain, food consumption haematology, clinical chemistry and urinalysis parameters were recorded together with a limited functional observation battery, organ weights and macroscopic and microscopic examinations at termination.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at weekly intervals - assessment in homecage, then in observers hands and then outside the homecage
Assessments included posture, sleeping, locomotion,vocalisations, tremors and convulsions, response to capture and handling, salivation, grading of heart beat, body temperature, exophthalmus and pupil size, exhibition of any discoloration of fur,skin or lacrimation. Outside the cage the assessment of posture, grooming, vocalisations, occurrence of straub tail, gait, tremor, convulsion pilo-erection and palpebral opening; exploration and respiratory rate and any exhibiion of stereotypy or bizarre behaviour.
A functional assessment was completed on the final day of treatment to assess various reflex responses.
BODY WEIGHT: recorded on days 1, 7, 14, 21, 28, 35 and 42 of treatment and days 1, 7, and 14 of recovery for males.
Females were weighed on days 1, 7, and 14 of treatment; days 0, 7, 14 and 20 of pregnancy and days 0 and 4 of lactation
Bodyweights and bodyweight gains are reported.
Food consumption was recorded for the males and for the satellite females (treated at 200 mg/kg) on days 1-2, 7-8, 14-15, 29-30, 35-36 and 41-42 and then days 6-7 and 13-14 of the recovery phase.
Urinalysis was performed on Day 31 and 32 for males and females respectively. Parameters assessed included colour, turbidity, pH, protein, glucose, ketone and bilirubin levels, occult blood, urobilinogen and presence in urinary sediment of crystals by incidence and type/shape and urinary specific gravity.
Clinical pathology in the form of standard haematology and biochemical parameters were assessed on Day 43 of treatment and on Day 15 of the recovery phase for male rats and on Day 5 of lactation for the females.
Organ weights were recorded on Day 43 of treatment and on Day 15 of the recovery phase for male rats and on Day 5 of lactation for the females.
Necropsy was completed on termination of treatment or after completion of the recovery phase or on day 5 of lactation. Macroscpic findings were recorded at each scheduled necropsy. Histopathological findings were documented for tissues sampled following each of the scheduled necropsy events. The list of tissues examined was in accordance with the test guideline.
The reproductive performance of the parents was recorded for the twelve pairings per treatment group; the number of pairs copulating provided the copulation index and the number of pregnant females was used to calculate the fertility index. the mean number of days from pairing to copulation was also calculated
All females examined for oestrous cyclicity . The number of rats showing a 4 day cycle in the pre-treatment phase was recorded, together with number with 5-day cycle. Mean cycle duration was calculated - Ovaries and uterine content:
- No data
- Fetal examinations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring on day 0 of lactation:
number of pups, stillbirths, live births, birth index and live birth index
Bodyweights recorded on day 0 and 4 of lactation
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Necropsy of live pups surviving to lactation day 4- examination of external and visceral changes - Statistics:
- No data
- Indices:
- Number of newborn, delivery index, number of live newborn, birth index and live bith index calculated on day 0 of lactation. On day 4 of lactation the number of live pups, viability index and sex ratio were calculated.
- Historical control data:
- No data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Oral administration of 4,4'-biphenyldiol at dose levels of 8, 40 or 200 mg/kg bw/day did not cause death or a moribund condition in any animals. None of the scores obtained during detailed clinical observations differed in a biologically significant manner between the control and the compound-treated groups.
No apparent changes were observed in general clinical conditions, except that urine in the 200 mg/kg-treated group became cloudy with elapse of time after excretion. Urinalysis was performed on treatment days 31 and 32 in male and female rats, respectively, calcium oxalate-like urinary crystal sediments were found in males given 200 mg/kg and in females given 40 or 200 mg/kg. Turbidity was enhanced at dose levels of 40 or 200 mg/kg, and urinary specific gravity was decreased in these females. These changes in urine parameters were not found when urinalysis was performed 11 days after cessation of the treatment (on day 11 of recovery) in either sex for the satellite animals.
Body weight, weight gain and food consumption were not affected by treatment at any dose level in either sex. No animals showed any abnormality in functional parameters after the final treatment.
At necropsy on termination of the treatment, no apparent effects of the compound were found on haematological or blood-biochemical examination at any dose level of the compound in either sex.
The reproductive and developmental toxicity indices evaluated in this screening study indicated no adverse effects on the dams. No effects were apparent in the female oestrous cycle either during the pre-treatment, mating or treament phases. The reproductive indices included the numbers of pairings examined, copulating and the number of resulting pregnant females and the length of pairing time required before copulation. There were no changes between control and treated groups.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- External malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There were no adverse effects of administration on offspring viability, morphology or growth.
Pup development indices were evaluated to assess the duration of gestation, numbers of corpora lutea and implantations, the numbers of pups born, numbers of live born and sex ratio for the liveborn pups and survival and viability of pups to day 4 of lactation was also evaluated . None of the comparisons between treated and control groups revelaed any significant changes in these indices or any statistically significant effects. Similarly no effects were apparent when newborn or neonate (lactation day 4) pup weights were assessed.
Morphological evaluations for external and visceral changes showed no effects on the live pups at birth or those that survived to lactation Day 4. The dead pups examined (3 controls and 1, 6 or 12 pups in the 8, 40 or 200 mg/kg bw/day groups) also had no external and visceral changes .
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Combined repeat dose and reproductive/developmental toxicity screening test for 4,4’-biphenyldiol
|
4,4’-biphenyldiol mg/kg bw/day |
|||
|
0 |
8 |
40 |
200 |
No. of females examined |
12 |
12 |
12 |
12 |
No. of females showing 4-day cycle in pre-treatment phase |
12 |
12 |
12 |
12 |
No. of females showing 4-day cycle in treatment phase |
12 |
11 |
12 |
12 |
No. of females showing 4 and 5-day cycle in treatment phase |
0 |
1 |
0 |
0 |
Mean length of oestrous cycle in days |
4.0±0.0 |
4.0±0.1 |
4.0±0.0 |
4.0±0.0 |
Number of vaginal oestrous during mating period |
1.0±0.0 |
1.0±0.0 |
1.0±0.0 |
1.0±0.0 |
|
4,4’-biphenyldiol mg/kg bw/day |
|||
|
0 |
8 |
40 |
200 |
No. of pairs examined |
12 |
12 |
12 |
12 |
No. of pairs copulated |
11 |
11 |
12 |
12 |
Copulation index |
91.7 |
91.7 |
100.0 |
100.0 |
No. of pregnant females |
11 |
11 |
10 |
12 |
Fertility index |
100.0 |
100.0 |
83.3 |
100.0 |
Number of pairing days |
2.5±1.1 |
2.6±1.2 |
2.7±0.8 |
2.7±1.2 |
Development of pups up to Day 4 of lactation
|
4,4’-biphenyldiol mg/kg bw/day |
|||
|
0 |
8 |
40 |
200 |
No. of pregnant females |
11 |
11 |
10 |
12 |
No. of pregnant females with live neonates |
11 |
11 |
10 |
12 |
Gestation index |
100 |
100 |
100 |
100 |
Gestation length in days |
22.4±0.5 |
22.4±0.5 |
22.0±0.0 |
22.4±0.5 |
Number of corpora lutea |
15.9±1.6 |
16.5±1.1 |
16.2±1.2 |
15.2±1.5 |
Number of implantations |
15.5±1.7 |
14.3±3.6 |
16.0±1.6 |
14.7±1.7 |
Implantation Index |
97.1±4.3 |
86.9±21.6 |
98.7±4.2 |
96.7±5.3 |
|
|
|
|
|
Day 0 of lactation |
|
|
|
|
Number of newborn |
14.5±2.3 |
13.8±4.0 |
15.1±1.7 |
14.0±1.8 |
Delivery index |
93.2±6.9 |
94.6±12.2 |
94.4±4.8 |
95.5±5.2 |
Number of live newborn |
14.3±2.3 |
13.8±4.0 |
14.6±1.6 |
12.8±2.9 |
Birth index |
92.0±7.6 |
94.6±12.2 |
91.5±8.1 |
88.8±20.1 |
Live birth index |
98.7±3.0 |
100.0±0.0 |
97.0±7.5 |
93.3±20.8 |
Sex ratio on day 0 |
54.8±14.5 |
49.4±17.4 |
52.5±15.1 |
51.6±14.7 |
|
|
|
|
|
Day 4 of lactation |
|
|
|
|
Number of live pups |
13.9±2.1 |
13.6±4.0 |
14.5±1.5 |
12.4±4.2 |
Viability index |
97.7±4.0 |
98.8±2.6 |
99.4±2.0 |
91.7±28.9 |
|
|
|
|
|
Sex ratio on day 4 |
54.4±14.9 |
49.3±17.9 |
52.1±15.9 |
50.8±15.2 |
The
vehicle control was 5 ml/kg of 0.5% CMC Na solution.
Gestation index (number
of pregnant females with live newborns/number of pregnant females) x
100,%
Implantation index (number
of implantations/number of corpora lutea) x 100,%
Delivery index (number
of newborns/number of implantations) x 100,%
Birth index (number
of live newborns/number of implantations) x 100,%
Live birth index (number
of live newborns/number of newborns) x 100,%
sex ratio (day 0) (number
of male live newborns / number of live newborns) x 100,%
viability index (number
of live pups on day 4 of lactation/ number of live newborns) x 100,%
sex ratio (day 4) (number
of male live pups on day 4 of lactation / number of live pups on day 4
of lactation) x 100,%
Bodyweight of pups up to Day 4 of lactation
|
4,4’-biphenyldiol mg/kg bw/day |
|||
|
0 |
8 |
40 |
200 |
Day 0 of lactation |
|
|
|
|
Number of live newborn |
|
|
|
|
male |
7.7±2.1 |
6.9±3.0 |
7.6±2.1 |
6.5±2.2 |
female |
6.5±2.5 |
6.9±3.3 |
7.0±2.6 |
6.3±2.7 |
|
|
|
|
|
Birthweight of live newborn |
|
|
|
|
Males |
6.8±0.8 |
6.9±0.8 |
6.5±0.5 |
6.6±.0.8 |
females |
6.6±0.6 |
6.6±0.7 |
6.0±0.4 |
6.2±0.8 |
|
|
|
|
|
Day 4 of lactation |
|
|
|
|
Number of live pups |
|
|
|
|
Males |
7.5±2.3 |
6.8±3.1 |
7.5±2.2 |
6.8±2.0 |
females |
6.4±2.2 |
6.8±3.2 |
7.0±2.6 |
6.7±2.5 |
Birthweight of pups |
|
|
|
|
Males |
10.6±1.7 |
10.7±1.1 |
10.2±1.1 |
10.8±1.0 |
females |
10.3±1.4 |
10.4±1.4 |
9.8±1.0 |
10.0±0.9 |
Morphological findings of pups
|
4,4’-biphenyldiol mg/kg bw/day |
|||
|
0 |
8 |
40 |
200 |
Dead pups |
|
|
|
|
Number of dead pups examined |
3 |
1 |
6 |
12 |
External observations |
3 |
1 |
6 |
12 |
Visceral observations |
0 |
0 |
5 |
1 |
No. of pups with external changes |
0 |
0 |
0 |
0 |
No. of pups with visceral changes |
0 |
0 |
0 |
0 |
|
|
|
|
|
|
|
|
|
|
Live pups at birth (Day 0) |
|
|
|
|
Number of live neonates examined |
157 |
152 |
146 |
154 |
Number with external changes |
0 |
0 |
0 |
0 |
At necropsy on Day 4 |
|
|
|
|
Number of pups examined |
153 |
150 |
145 |
149 |
No. of pups with external changes |
0 |
0 |
0 |
0 |
No. of pups with visceral changes |
0 |
0 |
0 |
0 |
Applicant's summary and conclusion
- Conclusions:
- Treatment with up to 200 mg/kg bw/d did not affect early offspring development. The no observed adverse effect level (NOAEL) for repeat dose toxicity of 4,4'-biphenyldiol is considered to be 40 mg/kg bw/d. In the absence of any effects on the parameters measured. the NOAEL for developmental toxicity is considered to be 200 mg/kg/ bw/d.
- Executive summary:
A combined repeat dose and reproductive/developmental toxicity screening test was conducted in rats according to the OECD Test Guideline 422 with 4,4'-biphenyldiol. No effects on developmental parameters were observed at any dose level. In the absence of any effects on developmental parameters, a NOAEL for developmental toxicity of 200 mg/kg bw/d can be determined. A NOAEL for general toxicity of 40 mg/kg bw/d can be determined based on liver effects at the highest dose level. Effects of treatment on urinalysis parameters seen at 40 and 200 mg/kg bw/d are not considered to be of toxicological significance.
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