Biphenyl-2-ol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Reference 3

Reference Type:

secondary source

Title:

O-Phenylphenol and its Sodium and Potassium Salts: A Toxicological Assessment

Author:

Bomhard, E. M. et al.

Year:

2002

Bibliographic source:

Crit. Rev. Toxicol. 32(6):551-626

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

(1981)

Deviations:

yes

Remarks:

treatment period ended on day 19 of gestation, food consumption was not recorded, mortality (spontaneous + sacrificed moribund) was 5 out of 24 (21%) in the highest dose group

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Version / remarks:

(1988)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPP 83-3 (Prenatal Developmental Toxicity Study)

Version / remarks:

(b) (1984)

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: MAFF, 59 NohSan No. 4200 (1985)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Biphenyl-2-ol

EC Number:

201-993-5

EC Name:

Biphenyl-2-ol

Cas Number:

90-43-7

Molecular formula:

C12H10O

IUPAC Name:

[1,1'-biphenyl]-2-ol

Details on test material:

- Name of test material (as cited in study report): ortho-phenylphenol
- Molecular formula: C12H10O
- Molecular weight: 170.1 g/mol
- Physical state: solid
- Analytical purity: 99.88%
- Impurities (identity and concentrations): none at levels of 0.1% or greater
- Lot/batch No.: Mixture of equal amounts of OPP obtained from Mobay Corporation (Pittsburgh, PA; Lot #BK 553730) and The Dow Chemical Company (Midland, MI; Lot #MM 880330)

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products, Inc., Kalamazoo, MI and Denver, PA, USA
- Age at study initiation: 9-10 months
- Weight at study initiation: 3.5-4.5 kg
- Housing: individually in cages with wire floors
- Diet: 4 oz/day (=113.4 g/day) Certified Laboratory Rabbit Chow No. 5322 (Purina Mills, Inc., St. Louis, MO) prior to study and was increased to 8 oz/day (= 226.8 g/day) to allow for the increased nutritional demands during pregnancy.
- Water: tap water (municipal water supply by the City of Midland)
- Acclimation period: at least 2 weeks

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water):solubility characteristics of OPP
- Amount of vehicle (if gavage): 2 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses of dosing solutions showed that the concentration of OPP ranged from 102% to 103% of the targeted concentrations, the mixing procedure produced a homogeneous solution and OPP was stable in corn oil for a minimum of 30 days.

Details on mating procedure:

- Impregnation procedure: artificial insemination (with the day of insemination considered Day 0 of gestation)

Duration of treatment / exposure:

on Gestation Days 9-17

Frequency of treatment:

daily

Duration of test:

until Day 28 of gestation

No. of animals per sex per dose:

16-24 inseminated females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on the results of a probe study

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: on Day 0, daily during the dosing period, and on Days 20 and 28 of gestation

POST-MORTEM EXAMINATIONS: Yes (limited gross pathologic examination)
- Sacrifice on gestation day 28
- Organs examined: liver, kidney, gravid uteri (weigths), histopathologic examination of kidneys to better define the degree of renal toxicity

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number and position of resorption sites: Yes
- Number of early resorptions: Yes (in apparently non-pregnant animals)
- Number and position of foetuses in utero: Yes
- Number of live and dead foetuses: Yes

Fetal examinations:

- Sex and body weights: Yes: all per litter
- External examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter (fresh examination of brain)

Statistics:

Maternal body weights, weight gains, organ weights (absolute and relative) and foetal body weights were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, a parametric or non-parametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, analysis by Dunnett's test or the Wilcoxon Rank-Sum test with Bonferoni's correction was performed. Statistical evaluation of the frequency of pre-implantation loss, resorptions and foetal alterations among litters and the foetal population was performed using a censored Wilcoxon test with Bonferroni's correction. The number of corpura lutea and implants, and litter size were evaluated using a non.parametric ANOVA folowed by the Wilcoxon Rank-Sum test with Bonferroni's correction. Pregnancy rates were analysed using the Fisher exact probability test. Foetal sex ratios were analysed using a binominal distribution test. Statistical outliers were identified using a sequential method, but were not excluded unless justified by sound scientific reasons unrelated to treatment.
Teh nomina alpha levels used were a=0.01 (Bartlett's test), a=0.10 (parametric and non-parametric ANOVA), a=0.05 two-sided with Bonferroni's correction (Wilcoxon Rank-Sum Test), a=0.05 two-sided (Dunnett's test, binominal distribution test), a=0.05 one-sided (Fisher's test, censored Wilcoxon test), and a= 0.02 two-sided (sequential outliers test).
Because numerous measurements were statistically compared in the same group of animals, the overall false positive (Type I errors) was expected to be much greater than the alpha levels would suggest. Therefore, the final interpretation of the numerical data considered the statistical analyses along with other factors such as dose-response relationship and whether the results were significant in light of other biologic or pathologic findings.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: at 250 mg/kg bw/day effects on gastrointestinal tract and renal toxicity

Details on maternal toxic effects:
- Control group: 2 deaths (11%), (1 due to umbilical herniation and volvulus of the jejunum, 1 rabbit was euthanized after spontaneous abortion)
- 25 mg/kg bw/day: 2 deaths (13%), (1 as a result of blockage of gastrointestinal tract by a large hairball, 1 rabbit was euthanized after spontaneous abortion)
- 100 mg/kg bw/day: 1 death (6%), (caused by gavage error)
- 250 mg/kg bw/day: 5 deaths (21%), (4 deaths considered treatment-related, 1 rabbit was euthanized after spontaneous abortion), increased incidence of blood found in the urine and faeces, decreased amount of faeces, decreased activity, soiling, treatment-related effects within the gastrointestinal tract (ulceration and haemorrhage of the gastric mucosa, haemolysed blood within intestinal tract and decreased content and increased fluidity of ingesta), treatment-related effects on the kidneys were found in 10/24 rabbits (the kidneys had focal to multifocal tubular degeneration, slight to moderate in degree, accompanied by inflammation that was focal to multifocal and slight in degree)

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The test substance had no effect on intrauterine development.