Sodium 2-biphenylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990

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:

1990

Report date:

1990

Reference 2

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:

EPA OPP 83-1 (Chronic Toxicity)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Version / remarks:

(1998)

Deviations:

yes

Remarks:

the animals were dosed for 1 year and only 4 animals/dose/sex were used for the study

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:

2-phenylphenol

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): Ortho-phenylphenol, OPP
- Molecular formula: C12H10O
- Molecular weight: 170.1 g/mol
- Physical state: solid
- Analytical purity: 99.7%
- Composition of test material, percentage of components: mixture of equal amounts of OPP obtained from Mobay Corporation (Pittsburgh, PA) and The Dow Chemical Company (Midland, MI)
- Lot/batch No.: BK553730 (Mobay Corporation) and MM 880330 (The Dow Chemical Company)

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Marshall Research Animals (North Rose, NY)
- Age at study initiation: approximately 4 months
- Housing: individually in cages made of stainless steel, 1 x 1.3 x 1.3 m (witdth x length x hight); stacked two high; equipped with flattened-tube grid flooring with underlying tilt pants to faciliate cleaning, a stainless steel feeder, and a pressure activated water nipple
- Diet: basal diet in pelleted form of Purina Certified Laboratory Dog Chow #50007 (Ralston Purina Co., St. Louis, MO), ad libitum
- Water: municipal drinking water, ad libitum
- Acclimation period: at least 30 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared at least weekly by melting known amounts of solid OPP at 80°C in a water bath and mixing in a volumetric flask with preheated (70-80°C) food grade peanut oil using a stir bar for approximately 10 min. Additional warmed peanut oil was added using the numeber of dilution steps andmixing needed. Following cooling of the OPP-peanut oil mixtures to room temperature to allow for temperature-related changes in volume, dosing solutions were adjusted to appropriate volumes with peanut oil at ambient tempreature and stirred for an additional 5 min to ensure a homogenous mixture. Dosing solutions were stored at room temperature.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of test substance and availability of reliable supplier
- Amount of vehicle (if gavage): 3-5 mL dosing volume
- Supplier: Somillo brand, Suffolk Oil Mill, Inc., Suffolk, VA or Gordon Food Service, Bay City, MI
- Purity: food grade

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Aliquots of the 300 nd 1000 mg/kg dosing solutions were analysed to verify targeted test material concentrations. The results indicated and acceptable agreement between the observed versus targeted concentrations of OPP in peanut oil.

Duration of treatment / exposure:

1 year

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
30, 100 300 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

4

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on a preliminary four week toxicity study
- Rationale for animal assignment (if not random): by body weight, whereas litter mates of the same sex were not assigned to the same treatment groups

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations included: animal's movement within the pen, general health status including evidence of cchanges in dietary intake, faecal production, emesis, and evidence of untoward effects related to treatment

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first 13 weeks, monthly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-exposure and pre-termination
- Dose groups that were examined: all dogs

HAEMATOLOGY: Yes
- Time schedule for collection of blood: twice prior to initiation of dosing, after 3 and 6 months and prior to termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes (overnight)
- How many animals: all dogs
- Parameters checked included: haematocrit, haemoglobin, erythrocyte count, total and differential leukocyte count, platelet count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: twice prior to initiation of dosing, after 3 and 6 months and prior to termination
- Animals fasted: Yes (overnight)
- How many animals: all dogs
- Parameters checked included: alkaline phosphatase, alanine transaminase, aspartate transaminase, creatinine phosphokinase, serum urea nitrogen, creatinine, total protein, albumin, globulin, glucose, total bilirubin, cholesterol, triglycerides, Na, K, Ca, Cl, and P

URINALYSIS: Yes
- Time schedule for collection of urine: after 6 months and during necropsy
- Metabolism cages used for collection of urine: No
- Parameters checked included: semiquantitative determination of pH, bilirubin, glucose, proteins, ketones, occult blood, urobilinogen, specific gravity, colour, appearance and microsediment

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes (brain, liver, kidneys, thyroid with parathyroid, pituitary, adrenals, ovaries, testes)
HISTOPATHOLOGY: Yes (brain, liver, kidneys, thyroid with parathyroid, pituitary, adrenals, ovaries, testes, lung, eyes, urinary bladder, bone marrow)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

pronounced emetic response

Mortality:

mortality observed, treatment-related

Description (incidence):

pronounced emetic response

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Two high dose males (300 mg/kg bw/day) died after test days 137 and 138 due o inadvertent deposition of dosing solutions in the lungs.
Dose-related emetic activity was noted in all animals during the in-life phase. In general, emetic activity was observed to occur more frequently in and to involve greater volumes in the high dose group (300 mg/kg bw/day) than in dogs of the other dose groups (30 and 100 mg/kg bw/day).

BODY WEIGHT AND WEIGHT GAIN
There was no test material-related effect noted.

FOOD CONSUMPTION
There was no test material-related effect noted.

OPHTHALMOSCOPIC EXAMINATION
There was no test material-related effect noted.

HAEMATOLOGY
There was no test material-related effect noted.

CLINICAL CHEMISTRY
There was no test material-related effect noted.

URINALYSIS
There was no test material-related effect noted.

NEUROBEHAVIOUR

ORGAN WEIGHTS
There was no test material-related effect noted.

GROSS PATHOLOGY
There was no test material-related effect noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was no test material-related effect noted.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The pronounced emetic response/resultant loss of test material after gavage precluded the administration of higher dose levels to the Beagle dog. The finding was not considered a true adverse effect.

Target system / organ toxicity

Critical effects observed:

not specified