Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 November 1996 - 13 Aug 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study undertaken at GLP accredited laboratory to internationally accepted guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Bisphenol-M
- Substance type: Monomer
- Physical state: Solid
- Analytical purity: 99.5%
- Purity test date: 27 January 1997
- Lot/batch No.: 681001
- Storage condition of test material: Room temperature (ca 15-25°C)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Laboratory supplier
- Housing: Polypropylene cages with stainless steel wire grid tops and bottoms.
- Diet: Rat and Mouse (Modified) No.1 SQC Expanded (Pelleted) Maintenance Diet was available to the animals ad libitum except during collection of urine samples where access was not allowed.
- Water: The animals had access to domestic mains water ad libitum except during collection of urine samples where access was not allowed.
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±2
- Humidity (%): 50
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
High Viscosity, 0,5 %
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations were prepared daily on the day of use in the study.

VEHICLE
- Concentration in vehicle: 1 - 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bodyweight
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of formulations were undertaken with regards to concentration and homogeneity on triplicate samples from each formulation (including Control) immediately after preparation. Samples were taken from the formulations used on Days 1 and 22 of treatment and analysed in the Inveresk Product Chemistry Laboratory using Method No. 7634 developed under the provisions ofInveresk Project No. 376342.
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
10 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day Male: 5 animals at 10 mg/kg bw/day Male: 5 animals at 100 mg/kg bw/day Male: 5 animals at 1000 mg/kg bw/day Female: 5 animals at 0 mg/kg bw/day Female: 5 animals at 10 mg/kg bw/day Female: 5 animals at 100 mg/kg bw/day Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected, in agreement with the Sponsor, based on results obtained from a One Week Dose Range Finding Study in Rats with Administration by Gavage (Inveresk Project No. 453526) where no adverse effects of treatment at levels up to 1000 mg/kg/day were noted.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: Yes, isofluorane
- Animals fasted: No
- How many animals: All

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No
- How many animals: All

URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Organ weights and histology

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Slight differences in the group mean values for haematology and coagulation analysis were considered unrelated to treatment with Bisphenol-M.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Group mean Aspartate Aminotransferase and Alanine Aminotransferase were increased in males treated at 1000 mg/kg/day when compared to Control. Other slight differences in the group mean values were considered unrelated to treatment with Bisphenol-M.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
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
There were no premature decedents throughout the study. Soft faeces were noted for all animals treated at 1000 mg/kg/day following completion of the first day of treatment and generally persisted throughout the remainder of the treatment period. Animal 20, a male treated at 1000 mg/kg/day, showed agitated behaviour from Day 10 of treatment up until termination. Additionally, a reduction in body weight was noted for this animal throughout Days 13-17 of treatment. No other animal treated at this level showed a similar effect therefore this observation was considered not to be related to treatment with Bisphenol-M.

BODY WEIGHT AND WEIGHT GAIN
There were no effects on body weight performance/body weight gain throughout the treatment period at any level ofBisphenol-M which were considered to be related to treatment.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)

FOOD EFFICIENCY
No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

OPHTHALMOSCOPIC EXAMINATION
No data

HAEMATOLOGY
Slight differences in the group mean values for haematology and coagulation analysis were considered unrelated to treatment with Bisphenol-M.

CLINICAL CHEMISTRY
Group mean Aspartate Aminotransferase and Alanine Aminotransferase were increased in males treated at 1000 mg.kg-1.day-l when compared to Control. Other slight differences in the group mean values for the remaining clinical chemistry parameters were considered unrelated to treatment with Bisphenol-M.

URINALYSIS
No data

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
Slight differences in the group mean organ weights for males and females were not considered to be related to treatment at any level ofBisphenol-M.

GROSS PATHOLOGY
Pelvic dilation ofthe right kidney was noted for one male and one female treated at 1000 mg/kg/day and additionally in one female treated at 10 mg/kg/day. This observation is often seen in rats of this strain and age at Inveresk therefore is not considered to be related to treatment with Bisphenol-M.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histological findings were representative of the background pathology seen in rats of this age and strain at Inveresk.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)

HISTORICAL CONTROL DATA (if applicable)

OTHER FINDINGS

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Dosing Sprague-Dawley rats by gavage for 4 weeks with Bisphenol-M at dose levels up to 1000 mg/kg/day produced clinical effects only at 1000 mg/kg/day, apparent as soft faeces following the first day of treatment then generally throughout the remainder of the treatment period. There were no histological findings which correlated with the increase in Aspartate aminotransferase and Alanine aminotransferase noted at 1000 mg/kg/day.

There were no effects on body weight performance, food or water consumption, organ weights, necropsy or histological findings at levels up to 1000 mg/kg/day. Additionally no treatment related clinical observations or effects on laboratory investigation parameters were noted at 100 or 10 mg/kg/day .

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, it was considered that treatment with Bisphenol-M resulted in slight effects at 1000 mg/kg/day and no adverse effects of treatment at 100 or 10 mg/kg/day. Therefore Bisphenol-M is not classified.