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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles and was conducted in compliance with good laboratory practice (GLP) standards.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of 30 male and 30 female rats were exposed to 0, 10, 50, or 150 mg/m3 aerosolised Bisphenol A via whole body exposure under dynamic airflow conditions for 6 hours per day, 5 days per week, for 13 weeks. Animals were observed daily and weighed weekly. Ten animals/sex/exposure group were necropsied on the day after the last exposure, and 10 animals/sex/exposure group were necropsied 4 and 12 weeks after the last exposure. Blood samples were obtained at each sacrifice for hematologic and clinical chemistry determinations. Major organs were weighed and tissues were evaluated histopathologically.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report): Bisphenol A
- Substance type: Polycarbonate grade
- Physical state: Material was screened with a 1 mm mesh stainless steel screen to separate the larger particles from the smaller particles. The smaller particles were used to generate the BPA aerosol.
- Analytical purity: 99.7 %
- Impurities (identity and concentrations): 0.1 % phenol; 0.1 % isopropenyl phenol; 0.1-0.3 % 2,4-isopropylidene diphenyl.
- Stability under test conditions: There was no indication of decomposition of the test material during the course of the study.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, New York, United States.
- Age at study initiation: 7 weeks
- Housing: Animals were individually housed in stainless steel wire cages throughout the study.
- Diet: Ad libitum (except during exposure) Ground Purina Certified Rodent Chow #5002 (Ralston Purina Company, St. Louis, Missouri, United States).
- Water: Ad libitum (except during exposure) municipal tap water.
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50
- Photoperiod (hrs dark/hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: The APS 33-measured MMAD was 1.5-2.9 microns; the gravimetrically-measured MMAD was 2.2-5.2 microns.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 liter stainless steel and glass Rochester-type chambers operated under dynamic airflow conditions.
- Method of conditioning air: Air was filtered with an Absolute Filter (Cambridge Filter Corporation, Syracuse, New York, United States).
- System of generating particulates/aerosols: Modified Marple dust generator (Marple et al., 1978). Approximately 60 liters/minute of dry, compressed air was used to aerosolize the particles in the dust generator.
- Temperature, humidity in air chamber: 22 degrees C, 50% relative humidity
- Air flow rate: 225 liters/minute
- Air change rate: 13.5 air changes/hour
- Method of particle size determination: Aerodynamic particle sizer (APS 33, TSI Incorporated, St. Paul, Minnesota, United States)

TEST ATMOSPHERE
- Brief description of analytical method used: BPA concentration was determined either gravimetrically or with a mass monitor at least three times per day for each chamber. Aerodynamic particle size was measured approximately weekly with a cascade impactor (Model 266, Sierra Instruments, Carmel Valley, California, United States) and aerodynamic particle sizer (APS 33) during the 13-week exposure period.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During exposure, BPA concentration was determined either gravimetrically or with a mass monitor (RamS, MIE Corporation, Bedford, Massachusetts, United States) at least three times per day for each chamber. The mass monitors were calibrated at least bi-weekly with gravimetric measurements of BPA. The mass monitors were evaluated with one gravimetric measurement on each day of exposure.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 50, or 150 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
30
Control animals:
yes, sham-exposed

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: After each exposure period

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Once per week

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined once per week.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to the initial exposure to BPA.
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At all scheduled necropsies.
- Animals fasted: Yes, overnight.
- Parameters examined: hematocrit, hemoglobin, erythrocyte count (RBC), red blood cell indices (MCV, MCH, MCHC), total leukocyte (WBC) and platelet (PLAT) count, morphology of leukocytes, erythrocytes, and platelets.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At all scheduled necropsies.
- Animals fasted: Yes, overnight.
- Parameters examined: serum urea nitrogen (UN), glutamic pyruvic transaminase activity (SGPT), glutamic oxaloacetic transaminase activity (SGOT), alkaline phosphatase activity (AP), glucose, total protein, albumin, and globulins.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: After each exposure period.
- Battery of functions tested: Specific observations for lethargy, tremors, convulsions, salivation, lacrimation, diarrhea, and other signs of altered central nervous system function.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organ weights: lung, brain, liver, kidneys, testes
- A comprehensive gross pathological examination was peformed on all animals.

HISTOPATHOLOGY: Yes
- A comprehensive list of tissues were examined from animals sacrificed immediately after exposure to 0 or 150 mg/m3 BPA.
- Nasal tissues, lungs, cecum, and any grossly visible lesions were examined from rats sacrificed immediately after exposure to 10 or 50 mg/m3.
- After a 4-week recovery period, the nasal tissues, lungs, mediastinal tissues, mediastinal lymph nodes, trachea, cecum, and any grossly visible lesions from the control and 150 mg/m3 groups and the nasal tissues, lungs, cecum, and grossly visible lesions from rats exposed to 10 or 50 mg/m3 were examined.
- After a 12-week recovery period, the nasal tissues, lungs, mediastinal tissues, mediastinal lymph nodes, trachea, kidneys, and any grossly visible lesions from the control and 150 mg/m3 groups and the nasal tissues, kidneys, and grossly visible lesions from rats in the 10 and 50 mg/m3 groups were examined.
Statistics:
Descriptive statistics (mean and standard deviation) were used to report chamber concentrations, temperature, relative humidity, airflow, food consumption, red blood cell indices, and white blood cell differential counts. Body weights, organ weights, clinical chemistry data, and appropriate hematology data were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, exploratory data analysis was peformed by parametric or non-parametric analysis of variance (ANOVA), followed by Dunnett's test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: A slight amount of red material, likely porphyrin, around the nose and perineal soiling was observed in male and female rats exposed to 50 or 150 mg/m3 BPA after 13 weeks of exposure. These effects were assumed to be stress-related.

BODY WEIGHT: Body weight decreased in male and female rats in the 50 and 150 mg/m3 dose groups after 13 weeks of exposure, in males and females in the 150 mg/m3 dose groups after the 4-week recovery period, and in males in the 150 mg/m3 dose group during the final 8 weeks of the 12-week recovery period.

FOOD CONSUMPTION: No effects.

HAEMATOLOGY: Male rats exposed to 10 mg/m3 had increased hemoglobin concentration but this slight increase was of no biological significance.

CLINICAL CHEMISTRY: Several effects were observed that were not considered to be biologically significant. For the 13-week exposure groups, these were decreased SGPT, SGOT, and glucose in males at 150 mg/m3 BPA; decreased total protein and albumin and increased AP in females at 150 mg/m3; and increased AP in females at 50 mg/m3. For the 13-week exposure plus 4-week recovery groups, these were increased glucose in males at 150 mg/m3; increased AP and decreased SGPT in females at 150 mg/m3; and increased AP in females at 10 mg/m3. For the 13-week exposure plus 12-week recovery group, these were increased UN in males at 10 or 150 mg/m3 and decreased total protein and globulin in females at 150 mg/m3.

ORGAN WEIGHTS: In the 13-week exposure groups, decreased absolute liver weight in males at 10 or 150 mg/m3, decreased absolute liver and kidney weights in females at 150 mg/m3, increased relative brain weights in females at 50 or 150 mg/m3, and increased relative lung weight in females at 150 mg/m3 were observed. In rats sacrificed 4 weeks after exposure, males exposed to 150 mg/m3 BPA had increased relative brain weight. In rats sacrificed 12 weeks after exposure, decreased absolute kidney and lung weights were observed in males at 150 mg/m3 and decreased absolute and relative kidney weights were observed in females at 150 mg/m3. These changes were not associated with microscopic changes and were not considered to be toxicologically significant.

GROSS PATHOLOGY: Increased cecal size attributable to distention of the cecum with food ingesta was observed in males and females exposed to 50 and 150 mg/m3 BPA for 13 weeks and in males exposed to 150 mg/m3 BPA for 13 weeks with a 4-week recovery period.

HISTOPATHOLOGY: NON-NEOPLASTIC: In the nasal cavity, slight hyperplasia of the stratified squamous epithelium, slight hyperplasia of the respiratory epithelium, and slight chronic inflammation of the underlying submucosa were observed in all animals exposed to 50 or 150 mg/m3 for 13 weeks. These changes were also observed in all animals exposed to 150 mg/m3 BPA for 13 weeks plus a 4-week recovery period, but with significanly less magnitude and severity.

Effect levels

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Dose descriptor:
LOEC
Remarks:
Systemic
Effect level:
10 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: Based on decreased absolute liver weight in males, increased AP in females, and increased UN in males at 10 mg/m3 Bisphenol A. The authors noted that all of these effects are not toxicologically significant, however.
Dose descriptor:
NOEC
Remarks:
Respiratory
Effect level:
10 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: Based on reversible epithelial hyperplasia and chronic inflammation in the nasal cavity in males and females at 50 mg/m3.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The authors concluded that inhalation exposure to BPA did not result in any lower respiratory tract effects at any concentration tested.
Executive summary:

Groups of 30 male and 30 female rats were exposed to 0, 10, 50, or 150 mg/m3 aerosolised Bisphenol A via whole body exposure under dynamic airflow conditions for 6 hours per day, 5 days per week, for 13 weeks. Animals were observed daily and weighed weekly. Ten animals/sex/exposure group were necropsied on the day after the last exposure, and 10 animals/sex/exposure group were necropsied 4 and 12 weeks after the last exposure. Blood samples were obtained at each sacrifice for hematologic and clinical chemistry determinations. Major organs were weighed and tissues were evaluated histopathologically. Slight stress-related effects were observed at all concentrations of Bisphenol A, but except for decreased body weight of male rats at the highest dose, these effects disappeared relatively quickly after cessation of exposure. Enlarged ceca observed in rats necropsied the day after exposure to the two highest doses were not apparent in rats sacrificed 12 weeks later. Examination of the respiratory tract revealed slight epithelial hyperplasia and chronic inflammation in the submucosa in the nasal cavity at the two highest doses. Similar but less severe changes were observed in rats after 4 weeks of recovery but only in the highest dose group. The minor morphological changes were fully reversible within 12 weeks following exposure. In conclusion, exposure to Bisphenol A by inhalation did not result in any lower respiratory tract effects at any concentration tested.