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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
The 2-year study in rats was begun in November, 1978. The 2-year study in mice was begun in August, 1978.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
It is a study that has been published in a peer reviewed journal. The restriction is also due to the use of the read across approach: the test was performed not with 3-PPB but with Benzyl acetate, a substance which has been demonstrated to be very similar in structure, physical/chemical properties and toxicological profile .

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thirteen-week studies were conducted to evaluate the cumulative toxicity of benzyl acetate and to determine the doses to be used in the 2-year studies. Four-week-old male and female F344/ N rats were obtained from Harlan Industries, observed for 13 days, and assigned by species and sex to cages according to a table of random numbers. The cages were then assigned to dosed and control groups according to another table of random numbers. Rats were housed five per cage in polycarbonate cages covered with spun-bonded polyester filters. Racks and filters were replaced every 2 weeks. Cages and bedding were replaced twice per week. Water, via an automatic watering system, and Wayne Lab Blox@ were available ad libitum. Groups of 10 rats of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/ kg benzyl acetate in corn oil by gavage, 5 days per week for 13 weeks. Animals were checked for mortality and signs of morbidity twice daily. Those animals that were judged moribund were killed and necropsied. Each animal was given a clinical examination weekly, including palpation for tissue masses or swelling. Individual body weight data were collected weekly. On days 92-96, survivors were killed with carbon dioxide. Necropsies were performed on animals that survived to the end of the study and on all animals found dead, unless precluded in whole or in part by autolysis or cannibalization. The following specimens were examined microscopically for controls, for the highest dosage group with at least 60% survivors at the time of the group kill, and for all animals that died before the survivors of the group were killed: gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, thigh muscle, bone, bone marrow, thymus, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duodenum, jejunum, ileum, colon, mesenteric lymph nodes, liver, pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, nasal cavity, brain, pituitary, and spinal cord, Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Benzyl Acetate
- Physical state: water-white liquid with a pear-like odour
- Other:
Melting Point: -51.3°C
Boiling Point: 213°C
Vapor Pressure: 1.99 mm Hg at 60'C
Density: 1.05
Refractive Index: 1.4998

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Harlan Industries Indianapolis. I N
- Age at study initiation: 6 weeks
- Weight at study initiation: 84.9-127.1
- Housing: Bedding: Beta-Chips heat treated hardwood chips
Cages: Polycarbonate
Cage filters: Spun-bonded polyester filters
- Diet (e.g. ad libitum): Wayne Lab-Blox Allied Mills. ad libitum
- Water (e.g. ad libitum): Tap water supplied through automatic watering system. ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-60
- Air changes (per hr): 15

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Doses were prepared on a weight-to-volume basis by pipetting the appropriate amount of benzyl acetate into a vessel and adding enough corn oil to give the desired concentration. Solutions were mixed until they were visually homogeneous. Rats received 5 ml/kg. Benzyl acetate/corn oil mixtures were analyzed at Midwest Research Institute and found to be stable at room temperature for at least 7 days. Once prepared, benzyl acetate/corn oil mixtures were stored at 5O°C for no longer than 11 days.


VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: Male and female rats: 0, 62.5, 125, 250, 500, 1,000 mg/kg body weight in corn oil
- Amount of vehicle (if gavage): 5 ml/kg for rat
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of benzyl acetate in corn oil were selected at random and analyzed periodically at Southern Research Institute. Results of these analyses and of reference analyses at Midwest Research Institute indicated that benzyl acetate/ corn oil mixtures were properly formulated.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
62.5, 125, 250, 500, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10 animals
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: based on 14-day study
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed daily for mortality and clinical signs.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly clinical examinations

BODY WEIGHT: Yes
- Time schedule for examinations: at the start and end of dosing

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Necropsies performed on all animals, following tissues examined histologically in control and highest-dose groups with 60% survivors: brain, pituitary, salivary glands, esophagus, mandibular lymph node, thymus, spleen, heart, thyroid, parathyroid. trachea, lungs and bronchi, stomach, liver, large and small intestines, pancreas, mesenteric lymph node, testicles or ovaries, prostate or uterus, seminal vesicles, mammary gland, skin, bone,bone marrow, thigh muscle, kidneys, urinary bladder, adrenal glands, gross lesions, tissues, masses, nasal cavity and spinal cord.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, following tissues examined histologically in control and highest-dose groups with 60% survilors: brain, pituitary, salivary glands, esophagus, mandibular lymph node, thymus, spleen, heart, thyroid, parathyroid. trachea, lungs and bronchi, stomach, liver, large and small intestines, pancreas, mesenteric lymph node, testicles or ovaries, prostate or uterus, seminal vesicles, mammary gland, skin, bone,bone marrow, thigh muscle, kidneys, urinary bladder, adrenal glands, gross lesions, tissues, masses, nasal cavity and spinal cord.
Other examinations:
No further data
Statistics:
No data

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY
Two of ten males and 1/10 females that received 1,000 mg/ kg died on day 86. No other animals died during the study.

CLINICAL SIGNS
The only clinical signs attributed to compound administration were observed in male and female rats receiving 1,000 mg/ kg and in females receiving 500 mg/kg. These signs included trembling, ataxia, and sluggishness.

BODY WEIGHT AND WEIGHT GAIN
Final mean body weight in male rats receiving 1,000 mg/kg was about 12% lower than the control group

GROSS PATHOLOGY
Thickened stomach walls were observed in 2/9 males and 4/ 10 females receiving 1,000 mg/kg.

HISTOPATHOLOGY
No compound-related histopathologic effects were observed.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 500
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Ovrall effects Clinical signs; mortality; body weight
Dose descriptor:
NOAEL
Effect level:
ca. 250
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Male/Female       Dose       Survival       Final weight relative to control %

Male                     0              10/10              -

62.5           10/10              100.4

125            10/10              101.9

250            10/10              102.4

500            10/10              102.6

1000           8/10                 87.6

Female                   0             10/10                  -

62.5           10/10              104.6

125            10/10                99.9       

250            10/10              101.7       

500            10/10              110.0       

1000           9/10                 94.6

Applicant's summary and conclusion

Conclusions:
In a 13 week study female and male rats received daily oral doses of 0, 62.5, 125, 250, 500, or 1000 mg/kg bw benzyl acetate. Based on clinical signs, mortality and gross pathology the NOAEL was considered to be 500 and 250 mg/kg body weight for male and female rats, respectively.