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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study on carcinogenicity (supervised by NTP); no data on hematology, clinical chemistry or urinalysis
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 451 (Carcinogenicity Studies)
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): Benzyl alcohol, NF grade (Stauffer Chemical Co., Westport, Connecticut)
- Purity 99 %
- Lot/batch No.: 4T 215P1

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: F344/N rats
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 8-9 weeks
- Weight at study initiation (mean): males: 211-213 g; females: 145-150 g
- Housing: 5 per cage
- Diet ad libitum
- Water ad libitum
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.9-31 (66-88 °F)
- Humidity (%): 20-80
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Administration volume: 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
extraction of benzyl alcohol with methanol followed by gas chromatographic analysis
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
once daily, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
200, and 400 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: For dose selection results from previously conducted 2-week and 3-month studies were used. "Because of reductions in relative weight gain, deaths, and lesions of the brain, thymus, skeletal muscle, and kidney, doses selected for rats for the 2-year studies were 200 and 400 mg/kg benzyl alcohol, administered in corn oil by gavage, 5 days per week."
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: observed twice daily; clinical signs were recorded at least once per month.

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: Body weights were recorded initially, once per week for the first 12 weeks of the studies and once per month thereafter.

CLINICAL PATHOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, necropsies were performed on all animals

HISTOPATHOLOGY: Yes, complete histopathology was performed on all female rats and on vehicle control and on high dose male rats, on male rats that died before month 22 and male rats with gross lesions.
The following tissues were examined: adrenal glands, brain, cecum, clitoral or preputial gland, colon, costochondral junction, duodenum, esophagus, eyes, gross lesions and tissue masses with regional lymph nodes, heart, ileum, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular and mesenteric lymph nodes, nasal cavity and turbinates, oral cavity, pancreas, parathyroids, pharynx, pituitary gland, rectum, salivary glands, sciatic nerve, scrotal sac/tunica vaginalis/seminal vesicles/ prostate/epididymis/testes or ovaries/uterus, skin, spinal cord, spleen, sternebrae or vertebrae or femur including marrow, thigh muscle, thymus, thyroid gland, trachea, urinary bladder, and Zymbal gland; pituitary gland and testis examined for low dose male rats.
Other examinations:
no further data
Statistics:
According to Kaplan and Meier, method of Cox (1972) and Tarone's (1975) life table test, indicential tumor analysis, Fisher's exact/Cochrane-Armitage trend analysis

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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:
BODY WEIGHTS AND CLINICAL SIGNS
Mean body weights of dosed and vehicle control male and female rats were generally comparable throughout the studies. No compound-related clinical signs were observed.

SURVIVAL
Survival in male rats was not affected by treatment (final survival rates: vehicle control 28/50, low dose: 27/50, high dose 24/50) but reduced survival of dosed female rats by half (final survival rates: vehicle control 36/50; low dose 18/50; high dose 17/50). Many of the early deaths were considered to be related to the gavage procedure.

NONNEOPLASTIC AND NEOPLASTIC LESIONS
Cited from NTP report: "No apparent compound-related non-neoplastic responses were observed. Dose-related negative trends in the incidences of anterior pituitary gland neoplasms were seen in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49)"....., which is an incidence of 58, 36, and 18 %, respectively. Historical incidence in NTP studies: 692/1654 (42 %).

Effect levels

Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: based on the fact that body weight gains in male and female mice were not affected and compound-related clinical signs were not observed at this dose level; no apparent compound-related non-neoplastic findings at pathology/histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Cited from abstact of NTP report: "No apparent compound-related non-neoplastic responses were observed."

Applicant's summary and conclusion

Executive summary:

In a study equivalent to OECD TG 451 (supervised by NTP) male and female F344/N rats received daily by gavage 0, 200 and 400 mg/kg bw/day benzyl alcohol diluted in corn oil for 104 weeks (5 days/week). No effect on body weight gain and and no compound-related clinical signs were observed throughout the study. Survival was reduce only for female rats, but in many cases deaths were attributed the gavage procedure. Gross necropsy and histopathology revealed no apparent compound-related non-neoplastic responses. Thus, 400 mg/kg can be considered a NOAEL from this study (NTP TR 343, 1989).