Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study. Original study report in Japanese, but basic data given.
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1998
Reference Type:
secondary source
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
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): Triacetin
- Source: Daihachi Chemical Industry. Co., Ltd.
- Physical state: not reported
- Analytical purity: > 98.2 %
- Lot No.: N-80302
- Stability under test conditions: Stability during use confirmed by gas chromatography.

Test animals

Species:
rat
Strain:
other: Crj: CD (SD) IGS
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: 9 weeks
- Weight at study initiation: 317 - 375 g for males, 203 - 240 g for females

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 3% gum arabicum purified water
Details on oral exposure:
Dosing volume: 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: for 44 days from 2 weeks prior to mating.
Females: for 41-48 days from 14 days before mating to day 3 postpartum
Frequency of treatment:
Once per day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations:  On days 1, 3, 7 and 14, the last day of the administration, the day sacrificed and once a week during the administration period. For pregnant females, body weight was determined on the day 0, 14 and 20 of gestation and on day 0 and 4 of lactation.

FOOD CONSUMPTION:
- Food consumption was determined on the same day when body weight was measured for 24 hr

HAEMATOLOGY: Yes,  for males conducted only at time of necropsy after 44 days of chemical  exposure.

CLINICAL CHEMISTRY: Yes,  for males conducted only at time of necropsy after 44 days of chemical  exposure.

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Organs examined at necropsy: Organ weight: for both sexes, brain, pituitary gland, thyroid gland, heart, liver, kidney, spleen, adrenal,  
thymus, and in addition for males, testes and epididymis.

HISTOPATHOLOGY: Yes
All animals in control and 1,000 mg/kg bw group, and unfertilized animals in other groups: brain, spinal cord, pituitary gland, eyeball, thyroid 
gland (including parathyroid gland), thymus, heart, trachea, lung, liver, kidney, adrenal, spleen, stomach, small  intestine, large intestine, pancreas, 
urinary bladder, bone marrow,  sciatic nerve, lymph node, testes, epididymis, prostate, seminal vesicle,  ovary, uterus, vagina, mammary gland and any organs, which might be  expected to have histopathological changes and thymus and lung of dead  animals.
Statistics:
Kruskal-Wallis test for non-continuous data
Dunnett's or Scheffe's test for continuous data
Chi square test for quantal data.

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):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs of toxicity observed.
One male at 1,000 mg/kg bw was dead 32 days after the administration started.

BODY WEIGHT AND WEIGHT GAIN
no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no effects

HAEMATOLOGY
Males: Decrease in differential leukocyte count (%) in neutrophils (band) at 40 (p<0.05) and 1,000 mg/kg bw (p<0.01), but within physiological  
changes.

CLINICAL CHEMISTRY
Males: Decrease in creatinine at 40 (p<0.01) and 1,000 mg/kg bw (p<0.01),  but within physiological changes. 
Increase in inorganic phosphorus at 200 mg/kg bw (p<0.05), but with no dose-related changes.

ORGAN WEIGHTS
No changes observed

GROSS PATHOLOGY
No changes observed

HISTOPATHOLOGY: NON-NEOPLASTIC
No changes observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; food consumption; haematology; clinical chemistry; gross pathology; organ weights; histopathology; no effects in highest dose group observed.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Triacetin was given to Sprague-Dawley rats by oral gavage according to OECD Guideline 422 for at least 40 days. The oral NOAEL was found to be 1000 mg/kg bw/d for male and female rats.
Executive summary:

In a combined repeated dose and reproductive/developmental toxicity screening test according to OECD Guideline 422, rats received oral gavage doses up to 1000 mg/kg bw/day of triacetin for 44 days from 2 weeks prior to mating for males and for 41- 48 days from 14 days before mating to day 3 postpartum for females.

Triacetin had no effects on clinical signs, body weight, food consumption, and organ weight or necropsy findings. No abnormalities in haematological or blood chemical parameters in males were found. No histopathological changes were observed in either sex. The NOAEL for repeated dose oral toxicity is thus considered to be 1000 mg/kg bw/day for both sexes.