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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Triacetin (CAS No 102-76-1). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
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:
Triacetin CAS No. 102-76-1
Author:
OECD
Year:
2002
Bibliographic source:
SIDS Initial Assessment Report For SIAM 15
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)
Deviations:
no
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: colourless clear liquid with slight odour
- 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
- Age at study initiation: 9 weeks
- Weight at study initiation: 317-375 g (males) and  203-240 g (females)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 31-62
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 3% gum arabicum in purified water
Details on oral exposure:
Dosing volume: 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
44 days from 14 days prior to mating (males)
41-48 days from 14 days before mating to day 3 postpartum (females)
Frequency of treatment:
once daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
40, 200, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: on Day 0, 3, 7 and 14 of administration and once a week thereafter. For pregnant females, body weight was determined on Day 0, 7, 14 and 20 of gestation and on Day 0 and 4 of lactation.

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

HAEMATOLOGY: Yes
- Time schedule for examinations: at time of necropsy after 44 days of chemical exposure (males).
- Parameters checked: red blood cell count, haemoglobin, haematrocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, reticulocyte ratio, platelets, white blood cell count, lymphocyte, neutrophilic segmented, neutrophilic band, eosinophil-, basophil-, monocyte-value.

CLINICAL CHEMISTRY: Yes
- Time schedule for examinations: at time of necropsy after 44 days of chemical  exposure (males).
- Parameters checked: aspartate aminotransferase, alanine aminotrasferase, gamma glutamyltransferase, nitrophenylphosphate, total bilirubin, urea nitrogen, creatinine, glucose, total cholesterol, triglycerides, total protein, albumin, A/G ratio, calcium, inorganic phophorus, Na, K, Cl.
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 in the high dose 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:
Regarding quantitative data (body weight, gain of body weight, food consumption, organ weight, haematology, clinical chemistry, number of corpora lutea, number of implantation sites and total number of offspring), Bartlett test was used. In case of equal variance and unequal variance, ANOVA and Kruskal-Wallis test was applied, respectively. If there was a significant difference, Dunnett test or Dunnett multiple-comparison was used.
For day of conceiving, number of estrus, gestation length, implantation index, delivery index, viability index at Day 0 and Day 4, Bartlett test and Kruskal-Wallis test was used. If a significant difference was found, Dunnett multi-comparison test was applied.
For histopathology findings, the Chi-square test was used. If a significant difference was observed, Chi-square of Armitage was used between control and administration group. Regarding copulation index, fertility index, gestation index and sex ratio of offspring was tested with Fisher’s exact test.

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 1000 mg/kg bw/day was dead 32 days after the administration started.

BODY WEIGHT AND WEIGHT GAIN
No effects were observed.

FOOD CONSUMPTION AND COMPOUND INTAKE
No effects were observed.

HAEMATOLOGY
In males a decrease in differential leukocyte count (%) in neutrophils (band) at 40 (p < 0.05) and 1000 mg/kg bw/day (p < 0.01) was observed, which was within physiological changes.

CLINICAL CHEMISTRY
In males a decrease in creatinine at 40 (p < 0.01) and 1000 mg/kg bw/day (p < 0.01) was observed,  which was within physiological changes. An increase in inorganic phosphorus at 200 mg/kg bw/day (p < 0.05) was apparent, but with no dose-related changes.

ORGAN WEIGHTS
No changes were observed.

GROSS PATHOLOGY
No changes were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
No changes were observed.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion