Reaction mass of glycerol 1,3-di(acetate) and glycerol acetate and triacetin

Repeated dose toxicity: oral

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 for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1998

Reference 2

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

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

Test material information

Constituent 1

Reference substance name:

Triacetin

EC Number:

203-051-9

EC Name:

Triacetin

Cas Number:

102-76-1

Molecular formula:

C9H14O6

IUPAC Name:

propane-1,2,3-triyl triacetate

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 or test system 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