Triacetin

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study

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:

1,3-bis(acetyloxy)propan-2-yl acetate

Details on test material:

- Name of test material (as cited in study report): Triacetin
- Physical state: colourless clear liquid with slight odour
- Source: Daihachi Chemical Industry. Co., Ltd.
- Analytical purity: > 98.2 %
- Lot/batch No.: N-80302
- Stability under test conditions: Stability confirmed during use 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: (P) 9 weeks
- Weight at study initiation: (P) males: 371-375 g; females: 203-240 g

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 arabic in purified water

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 7 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

(P) Males: 44 days from 2 weeks before mating.
(P) Females: 41-48 days from 14 days before mating to Day 3 postpartum.

Frequency of treatment:

once daily, 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
40, 200 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The general condition was observed once a day.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight was determined on Day 0, 3, 7 and 14 of administration and once a week thereafter. 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: Yes
Food consumption was determined on the same day when body weight was measured.

OTHER:
Haematology and biochemistry for males conducted only at time of necropsy after 44 days of exposure (for further details refer to 7.5.1 Repeated dose toxicity).

Oestrous cyclicity (parental animals):

Estrous cycle lengths were evaluated by vaginal smears, which were stained with Giemsa and microscopically observed.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were sacrificed the day after the last administration.
- Maternal animals: All surviving animals were sacrificed on Day 4 of lactation.

HISTOPATHOLOGY / ORGAN WEIGHTS
Microscopic examination of all animals in the control and the 1000 mg/kg bw/day group and unfertilized animals in the remaining 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.
Organ weight: brain, pituitary gland, thyroid gland, heart, liver, kidney, spleen, adrenal, thymus, and in addition for males, testes and epididymis.

Postmortem examinations (offspring):

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.

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, Chi-square was used. If a significant difference was observed, Chi-square of Armitage test 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.

Reproductive indices:

Copulation index (%): Number of copulated females/number of pairs x 100
Fertility Index (%): Number of pregnant females/numer of copulated females x 100
Gestation index (%): Number of pregnant animals delivered live offspring/ numer of pregnant animals x 100
Delivery index (%) and implantation index (%)

Offspring viability indices:

Viability index at Day 0 and 4 were determined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No dose-related changes in general clinical signs.
One male at 1000 mg/kg bw/day was dead 32 days after the administration started.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
For both sexes, no statistically significant difference from controls was observed in body weight and body weight gain during administration period. For both sexes, no statistically significant difference from controls was observed in food consumption during administration period.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No dose-related changes in organ weight.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No changes in gross pathology in both sexes.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Tissue pathology revealed no alteration of tissues even in the highest dose groups for both sexes.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING)
No effects on viability were observed.

CLINICAL SIGNS (OFFSPRING)
No effects were described.

BODY WEIGHT (OFFSPRING)
No effects were observed.

GROSS PATHOLOGY (OFFSPRING)
No abnormalities were found in scheduled sacrificed offsprings in all groups. One dead offspring showed pyelectasis at dosing of 40 mg/kg bw/day.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Differences in numbers of offspring or live offspring, the sex ratio, the live birth index, the viability index or body weights and findings on external features, clinical signs or necropsy of the offspring.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Table 1. Reproductive performance (P).

Group /Dose level	Fertility Index in % (P)	Copulation Index in % (P)
Group 1 (control)	90.9	91.7
Group 2 (40 mg/kg bw)	100	100
Group 3 (200 mg/kg bw	100	100
Group 4 (1000 mg/kg bw)	100	100

Table 2. Delivery data (P).

Parameter [mean]	Group 1 0 mg/kg bw	Group 2 40 mg/kg bw	Group 3 200 mg/kg bw	Group 4 1000 mg/kg bw
Number of corpora lutea	16.6	16.3	16.3	16.8
Number of Implantations sites	15.3	16.0	14.7	15.8
Total number of offsping	14.4	15.3	14.3	14.6
Implantation Index (%)	90.15	98.17	89.49	93.84
Delivery Index (%)	94.83	95.11	90.17	92.62
Gestation Index (%)	100	100	91.7	100

Table 3. Litter size and viability index (F1).

Parameter	Group 1 0 mg/kg bw	Group 2 40 mg/kg bw	Group 3 200 mg/kg bw	Group 4 1000 mg/kg bw
Total number of offspring at birth	14.4	15.3	15.6	14.6
Total number of live offspring at birth	14.2	15.3	15.5	14.6
Number of live offspring on Day 4	14.1	14.8	15.2	14.5
Viability index (%) Day 0 Day 4	98.71 99.38	100 97.17	98.86 98.3	100 99.41

Applicant's summary and conclusion

Conclusions:

The test material had no effect on reproductive performance.