2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions. Lack of test material details and no clinical biochemistry.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

lack of test material details and no clinical biochemistry

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

EC Number:

203-846-0

EC Name:

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

Cas Number:

111-21-7

Molecular formula:

C10H18O6

IUPAC Name:

2-[2-(2-acetyloxyethoxy)ethoxy]ethyl acetate

Details on test material:

- Name of test material (as cited in study report): Triethylene glycol diacetate
- Analytical purity: no data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 53 - 54 g
- Housing: 5 animals of the same sex per cage
- Diet: basal diet of ground Purina Laboratory Chow
- Water: ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Mixing appropriate amounts with: basal diet of ground Purina Laboratory chow

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.1, 1 %
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
25, 250 mg/rat/day
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
79.6, 796 mg/kg bw/day (males)
Basis:
other: mean dose value as calculated from the reported body weight and mean value per rat

Doses / concentrations 4

Remarks:

Doses / Concentrations:
119.5, 1195 mg/kg bw/day (females)
Basis:
other: mean dose value as calculated from the reported body weight and mean value per rat

No. of animals per sex per dose:

15

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each group was recorded at approximately weekly intervals

DIET EFFICIENCY: Yes
- Body weight gain in g/food consumption in g per unit time (Day 0- 27; Day 28-60; Day 61-89 and Day 0-89) X 100 calculated as time-weighted averages from the consumption and body weight gain data were determined.

FEED EFFICIENCY: Yes
- Diet efficiency (Body weight gain in g/food consumption in g per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain) x 1.01 or x 1.001, respectively

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 47 and Day 89
- How many animals: 10 animals per sex from the high dose group and the control group were examined.
- Parameters checked: hematocrit, hemoglobin, white blood cell value and differential blood values

URINALYSIS: Yes
- Time schedule for collection of urine: Day 47 and Day 89
- How many animals: 5 animals per sex from the high dose group and the control group were examined.
- Parameters checked: pH value, specific gravity, albumin, sugar, occult blood, ketones and physical characteristics were examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. Liver, kidneys, spleen, heart, brain, lungs and testes.
HISTOPATHOLOGY: Yes. Trachea, lung, heart, tongue, oesophagus, stomach, small and large intestine, liver, kidney, urinary bladder, pituitary, adrenal, pancreas, thyroid, parathyroid, testes, ovary and uterus, spleen, femoral bone marrow, cerebrum, cerebellum and eye.

Statistics:

Mean values were calculated and the Students´s t-test was applied.

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:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

High dose group (males): reduced white blood cell value (non adverse)

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

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:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
One animal in low dose group was found dead on Day 85, no treatment related effect.

BODY WEIGHT AND WEIGHT GAIN
No effects were observed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No effects were observed.

FOOD EFFICIENCY
No effects were observed.

HAEMATOLOGY
No treatment related effects were observed. White blood cell counts of the control and high dose males were within the normal range. However, at the 5% significance level (Student t-test) the average white blood cell count of the treated group was significantly lower than the control at Day 47 and 89. According to the author, it appeared that the control average white blood cell count was probably high (see Table 2 under "Any other information on results incl. tables").

URINALYSIS
No effects were observed.

ORGAN WEIGHTS
No effects were observed.

GROSS PATHOLOGY
No effects were observed. One high-dose male had multiple, yellowish nodules characteristic of chronic murine pneumonia in all lobes of the lungs.

HISTOPATHOLOGY: NON-NEOPLASTIC
No adverse effects were observed.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

>= 250 other: mg/rat/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

2

Dose descriptor:

NOAEL

Effect level:

>= 796 mg/kg bw/day (nominal)

Based on:

other: mean dose value as calculated from the reported body weight and mean value per rat

Sex:

male

Basis for effect level:

other: overall effects

3

Dose descriptor:

NOAEL

Effect level:

>= 1 195 mg/kg bw/day (nominal)

Based on:

other: mean dose value as calculated from the reported body weight and mean value per rat

Sex:

female

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

All animals exhibited varying, generally mild degree of chronic murine pneumonitis, with no discernable pattern of involment in different groups. Minimal focal chronic pyelonephritis was present in 2 animals in the high dose group and in one control animal one low dose group. There was no oxalate crystal precipitation in the kidneys of the test group animals or other evidence of nephrosis. Minimal focal chronic myocarditis was present in one animal each in the high dose and the control group. Squamous metaplasia of the epithelium of rare thyroid follicles was seen in two animas in each group. A parasitic worm was found within the colon of one control animal.

The abnormalities seen are typical of natural disease processes commonly found in laboratory rats. There is no morphologic evidence in the tissues examined of abnormality due to the experimental feeding program.

Table 1. Average Body Weights.

	Group [% diet]
Days on Diet	1	0.1	control	1	0.1	control
	Males			Females
0	56	50	54	53	53	55
7	99	86	96	92	88	93
14	150	138	147	130	127	129
20	200	187	202	166	158	163
27	250	235	251	184	176	185
34	303	280	292	209	202	210
40	343	320	332	226	217	225
47	361	345	342	235	228	233
53	400	377	382	244	241	242
60	408	394	386	258	253	260
64	427	404	414	257	254	261
70	432	419	428	263	263	268
76	462	440	454	273	271	279
82	472	442	464	279	284	284
89	476	462	465	280	280	284
Mean	322.6	305.3	313.9	209.9	206.3	211.4
Mean over all Males/Females			313.9			209.2

Table 2. Results of Hematology.

White blood cell value x 10^3	Group [% diet]
	1	control	1	control
	Males		Females
Day 47	17.9	23.1	19.1	18.6
Day 89	16.4	21	15.4	12.9