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Toxicological information

Repeated dose toxicity: oral

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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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
lack of test material details and no clinical biochemistry
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.1, 1 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
25, 250 mg/rat/day
Basis:
nominal in diet
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
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

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 250 other: mg/rat/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
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
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 103 

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

Applicant's summary and conclusion