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Diss Factsheets

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
Study period:
1970
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The information is used for read across to Isobornyl propionate.

Data source

Reference
Reference Type:
publication
Title:
Short-term Toxicity of Isobornyl Acetate in Rats.
Author:
Gaunt IF, Agrelo CE, Colley J, Lansdown AB, Grasso P.
Year:
1971
Bibliographic source:
Fd Cosmet. ToxicoL Vol. 9, pp. 355-366. Pergamon Press 1971.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl acetate
EC Number:
204-727-6
EC Name:
Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl acetate
Cas Number:
125-12-2
Molecular formula:
C12H20O2

Test animals

Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Weanling CFE rats were obtained from an SPF colony
- Weight at study initiation: 100 to 120 g (males) or 90 to 105 g (females)
- Housing: Five animals per cage in metal cages
- Diet: Spillers' Laboratory Small Animal Diet ad Libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1
- Humidity (%): 50 to 60

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
Administration in diet and drinking water was initially considered. In pilot experiments the following results were obtained:
- When a diet containing 2 to 5 % was exposed under animal-house conditions 8 % of the flavouring was lost in 24 hr.
- Rats offered a choice of the control diet or a diet containing 500, 2000 or 12,500 ppm showed a marked preference for the control diet and at the two highest levels only the control diet was eaten.
- Groups of five male rats fed diets containing the same concentrations for 3 weeks consumed less food and gained less weight than a similar group fed the control diet.
Since the test diet was rejected by rats, and since the substance evaporated from the diet and was insoluble in water, it was not possible to administer the flavouring either in the food or drinking water. Daily oral intubation of solutions of the substance in corn oil was therefore chosen as the method of administration.
Vehicle:
corn oil
Details on oral exposure:
- VEHICLE
- Justification for use and choice of vehicle: The substance is insoluble in water
- Amount of vehicle: 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
- 13 weeks (main study)
- Additional groups of 5 animals/sex were exposed for 2 to 6 weeks at dose-levels of 0, 90 and 270 mg/kg bw/day only
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
90 mg/kg bw/day (nominal)
Dose / conc.:
270 mg/kg bw/day (nominal)
No. of animals per sex per dose:
- 15 for the main study
- 5 for the additional groups exposed for 2 to 6 weeks
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:
Yes

BODY WEIGHT:
The body weight of the animals was measured weekly.

FOOD CONSUMPTION
The intake of food was measured weekly.

WATER CONSUMPTION
The intake of water was measured weekly.

HAEMATOLOGY:
- Time schedule for collection of blood: After receiving their final dose, the animals were fasted for 24 hr and then killed by an overdose of barbiturate.
- Anaesthetic used for blood collection: No, blood was collected from the aorta for haematological examination.
- Animals fasted: Yes, 24 hr
- How many animals: all animals
- Parameters examined: The blood was examined for haemoglobin content, packed cell volume, counts of erythrocytes, reticulocytes and total and individual types of leucocyte.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: After receiving their final dose, the animals were fasted for 24 hr and then killed by an overdose of barbiturate. Blood was collected from the aorta for serum analyses.
- Animals fasted: Yes, 24 hr
- How many animals: all animals
- Parameters examined: The serum was analysed for urea, glucose, total protein and albumin and the activities of glutamic-oxalacetic and glutamic-pyruvic transaminase and lactic dehydrogenase enzymes.

URINALYSIS:
Urine was collected from all rats during the final week of treatment and, additionally, during week 6 from five rats of each sex of each group of the main study. It was examined for appearance, microscopic constituents and content of glucose, ketones, bile salts and blood. A concentration and dilution test was carried out on the same rats. At week 2 this was limited to measurement of the volume and specific gravity of urine produced during a 6-hr period of water deprivation. At week 6 and 13 similar measurements were made on the urine produced in 2 hr after a water load of 25 mL/kg and in a 4-hr period after 16 hr without water.
Sacrifice and pathology:
SACRIFICE
After receiving their final dose, the animals were fasted for 24 hr and then killed by an overdose of barbiturate.

GROSS PATHOLOGY:
The animals were examined for gross abnormalities.

ORGAN WEIGHTS
The brain, pituitary, thyroid, heart, liver, spleen, adrenals, kidneys and gonads were weighed. In addition, after 13 wk of treatment the stomach, small intestine and caecum were weighed.

HISTOPATHOLOGY:
Samples of the following organs were preserved in 10% buffered formalin: brain, pituitary, thyroid, heart, liver, spleen, adrenals, kidneys, gonads, stomach, small intestine and caecum, lung, lymph nodes, thymus, urinary bladder, colon, rectum, pancreas, uterus and muscle. Paraffin wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination.
Statistics:
Statistical analysis was performed according to White, C. (1952): The use of ranks in a test of significance for comparing two treatments. Biometrics 8, 33.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No abnormalities in behaviour or appearance occurred during the study.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were no significant differences between test and control animals in the rate of bodyweight gain during the treatment period, but a slight decrease in weight seen in males of the highest dosage group became significant after the 24-hr fast prior to death in animals killed at both 6 and 13 wk.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No differences in food consumption between test and control groups were detected
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Throughout the study, water consumption was increased in males given 270 mg/kg/day but not in females.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
- After treatment for 6 or 13 weeks there were no differences between the test and control groups in the results of the haematological studies.
- Increases seen at week 2 in the haemoglobin concentration in female rats and in total leucocyte counts in male rats receiving 270 mg/kg and in erythrocyte counts in males given 90 or 270 mg/kg were not seen at week 6 or 13. The increased erythrocyte and leucocyte counts and haemoglobin concentrations at week 2 cannot be ascribed to the treatment.
- The reticulocyte count of all younger rats was higher than that of the older animals and red cells showed a marked polychromasia.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The results of the serum analyses were similar in test and control rats
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
- The urine of all rats was of normal colour and free from glucose, blood, bile and ketones.
- The females treated with test substance gave results similar to those of female controls throughout.
- In males there were no differences between control and treated rats at week 2 but at week 6 cell excretion was increased in rats receiving 270 mg/kg/day and at week 13 this effect was seen also in animals receiving 90 mg/kg/day. The males given 270 mg/kg/day also showed an impairment of urine-concentrating ability. At week 6 this was seen only after prolonged (16-20 hr) water deprivation but at week 13 it was also seen after dehydration for 6 hr. At the lower dosage levels there were no significant changes in the results of the concentration test.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Although the absolute kidney weight was increased only in high dose females at week 13 the kidney weight expressed relative to body weight was increased at week 6 in males and at week 13 in both sexes.
- The relative liver weight was increased in both sexes of rats given 270 mg/kg/day for 13 weeks. There were no changes in liver weight at week 2 or 6.
- Both absolute and relative caecal weights were increased at week 13 at the highest level of treatment.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormalities were seen at autopsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Histological examination showed that there was a varying degree of pulmonary change suggestive of a mild infection; this was common to test and control animals.
- Histological changes associated with treatment were confined to treatment at the 270 mg/kg level. In the kidneys there was an increased incidence of focal tubular degeneration and atrophy and, in males only, a vacuolation of the tubular epithelium. Vacuolation of the epithelial cells of the intrahepatic bile ducts was also seen in males.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 270 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No human-relevant adverse effects were observed
Dose descriptor:
NOAEL
Remarks:
(rat specific)
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
water consumption and compound intake
Remarks on result:
other: Alpha hydrocarbon nephropathy and liver hypertrophy are considered rodent specific effects

Target system / organ toxicity

open allclose all
Critical effects observed:
yes
Lowest effective dose / conc.:
270 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no
Critical effects observed:
yes
Lowest effective dose / conc.:
90 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
In the sub-chronic toxicity study a NOAEL of 15 mg/kg bw was derived based on renal toxicity and mild hepatotoxicity (rat specific effect) and a NOAEL of 270 mg/kg bw/day was derived based on the absence of human-relevant adverse effects.
Executive summary:

In the sub-chronic oral toxicity study, similar to OECD TG 408, 15 male and female CFE rats were exposed daily to 0 (vehicle control), 15, 90 and 270 mg/kg bw/day by oral gavage for a period of 13 weeks. 5 additional animals/ sex were exposed for 2 to 6 weeks for the 0, 90 and 270 mg/kg bw /day dose groups. Corn oil was used as vehicle. The body weight of the animals and their intake of food and water were measured weekly.

Urine was collected for urinalysis from all rats during the final week of treatment and, additionally, during week 6 from five rats of each sex of each group of the main study. After receiving their final dose, the animals were fasted for 24 hr and then killed by an overdose of barbiturate. Blood was collected from the aorta for haematological examination and serum analyses. Gross pathology, histopathology and measurement of organ weights was performed.

No deaths and no abnormalities in behaviour or appearance occurred during the study. There were no significant differences between test and control animals in the rate of bodyweight gain. No treatment related haematological effects or alterations in serum parameters were observed. Urinalysis revealed increased cell excretion in rats receiving 270 mg/kg/day and at week 13 this effect was seen also in animals receiving 90 mg/kg/day. The males given 270 mg/kg/day also showed an impairment of urine-concentrating ability. At week 6 this was seen only after prolonged (16-20 hr) water deprivation but at week 13 it was also seen after dehydration for 6 hr. Although the absolute kidney weight was increased only in females at week 13, the kidney weight expressed relative to body weight was increased at week 6 in males and at week 13 in both sexes. The relative liver weight was increased in both sexes of rats given 270 mg/kg/day for 13 wk. Both absolute and relative caecal weights were increased at week 13 at the highest level of treatment. No abnormalities were seen at autopsy but the histological examination revealed focal tubular degeneration and atrophy in the kidneys in the high dose group and, in males only, a vacuolation of the tubular epithelium. Slight vacuolation of the epithelial cells of the intrahepatic bile ducts was also seen in males but not considered adverse. Based on these results a NOAEL of 270 mg/kg bw/day was derived in the absence of human-relevant adverse effects.