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Administrative data

Description of key information

Key study: Test method similar to OECD 408. No data on GLP. Based on the read-across approach, the NOEL for dextro alpha fenchyl acetate after an oral exposure of 13 weeks was determined to be 15 mg/kg bw/day in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic 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: The analogue isobornyl acetate which shares the same functional groups with dextro alpha fenchyl acetate also has comparable values for the relevant molecular properties. A scientific review (peer reviewed). Similar to OECD guideline. No data on GLP.
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
Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Weight at study initiation: 100-120 g (male) and 90-105 g (female)
- Housing: 5 per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1ºC
- Humidity (%): 50-60%
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 5 ml total dose/kg/day
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks ( 0, 15, 90 or 270 mg/kg bw/day)
2 to 6 weeks (0, 90 or 270 mg/kg bw/day)
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 15, 90 or 270 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
15 male and 15 female: 0, 15, 90 or 270 mg/kg bw/day (13 weeks)
5 male and 5 female: 0, 90 or 270 mg/kg bw/day (2-6 weeks)
Control animals:
yes
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD INTAKE:
- Time schedule for examinations: Weekly

WATER CONSUMPTION:
- Time schedule for examinations: Weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After receiving their final dose
- Anaesthetic used for blood collection: Yes (overdose of barbiturate)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked: The blood was examined for haemoglobin content, packed cell volume, counts of erythrocytes, reticulocytes and total and individual types of leucocyte. 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: Yes
- Time schedule for collection of urine: final week of treatment
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: appearance, microscopic constituents and content of glucose, ketones, bile salts and blood. A concentration and dilution test was carried out on the same rats.
- Others: At wk 2 this was limited to measurement of the volume and specific gravity of urine produced during a 6-hr period of water deprivation. At wk 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:
GROSS PATHOLOGY: Yes
Gross abnormalities.
Organ weights: brain, pituitary, thyroid, heart, liver, spleen, adrenals, kidneys and gonads. In addition, after 13 wk of treatment the stomach, small intestine and caecum were weighed.

HISTOPATHOLOGY: Yes
Samples of the above organs and of lung, lymph nodes, thymus, urinary bladder, colon, rectum, pancreas, uterus and muscle were preserved in 10% buffered formalin. Paraffin wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination.
Clinical signs:
no effects observed
Description (incidence and severity):
(no deaths and no abnormalities in behaviour or appearance occurred during the study)
Mortality:
no mortality observed
Description (incidence):
(no deaths and no abnormalities in behaviour or appearance occurred during the study)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
(no significant differences between test and control animals)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
(no significant differences between test and control animals)
Food efficiency:
no effects observed
Description (incidence and severity):
(no significant differences between test and control animals)
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
(Only in males treated with the higher dose increase of mean water consumption was observed)
Haematological findings:
no effects observed
Description (incidence and severity):
(no differences between the test and control groups )
Urinalysis findings:
no effects observed
Description (incidence and severity):
(females treated with IBA gave results similar to those of female controls throughout. In males there were no differences between control and IBA-treated rats at week 2 but at week 6 cell excretion was increased in rats receiving 270 mg/kg bw/day)
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
(there was increase of weight of some organs)
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
(histological changes associated with IBA treatment were confined to treatment at the 270 mg/kg bw/day level)
Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths and no abnormalities in behaviour or appearance occurred during the study.

BODY WEIGHT AND WEIGHT GAIN
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:
No differences in food consumption between test and control groups were detected.

WATER CONSUMPTION:
Throughout the study, water consumption was increased in males given 270 mg/kg/day but not in females.

HAEMATOLOGY
After treatment for 6 or 13 wk there were no differences between the test and control groups in the results of the haematological studies. Increases seen at wk 2 in the haemoglobin concentration in female rats and in total leucocyte counts in male rats receiving 270 mg IBA/kg and in erythrocyte counts in males given 90 or 270 mg/kg were not seen at wk 6 or 13. The reticulocyte count of all younger rats was higher than that of the
older animals and red cells showed a marked polychromasia. The results of the serum analyses were similar in test and control rats.

URINALYSIS
The urine of all rats was of normal colour and free from glucose, blood, bile and ketones. The females treated with IBA gave results similar to those of female controls throughout. In males there were no differences between control and IBA-treated rats at wk 2 but at wk 6 cell excretion was increased in rats receiving 270 mg/kg/day and at wk 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 wk 6 this was seen only after prolonged (16-20 hr) water deprivation but at wk 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.

ORGAN WEIGHTS
Although the absolute kidney weight was increased only in females at wk 13 the kidney weight expressed relative to body weight was increased at wk 6 in males and af wk 13 in both sexes. The relative liver weight was increased in both sexes of rats given 270 mg/kg/day for 13 wk. There were no changes in liver weight at wk 2 or 6. Both absolute and relative caecal weights were increased at wk 13 at the highest level of treatment.

GROSS PATHOLOGY
No abnormalities were seen at autopsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
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 IBA 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.

Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Read-across from an analogue
Critical effects observed:
not specified

The data matrix is included in the reporting format attached.

Conclusions:
Based on the read-across approach, the NOEL after an oral exposure of 13 weeks was 15 mg/kg bw/day in rats.
Executive summary:

A repeated dose toxicity study (oral route) was performed with the analogue substance isobornyl acetate according to a similar method to OECD guideline 408. The substance was dissolved in corn oil and administered daily to rats by stomach tube in doses: 0 (control), 15, 90 or 270 mg/kg body weight/day during 13 weeks. There were no differences between treated and control animals in the rate of body-weight gain, the food intake or the results of haematological investigations. In male rats given 270 mg/kg bw/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity were also seen with daily doses of 90 mg/kg bw/day. Vacuolation of the epithelium of the intrahepatic bile-duct and increase in liver weights were found at 270 mg/kg bw/day. The caecum were also enlarged at this dosage level. The no-effect level (NOEL) found was at 15 mg/kg bw/day. Based on these results, the read-across approach was applied and the NOEL for dextro alpha fenchyl acetate after an oral exposure of 13 weeks was determined to be 15 mg/kg bw/day in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study has Klimisch score 2.

Additional information

Key study: Read-across from experimental data on the analogue isobornyl acetate.

A repeated dose toxicity study was performed with the analogue substance isobornyl acetate (test method similar to OECD 408). Rats were exposed to 0 (control), 15, 90 or 270 mg/kg bw/day by gavage during 13 weeks. In male rats given 270 mg/kg bw/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity were also seen with daily doses of 90 mg/kg bw/day. Vacuolation of the epithelium of the intrahepatic bile-duct and increase in liver weights were found at 270 mg/kg bw/day. The caecum were also enlarged at this dosage level. The NOEL was determined to be 15 mg/kg bw/day. Based on these results, the read-across approach was applied and the NOEL for dextro alpha fenchyl acetate after an oral exposure of 13 weeks was determined to be 15 mg/kg bw/day in rats.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available.

Justification for classification or non-classification

Based on the available data, the substance is not classified for specific target organ toxicity by repeated exposure (STOT-RE) according to CLP Regulation (EC) no 1272/2008.