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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Short-term toxicity of hydratropic aldehyde in rats
Author:
Pelling D,Gaunt If ,Butterworth Kr ,Hardy J ,Lansdown A Bg ,Gangolli Sd
Year:
1976
Bibliographic source:
Fd Cosmet. Toxicol. Vol. 14. pp. 249-253, 1976

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Repeated dose toxicity test was performed on rats for 15 weeks with different concentrations as 0 (control), 10, 50 or 500 mg/kg body weight/day.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Hydratropaldehyde- Molecular formula: C9H10O- Molecular weight: 134.17 g/mol- Smiles notation: CC(C=O)C1=CC=CC=C1- Substance type: Liquid- Physical state: Organic- Impurities (identity and concentrations): No data- Purity: minimum 98%

Test animals

Species:
rat
Strain:
other: CFE strain
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: specified-pathogen free breeding colony
- Age at study initiation: No data available
- Weight at study initiation:
Male: 65-100 g
Females: 60-90 g
- Fasting period before study: No data available
- Housing: They were housed five in a cage in an animal room maintained at 21 ± 1°C and 50-60% relative humidity.
- Diet (e.g. ad libitum): Spillers’ Laboratory Small Animal Diet, ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1°C
- Humidity (%):50-60%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: The concentrations of the solutions were selected so that each rat was given 5 ml/kg of the appropriate solution.

DIET PREPARATION
- Rate of preparation of diet (frequency): Not applicable as chemical given through oral route
- Mixing appropriate amounts with (Type of food): Not applicable
- Storage temperature of food: Not applicable

VEHICLE
- Justification for use and choice of vehicle (if other than water): Becauce of chemical volatility and low solubility in water the flavouring could not be administered to the rats in the diet or drinking-water and was given instead by daily oral intubation as a solution in corn oil.
- Concentration in vehicle: No data available
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
15 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (control), 10, 50 and 500 mg/kg body weight/day.
Basis:
actual ingested
No. of animals per sex per dose:
15 male rats and 15 females were used.
In addition, groups of five rats of each sex were given daily doses at the same levels for 6 wk and groups of ten male and five female rats were treated for 2wk.
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly up to wk 14

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, was determined during the 24 hr preceding each weighing.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: was determined during the 24 hr preceding each weighing

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the time of autopsy.
- Anaesthetic used for blood collection: Yes
- Animals fasted: yes, the animals were deprived of food for 24 hr
- How many animals: animals mention but not exact numbers
- Parameters checked in table [No.?] were examined. Haemoglobin content packed cell volume and counts of erythrocytes and leucocytes.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the time of autopsy
- Animals fasted: Yes, the animals were deprived of food for 24 hr
- How many animals: animals mention but not exact numbers
- Parameters checked: The serum was analysed for urea, glucose, total protein and albumin as well as for the activities of glutamic-oxalacetic transaminases, glutamic-pyruvic transaminases and lactic dehydrogenase.

URINALYSIS: Yes
- Time schedule for collection of urine: At the final week of treatment.
In addition, at wk 6 and 14, the same measurements were made on the urine produced during a 4-hr period commencing after 16 hr without water. The number of cells in the urine was counted using the 2-hr sample.

- Metabolism cages used for collection of urine: No data

- Animals fasted: No data

- Parameters checked: examined for appearance, microscopic constituents and content of albumin, glucose, ketones, bile salts and blood.
Renal concentrating and diluting ability was assessed at the same intervals by measuring the specific gravity and volume of the urine produced during a 6-hr period of water deprivation and in the 2-hr period after a water load of 25 ml/kg.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: No data sensory activity / grip strength / motor activity / other:

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes HISTOPATHOLOGY: Yes, Samples of organs were preserved in 10% buffered formalin.
Paraffin-wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination.
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No deaths and no abnormalities in behaviour were seen during the study.
Mortality:
mortality observed, treatment-related
Description (incidence):
No deaths and no abnormalities in behaviour were seen during the study.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At the highest dose level the overall food intake was slightly increased in both sexes.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The results of the serum analyses were similar in test and control rats.
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At autopsy, small lung lesions were observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No histological changes related to the period or level of treatment was seen in any of the organs examined.
Histopathological findings: neoplastic:
not specified
Details on results:
Body weight and weight gain:
The males given two highest levels of hydratropic aldehyde gained slightly less weight than the controls. The differences were not statistically signific
ant. No differences between treated and control groups were detected in the male rats given 10 mg/kg/day or in the females at any dose level.

Water consumption and compound intake:
The overall water intake in the group 10 mg/kg/day were increased by 15 and 21%, compared with the controls, in males and females. In the males the differences in water intake between treated and control groups were statistically significant only at 28. 41, and 56 days.

Haematology:
The haemoglobin concentration was decreased by 5-7% compared with the controls in the males given 500 mg hydratropic aldehyde/kg/day at wk 6 and in both sexes at wk 15, It was decreased by a similar amount in the females given 50 mg/kg/day for 15 wk and the decreases in haemoglobin concentration at the higher dosage levels after 6 and 15 wk were probably related to treatment..

Urinanalysis:
The urine of all the rats was free from bile, blood, glucose and ketones and the concentrations of albumin were similar in all groups. The renal concentration, cell excretion rates and dilution tests showed no statistically significant differences between treated and control animals.

Organ weights:
Increases in the weights of several organs, notably the liver, kidney and stomach in animals treated with the highest dose level of 500 mg/kg/day.
There were increases in relative liver weight at the lower dose levels these were confined to the males at wk 15. The liver weight was increased in animals receiving 500 mg/kg/day, without any histopathological change. Slight increases in relative liver weight were noted with 10 and 50 mg/kg/day, but these were not considered to be related to treatment.

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Clinical signs and mortality, Histopathology, organ weight

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The endpoint for the repeated dose toxicity was found to be NOAEL at 10 mg/kg/day for rat when treated with Hydratropic aldehyde (93-53-8).
Executive summary:

Repeated dose toxicity test was performed on rats for 15 weeks with different concentrations as 0 (control), 10, 50 or 500 mg/kg body weight/day. Rats of CFE strain were used and given Spillers’ Laboratory Small Animal Diet and waterad lib. 15 male and female rats per dose were given daily oral intubation of hydratropic aldehyde of different concentrations where corn oil is used as a vehicle. The rats were weighed weekly up to wk 14 and the consumption of food and water was determined during the 24 hr preceding each weighing. On the day after the final dose, the animals were deprived of food for 24 hr and killed by exsanguination from the aorta under barbiturate anaesthesia and the blood was used for haematological examinations and serum analyses. Gross and histopathology were done. Urine was collected during the final week of treatment and examined for appearance, microscopic constituents and content of albumin, glucose, ketones, bile salts and blood.Slight increases in relative liver weight were noted with 10 and 50 mg/kg/day, but these were not considered to be related to treatment. There were statistically significant increases in water consumption at the highest dose level and small reductions in haemoglobin concentration in rats given 50 or 500 mg/kg/day.The histological appearance of all tissues was similar in the test and control groups.

Therefore, endpoint for the repeated dose toxicity was found to be NOAEL at 10 mg/kg/day for rat when treated with Hydratropic aldehyde (93-53-8).