Hydratropaldehyde

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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

Qualifier:

according to guideline

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

Species:

rat

Strain:

other: CFE strain

Sex:

male/female

Details on test animals or test system 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

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

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

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

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.

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

Critical effects observed:

not specified

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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from peer reviwed publication

Additional information

Repeated dose toxicity: Oral

Various studies for the test compound and prediction model based estimation have been used to determine the toxic nature of the test compoun upon repeated application. The studies are summarized below:

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).

Repeated dose toxicity test was performed (Fragrance ,aterail association of United States, 2010) on maleSprague-Dawley (SD) rat. The group of 10 rats were used for treatment at different concentrations as 25, 75, or 250 mg/kg/day in a corn oil vehicle for 14 days. Two groups of 10 control animals were used. The rats were evaluated for viability and clinical observations, body weights and feed consumption, full necropsy, liver, kidney, and reproductive organs weights, sperm count, motility and morphology, and  histopathology on liver, kidneys, reproduction organs from control and high dose groups. Adverse effects on male reproductive capacity were noted for hydratropic aldehyde.Treatment with hydratropic aldehyde resulted in decreased cauda epididymal sperm count and density at 75 and 250 mg/kg/day.

Therefore, end point for the repeated dose toxicity for Hydratropic aldehyde (93-53-8) was found to be LOAEL at concentration of 75 mg/kg/day and the NOAEL was found to be 25 mg/Kg bw.

The No observed Adverse Effect Level (NOAEL) for the test compound Hydratropic aldehyde is found to be 478.388885498 mg/Kg bw/day (SSS QSAR, 2016)

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
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).