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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Experimental design is similar to OECD 407 and was conducted under no GLP conditions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Acetaldehyde: obtained from Merck-Schuchardt, Schuchardt, Federal Republic of Germany

Test animals

Species:
rat
Strain:
other: Cpb:WU; Wistar random
Sex:
male/female
Details on test animals and environmental conditions:
Cages were randomized over the racks
Temperature in the animal room was kept at 22 +/- 2 degree Celcius
Relative humidity was between 40 and 70%

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Test subtances were given to teh animals via the drinking water at various concnetrtaions to provide doses of 25, 125 or 625 mg acetaldehyde /kg BW / day. Fresh solutions were prepared every week and stored in a refirgerator at about 4 degree Celcius. The concentrations required were adapted to teh changes in body weight and fluid consumtion as measured over the previous week. Fluid consumption was measured on a cage basis the whole study.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
25 mg acetaldehyde /kg BW/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
125 mg acetaldehyde/kg BW/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
625 mg acetaldehyde/kg BW/day
Basis:
actual ingested
No. of animals per sex per dose:
10 males and 10 females per group
Control animals:
yes, concurrent vehicle
other: negative control based on the amount of liquid consumed.

Examinations

Observations and examinations performed and frequency:
Clinical Signs: observation on the genral coditions and behavior of all animals were checked daily. All signs of illness or reaction to treatment were recorded.

Body Weights: the individual body weights of all rats were recorded initially, and on day 7, 14, 21, 28 of the study. In addition, females were weighted on the day of autopsy (day 29).

Food Consumption: It was measured per cage over weekly periods and the efficiency of food utilization was claculated and expressed as gram weight gain per gram food consumed.

Intake of Drinking Solutions: Fluid consumption was measure on a cage basis during the whole study.

Haematology: Samples of blood were collected from the tip of the tail of all male rats on day 21 and of all female rats on day 22, and examined for the following parameteres: haemoglibin, packed cell volume, red blood cells, white blood cells, mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC).

Clinical Chemistry: On day 23 for males and and on day 25 for females, blood was collected from the tip of the tail of all animlas after deprivation of water for 24 hours and of food during the last 16 hours of this period and examined for glucose. At autopsy, blood sampels were collected from the aorta od all whilst under ether anaesthesis. Blood was sample were analyzed for the follwoing parameters: alkaline phosphatases (ALP), glutamic-oxalacetic transsaminase (GOT)/aspartate amino transferase (ASAT), glutamic-pysuvic transaminase (GOT)/aspartate amino transfearse (ASAT), glutamic-pysuvic transaminase (GPT), alanina amino transferase (ALAT), total protein, albumin, bilirubin total, urea, creatinine, inorganic phosphatase, chloride (Cl), sodium (Na), potasium (K), and calcium (Ca).

Urinalysis: On day 23 all male rats and on day 25 all female rats were deprived of water for 24 hours and of food for 16 hours. Urine was collected from individual animals during the last 16 hours of the deprivation period. The following determinations were carried out in individual samples: volume and density.
Sacrifice and pathology:
Autopsy: In week 5, the animlas were sacrificed, males on day 28 and 29 and females on day 30 and 31. Samples of the follwoing tissues and organs of all animals were collected and preserved: adrenals, brain, heart, kidneys, lips, liver, pancreas, pharynx, stomach (fore and glandular part), spleen, testes, thymus, thyroid, nasal cavity, oesophagous, ovaries, tongue, urinary bladder, uterus with cervix, all gross lesions. Only the following organs were weighed: adrenals, brain, heart, kidneys, liver, spleen, testes, thymus, thyroid, and ovaries.

Microscopic examination: Tissues samples of the liver, kidneys, tongue, pharyx, oesophagus, stomach and nasal cavity (6 standard cross sections) of all controlIt was carried out on the stomach of all rats of the low- and mid dose groups.
Statistics:
Data on body and organ weights, red blood cell paratmetrs, clinical chemistry and urinary parameters were evaluated by one-way analysis of (co-) variance, followed by Dunnett's multiple comparison test. Data on food and water intake and food efficiency were evaluated by analysis of variance followed by the LSD test. White blood cell counst were analyzed by the Mann-Whitney U-tets. The histopathological changes were evaluated by the Fisher exact probability test.

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):
effects observed, treatment-related
Description (incidence and severity):
food intake in male and female high-dose animals receiving acetaldehyde was slightly lower than in control, but the differences with the control did not always reach the level of statistical significance.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Fluid intake was statistically significantly decreased in the high-dose group. Overall, the intake of the test substance in the dosed groups was somewhat higher than the intended levels.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In high-dose, plasma level of urea was significantly increased and bilirubin was significanlty decreased in males, while plasma alkaline phosphatase and glutamic pyruvic transaminase activities were statistically significantly decreased in females.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
In the high-dose group, the density of the urine was slightly increased. The difference with the controls occassionally reached the level of statistical significance. Also, there was a tendency towards lower volumes of urine in the high-dose group.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Kidneys were statistically significantly increased in males at the high-dose.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
some effect but these were considered to be toxicologically unimportant.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
changes were seen in the stomach only. Most males and females showed (focal) hyperkeratosis of the forestomach. No morphological changes were observed in the kidneys or liver that could be related to treatment.
Histopathological findings: neoplastic:
no effects observed
Details on results:
Acetaldehyde induced hyperkeratosis in the forestomach in both sexes. The effect is attributed to the well-know irritating properties of acetaldehyde. The drecease in GPT-activity seen in males of the acetandehyde high-dose group was not accompanied by histopathological changes in the lievr, and is, therefore, considered an irrelevant finding of toxicological concern. The finding that the acetaldehyde high-dose rats produced less urine with a higher density, and the fact that these rats showed increases in relative kidney weight and plasma urea concentration, and slight decreases in food intake, alkaline phosphatase activity and total bilirubin level, were atributed to the decrease in water intake observed in these animals, because similar changes occureed in the rats of the additional group (restricted water intake) receiving the same amount of drinking water.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The additional group of rats which received a restricted amount of drinking water showed a number of statistically significant defferences with the controls given drinking water ad libitum: 1) decrease in BW; 2) decrease in food efficiency in the first two weeks of the study; 3) higher values for RBC count and packed cell volume; 4) decrease in urinary volume and an increase in density of the urine; 5) decrease in plasma alkaline phosphate activity, plasma bilirubin (males only) and in plasma sodium, calcum and phosphorus content (females only); 6) increase in plasma urea levels; 7) increase in the relative weights of kidneys (in males and females) and in that the brain, testes and heart in males; 8) decrease in absolute and relative weights of the liver.

Applicant's summary and conclusion

Conclusions:
It was concluded that the ingestion of acetaldhyde at 125 mg/ kg BW / day for 4 weeks resulted in hyperkeratosis of the forestomach. The No-toxic effect level of acetaldehyde was 125 mg/kg/day.
Executive summary:

In a 4 -week oral study with three test groups of 10 male and 10 female rats was conducted. The test substance was administered via the drinking water at 25, 125 or 625 mg/kg BW/day. There was two control groups, one consisted of 20 males and 20 females which recieved drinking water ad libitum and another one which consisted of 10 male and 10 females and were given the a restricted amount of water. General conditions, behavior, survival and body weighty were not adversely affected in any of the test groups receiving acetaldehyde. Food and liquid intake were decreased in the high-dose group. Haematology did not show treatment-related differences among the groups. The density of the urine was slightly higher in the acetaldehyde high-dose group than the controls. A statistically significant decreased in alkaline phosphatase and glutamic-pyruvic transaminase activities in females were observed in the acetaldehyde high-dose. The relative weights of the kidneys were increased in the high-dose but it was not statistically siugnificantly high. The gross examination of the acetaldehyde consuming animals did not exhibit gross lesions. Upon micorscopic examination, hyperkearatosis in the forestomach of most male and female rats. Rats which receive a restricted amount of drinking water showed the a number of statistically sigmificant differences with the control given drinking water at libitum.