Acetaldehyde oxime

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Old study but very well documented.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

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

Remarks:

study performed in 1976

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Acetaldehyde oxime

EC Number:

203-479-6

EC Name:

Acetaldehyde oxime

Cas Number:

107-29-9

Molecular formula:

C2H5NO

IUPAC Name:

acetaldehyde oxime

Details on test material:

- acetalaldehyde oxime
- Lot No.: 50-4831-30C
- description: clear liquid with an unpleasant odor
- date of receipt: 1976-03-19

Test animals

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, Massachusetts
- Age at study initiation:
- Weight at study initiation:
- Housing: individually in elevated wire mesh cages
- Diet: ad libitum (Purina Laboratory Chow)
- Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: solutions of the test material were prepared in a vehicle of distilled water on a weight-per-volume basis

The prescribed daily doses were administered by oral intubation in 2 equally divided doses at a total daily volume of 2.0 mL of test solution/kg of body weight. Dosages were adjusted to the weekly individual body weights.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
actual ingested

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

All of the animals were observed daily for mortality, morbidity, and signs of toxic and pharmacologic effect.

CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY: No data

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at weeks 4, 8 and 13
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 rats/sex/group
- Parameters checked: hematocrit, hemoglobin levels, erythrocyte count, total and differential leukocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at weeks 4, 8 and 13
- Animals fasted: Yes
- How many animals: 5
- Parameters checked:
at each interval on the same animals: fasting glucose, blood urea nitrogen (BUN), total protein, total bilirubin (BIT), serum glutamic-pyruvic transaminase (SG-PT), alkaline phosphatase and serum electrophoresis
at week 13: serum glutamic-oxaloacetic transaminase (SG-OT), serum albumin, serum sodium, serum potassium, serum chloride, serum calcium and carbon dioxide
Erythrocyte and plasma cholinesterase levels were determined at weeks 4, 8 and 13 on an additional set of 5 rats/sex/group

URINALYSIS: Yes
- Time schedule for collection of urine: at weeks 4, 8 and 13
- performed on pooled samples of 5 rats/sex/group
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes / No / No data
- Parameters checked at each interval: specific gravity, pH, ketones, total protein, bilirubin and microscopic examination of the sediment.

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

Necropsies were performed on all animals that died during the course of the study and on all surviving rats at week 13. Animals were sacrificied by exsanguination under sodium pentobarbital anesthesia (Diabutal, Diamond Laboratories Inc., Des Moines, Iowa)

Prior to sacrifice, all of the rats were fasted for 24 h and the terminal body weights were recorded. The following organs of each sacrificied rat were weighed and the organ/body ratios determined:
prior to fixation: liver, spleen, heart, kidneys and testes with epididymides
after fixation: thyroids and adrenals

The following tissues of each rat were preserved in 10% neutral buffered formalin: brain, thoracic spinal cord, pituitary, thyroids, adrenals, heart, lungs, spleen, liver, kidneys, stomach, small and large intestines, pancreas, urinary bladder, testes with epididymides and prostate or ovaries and uterus, salivary glands, mesenteric lymph nodes, eyes, nerve with muscle, bone marrow, rib junction and any unusual lesions.

All of the preserved tissues from the control and high-dose animals, and the spleen and liver tissue from all of the low and mid-dose animals sacrificed at week 13 were stained with hematoxylin and eosin and examined microscopically.

Statistics:

Statistical analyses of the food consumption data, hematology and blood chemistry, terminal body weights, organ weights, and organ/body weight ratios were performed by Bartlett's test for homogeneity of variances and the one-way classification analysis of variances. When differences were noted in the analysis of variances, Scheffe's method for judging all contrasts or Student's t-test were employed. Growth rates were obtained using Rao's technique.

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):

no effects observed

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL OBSERVATIONS AND MORTALITY:
Survival was 100% in all of the male groups and in the control., low- and mid-dose females. 2 high-dose group females died during weeks 3 and 4. Antemortem signs were observed in one of these animals and included: a hunched appearance, thinness, dyspnea, urine stains and anorexia.
No signs of compound-induced toxicity were observed in any of the surviving animals. Findings observed were generally of an incidental nature and were noted at comparable incidences in the treated and the control groups. These included wheezing, stains on the hair coat, chromodacryorrhea, localized alopecia and sores, lacrimation, cloudy, red or pale eyes, and a hunched appearance.

BODY WEIGHT AND FOOD CONSUMPTION:
The mean body weight and food consumption values of the control and the treated groups were generally comparable and no statistically significant differences were noted.

HAEMATOLOGY

CLINICAL CHEMISTRY

URINALYSIS
The results of urinalyses were generally unremarkable.

ORGAN WEIGHTS:
Moderate to marked increase of statistical significance were noted in the absolute and relative thyroid and spleen weights of the mid- and high-dose males and females and in the relative thyroid and spleen weights of the low-dose males. Slight, but statistically significant, elevations were also noted in the relative and/or absolute heart weights of the high-dose males and females and in the relative and/or absolute liver weights of the mid-dose males and high-dose males and females.

GROSS PATHOLOGY:
The following findings were noted in the 2 high-dose females that died. In animal 27912 (died week 3), the pericardial sac and mediastinum were completely distended apparently due to the rupture of a blood vessel into the sac, the lungs were collapsed and dark-red, the liver was dark-red with a granular appearance, the renal medulla was dark-red, and there was a grey uneven zone at the renal cortico-medullary junction. In animal 27900 (died week 4), there was a large amount of dark-pink fluid in the thoracic cavity, the lungs were covered with a thick, yellow, caseous material, the stomach lining was smooth, and the renal cortico-medullary junction was dark-red.
Enlargement and discoloration (dark-red) of the spleen were noted in the majority of the male and female mid- and high-dose animals sacrificed at termination. Other findings were incidental in nature and were found at comparable incidence in the control and treated groups.

HISTOPATHOLOGY: NON-NEOPLASTIC:
Compound-related histomorpholic alterations were noted in sections of the spleen and liver from rats of the mid- and high-dose levels. Alterations noted in the spleen consisted of increased extramedullary hematopoiesis, increased amounts of greenish-brown pigment in fixed macrophages, and congestion in the red pulp. Sections of spleen from the low-dose male and female rats were comparable in appearance to the control group. Liver sections from male and female rats in the mid- and high-dose groups revealed greenish-brown pigment in Kupffer cells and/or bile canaliculi.
Spontaneous disease and incidental lesions were noted in rats of the control and high-dose groups as follows. Microcysts were noted in the pituitary glands of 3 treated rats. Focal nonsuppurative adrenalitis was present in a single male treated rat. Focal nonsuppurative myocarditis was noted in heart sections of 17 control and 14 treated rats. In addition, fibrinopurulent pericarditis was noted in the 2 high-dose female rats that died (Nos. 27900 and 27912). Fibrinopurulent pleuritis was also present in treated female 27900. Lung sections of control and treated rats contained early lesions of chronic respiratory disease consisting of peribronchial and perivascular lymphoid hyperplasia with occasional small foci of pneumonitis occuring with comparable incidence and severity in the male and female control and treated rats.
Spontaneous disease lesions in the liver sections were principally microgranulomas that were present in liver sections from nearly all rats and minimal to slight nonsuppurative pericholangitis. Focal hepatic necrosis was noted in the liver of treated female 27912 and was possibly associated with a severe fibrinopurulent pleuritis noted in this animal.
Early chronic interstitial nephritis was noted principally in the male rats and was comparable in incidence and severity in the control and treated groups. Nonsuppurative pyelitis was present in the kidney of treated female 27908. Kidney sections from the female rats revealed occasional foci of mineralization at the cortical medullary junction and in the renal medulla, and microcalculi were present in the renal pelvis in a single control female and treated male.
Sections of the gastrointestinal tract were not remarkable except for the presence of nematode parasites in the large intestine of 12 control and 9 treated rats. Sections of pancreas revealed early nonsuppurative pancreatitis in 4 control and 6 treated rats along with lobular atrophy in 2 of the control rats. Sections of the gonads were not remarkable except for hypospermatogenesis in 2 control rats (Nos. 27736 and 27740) and in 4 treated rats (Nos. 27881, 27887, 27889 and 27898). Focal nonsuppurative prostatitis was noted in 2 control rats and a single treated rat. A sperm granuloma was present in the epididymis of control rat 27740. Sections of uterus from control and treated rats revealed hydrometra in comparable numbers of control and treated rats and occasional rats with early cystic endometrial hyperplasia.
Focal nonsuppurative sialoadenitis was present in the salivary glands of 2 control and 2 treated rats and lymphoreticular cell proliferation was present in the cervical lymph nodes in occasional control and treated rats apparently as a result of viral sialoadenitis. Anterior synechia was noted in the eye section of one treated male rat (No. 27876).

Effect levels

Basis for effect level:

other: No NOAEL was established in this study.

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In conclusion, acetaldehyde oxime, administered to rats for 13 weeks at levels of 25, 75 and 225 mg/kg/day produced an apparent effect upon red blood cells, causing increased destruction of these cells. Resultant effects included decreased hemogram values, several altered serum biochemistry parameters, increased absolute and relative spleen, liver, and thyroid weights, and histopathological alterations indicative of increased red cell turnover.
Although the effects noted, at the lowest dose (25 mg/kg/day) level were marginal and less frequent, on the basis of the results of this study, a definite "no-effect" level has not been established.

Executive summary:

The test material, acetaldehyde oxime, was evaluated for toxicological effects in cesarean-derived albino rats (25/sex/group) when administered orally for 13 weeks at levels of 25, 75 and 225 mg/kg/day (Groups 2, 3 and 4 respectively). A fourth group of animals (Group 1, 25/sex) was similarly treated with the vehicle (distilled water) and served as the control group.

The criteria evaluated for compound effect were clinical signs, mortality, body weight, food consumption, clinical laboratory data, organ weights, and organ/body weight ratios, and gross and microscopic pathology.

No effects attributable to the ingestion of acetaldehyde oxime were noted in evaluations of mortality rates, appearance and behavior, body weight and consumption values, or urinalysis values.

Analyses of the hematology values revealed dose-related decreases in the hematocrit and hemoglobin levels and erythrocyte counts in animals of all the treated groups. These differences were generally marginal in the low-dose group and statistically significant in the high-dose group. Analyses of the clinical chemistry data revealed statistically significant elevations in the total bilirubin levels of the high-dose males and females at week 13, and slight to statistically significant increases in the blood urea nitrogen, plasma cholinesterase, and erythrocyte cholinesterase levels of the mid- and high-dose males and females at most of the intervals. Decreases were also noted in the glucose levels of the high-dose males and females at week 13.

Slight to marked increases were found in the absolute and/or relative thyroid and spleen weights of the low-, mid- and high-dose males and females. Increases were also noted in the absolute and/or relative heart and liver weights of the mid- and high-dose males and females.

Gross alterations (enlargement and discoloration) were noted in the spleens of most of the male and female mid- and high-dose animals sacrificed at termination.

Microscopic evaluations of tissue sections revealed compound-related histomorphological alterations in the mid- and high-dose (75 and 225 mg/kg/day) males and females. These alterations consisted of congestion, increased pigment, and extramedullary hematopoieses in the spleen, and the presence of greenish-brown pigment in the Kupffer cells and the bile canaliculi of the liver. No compound-related effects were observed in the spleen and liver sections of the low-dose males and females.

In conclusion, acetaldehyde oxime, administered to rats for 13 weeks at levels of 25, 75 and 225 mg/kg/day produced an apparent effect upon red blood cells, causing increased destruction of these cells. Resultant effects included decreased hemogram values, several altered serum biochemistry parameters, increased absolute and relative spleen, liver, and thyroid weights, and histopathological alterations indicative of increased red cell turnover.

Although the effects noted, at the lowest dose (25 mg/kg/day) level were marginal and less frequent, on the basis of the results of this study, a definite "no-effect" level has not been established.