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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:
key study
Study period:
not indicated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study is well documented, meets generally accepted scientific principles, acceptable for assessment.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Comparative pathology on rats given methoxyacetone and five other aliphatic ketones in drinking water (ketone neurotoxicity)
Author:
EPA/OTS
Year:
1983
Bibliographic source:
EPA/OTS0206068, Doc #878212141

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study predated OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents). One dose level of the test item was administered orally via drinking water to a group of 5 female rats for 120 days. Extended neurophathological and histopathological examinations were performed.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentan-3-one
EC Number:
202-490-3
EC Name:
Pentan-3-one
Cas Number:
96-22-0
Molecular formula:
C5H10O
IUPAC Name:
pentan-3-one
Details on test material:
- no data

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Rats, approximately 4 weeks of age, used in this study were Wistar females obtained from Hilltop Laboratories, Scottdale, Pa. The rats were identified by toe-clipping. They were weighed and distributed among the treatment groups of five rats each by formal randomization. Only rats whose body weights were within two standard deviational units of the overall mean weight were accepted for the study. Any rat that lost weight or that had poor
tone during the preliminary observation period was rejected. The range of weights on the first day of study was 187 to 236 grams.
Rats were housed in suspended steel wire-mesh cages. The diet fed, provided in 12-oz. opal Blass jars, was Purina Laboratory Chow. Diet for each group was stored in a separate glass stock jar with a screw cap. These jars were weighed, full, at the beginning and, again, at the end of each week to determine the amount of diet consumed. Water was available at all times in nonfouling siphon water bottles equipped with stainless steel tips.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
The test item was administered in drinking water at a predetermined concentration based on body weight and water consumption. Fresh solutions were prepared each week. The concentration was adjusted as necessary to maintain a relatively constant dose level.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
- 120 days
Frequency of treatment:
- the test item was administered in drinking water which was available at all times
Doses / concentrations
Remarks:
Doses / Concentrations:
2.4 % in water (appr. 1860 mg/kg bw/d)
Basis:

No. of animals per sex per dose:
- 5 female rats (test item group), 10 female rats (control group)
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
The concentration of the test item in drinking water was adjusted as necessary to maintain a relatively constant dose level.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
NECROPSY PROCEDURE:
All rats were euthanized by CO2 narcosis fo11owed by severing the cervical spinal cord and exsanguination via jugular and carotid blood
vessels. Right and left sciatic and brachial nerves were dissected free and fixed in 3 % phosphate buffered glutaraldehyde. The entire vertebral column was removed, divided into sections and fixed in 10 % neutral buffered formalin (NBF). Anterior and posterior thigh muscles and distal portions of onerear leg were removed and fixed in 10 % NBF. Slices were made through the muscles to allow for proper fixation. All abdominal and thoracic viscera
were removed and representatlve samp1es were fixed in 10% NBF. The brain and skull were also fixed along with the abdominal and thoracic viscera.

Organ weights were recorded for the liver and kidneys.

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes (dorsal root ganglia, spinal roots, sciatic nerve, skeletal muscle, femur, femural marrow, nasal cavity, tongue, eyes, harderian glands, ears, adrenals, pituitary, brain, spinal cord, vertebrae, vertebral marrow, aorta ,heart, salvary glands, cervical lymph node, spleen, pancreas, thymus, mediastinal lymph node, trachea, esophagus, larynx, thyroids, parathyroids, lungs, kidneys, urinary bladder, ovaries, oviducts, uterine hirns, uterine body, stomach, duodenum, jejunum, ileum, cecum, colon, mesenteric lymph node, liver

Statistics:
no data

Results and discussion

Results of examinations

Details on results:
Neuropathological examinations did not show any substance related effect.
The incidence and severity of histological changes seen in some organs of the test item treated rats (hemorrhage and hemosederosis in medastinal lymph node, nematodiasis in the cecum, hemosiderosis in spleen, thymic hemorrhage) was comparable with the control group rats. The gastric gland dilatation noted in the stomach of 2/5 test group animals but not in control group animals represented spontaneous histologic alterations commonly seen in this stock of rats.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 860 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: not histopathological changes attributable to treatement

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In a subchronic toxicity study Diethyl ketone was administered to five female Wistar rats in drinking water for 120 days at a concentration of 2.4 % which corresponds to 1860 mg/kg bw/d. The study focused on neurohistopathology and histopathology. The organs examined fulfil the requirements of OECD test guideline 408. No neuropathological effects were noted. The histopathological changes observed in medastinal lymph nodes (hemorrhage and hemosederosis), cecum (nematodiasis), spleen (hemosiderosis) and thymus (hemorrhage) were not considered to be treatment related as they were also seen in the control group at comparable incidence and severity. The gastric gland dilatation noted in the stomach of 2/5 test group animals but not in control group animals represented spontaneous histologic alterations commonly seen in this stock of rats.

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