Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Conducted according to generally accepted protocols of the time. Basic data available but adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Principles of method if other than guideline:
Administration by gavage 5 days/week for 6 weeks.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Chemical name: Ethylene glycol monopropyl ether
Molecular Wt.: 148
Specific gravity: 0.966
Purity: >99.5%

Test animals

Species:
rat
Strain:
other: CR(COBS)CD:BR
Sex:
male
Details on test animals and environmental conditions:
Rats were purchased from Charles Rivers Breeding Laboratories, Wilmington, MA and weighed on average 235.7 +/- 15.1 g. Two hundred and eighty rats were randomly assigned to nine treatment groups of 30 rats each and one control group of 30 rats. Animals were received in a single shipment and were quarantined and acclimated to laboratory conditions for two weeks prior to the start of the studies. All animals were housed individually in suspended wire mesh cages. Purina Rodent Chow (5001) and water were available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Equimolar doses, expressed as millimoles/kg bw/day, equivalent to 1/2, 1/4 or 1/8th of the acute (fasted) LD50 were administered undiluted by gavage, 5 days/week for six weeks. This schedule provided 29-33 doses over a 44 day period. Control animals received a volume of distilled water equal to the largest volume given a treated animal. All doses were recalculated weekly to adjust for changes in animal body weights.

After a single dose of the test chemical, severe hematuria was noted at all dose levels. An additional lower dose of 1/16th of the LD50 value was added to provide a no effect level.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
six weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
195, 390, 780 and 1568 mg/kg bw/day
Basis:
other: actual administered
No. of animals per sex per dose:
10
Control animals:
other: received water by gavage

Examinations

Observations and examinations performed and frequency:
Animals were supplied water and feed ad libitum. Individual body weights and food consumption were recorded on days 0, 3, 6, 13, 20, 27, 34 and 41 of the study. Animals were observed daily (except for weekends) for mortality and clinical signs of toxicity. The appearance of urine and feces on dropping trays also was noted.
Sacrifice and pathology:
Animals that died spontaneously were autopsied and moribund animals and those that survived to term were euthanized and autopsied. The following tissues were collected, fixed and examined microscopically: lung, heart, thymus, kidneys, liver, spleen, brain, salivary glands, stomach cecum, colon, duodenum, jejunum, ileum, pancreas, esophagus, adrenal glands, pituitary, thyroid, parathyroid, trachea, mesenteric lymph nodes, testes, epididymis, prostate, seminal vesicles, coagulating gland, bone marrow, tongue, eyes and nasal cavities. The liver, kidneys, heart, testes, brain and spleen were trimmed and weighed before fixation.
Other examinations:
Blood was drawn from the inferior vena cava just prior to autopsy for hematologic and serum hematology and clinical chemistry determinations (hemoglobin, hematocrit, red blood cell count, red cell indices (mean corpuscular volume, hemoglobin and hemoglobin concentration), total and relative white cell counts, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase, lactic dehydrogenase, urea nitrogen, creatinine and glucose.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
Mortality

All doses: Two high dose animals (1560 mg/kg) and one animal given 780 mg/kg died spontaneously, and two animals in the 780 mg/kg group and 1
in the 390 mg/kg died of intubation error. All others survived to term. The hemoglobin concentration and red cell count were lower than control in
all groups of treated animals. There was no effect of treatment on clinical chemistries. There was no effect of treatment on the testes.

1560 mg/kg: There was a reduction in body weight gain at Day 3 and terminal body weight. Feed consumption at Days 3, 6, and 13 was reduced. Mean corpuscular volume (MCV) and hemoglobin (MCH) were increased, and hematocrit was decreased. Absolute and relative spleen weights and relative liver, kidney and heart weights were increased. All animals had bloody urine after the first dose and until termination. Other clinical signs included weakness, labored breathing, prostration and rales in some rats. Enlarged, dark spleens and splenic congestion were evident in 4/10 and 6/10 animals that were necropsied, respectively. Other pathological changes observed included hyperkeratosis of the stomach (9/10), focal hemosiderin in the liver (3/10), and proteinaceous casts (8/10) and hemosiderin (8/10) in the kidney and hyaline droplet degeneration of the proximal convoluted tubules (6/10).

780 mg/kg: MCV and MCH were increased, and mean corpuscular hemoglobin concentration (MCHC) was decreased. Absolute and relative spleen weights and relative liver, heart and kidney weights were increased. All animals had bloody urine after the first dose and until termination. Other clinical signs included weakness, labored breathing, prostration and rales in some rats. Enlarged, dark spleens, and splenic congestion were evident in 5/8 and 5/10 animals that were necropsied, respectively. Other pathological changes observed included hyperkeratosis and acanthosis of the stomach (9/10), extramedullary hematopoesis in the spleen (4/10), and hemosiderin (8/10) in the kidney.

390 mg/kg: Relative spleen, heart, brain and liver weights were increased. All animals had bloody urine after the first dose and until termination. Other clinical signs included weakness, labored breathing, prostration and rales in some rats. An enlarged dark spleen was evident in 1/9 animals that were necropsied. Other pathological changes observed included splenic congestion (10/10), extramedullary hematopoesis in the spleen (3/10), and chemosiderin (2/10) in the kidney.

195 mg/kg: Bloody urine was observed after the first dose and at Days 21 or 28 (2 rats). Relative heart weight was increased. Hemosiderin was evident in the kidneys of 2/10 animals.

Hyaline droplet degeneration was observed in the proximal convoluted tubules of all 10 control rats. Therefore, this finding in the high dose animals does not appear to be related to test material administration.

Hematologically, red blood cell counts and hemoglobin concentration were decreased significantly at all dose levels.

Clinical chemistry effects were varied and with no apparent trend.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 195 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Only minimal hematological and organ effects were noted at the lowest dose.
Dose descriptor:
LOAEL
Effect level:
195 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Compound-related mortality was minimal and only observed at the highest two dose levels. Significant compound-related histopathology was observed in the spleens of treated rats and consisted primarily of splenic congestion at all but the lowest dose level. Red pulp hypcellularity, hemosiderin and extramedulary hematopoiesis were present in some animals. Kidney effects included hyaline droplet degeneration, preteinaceous casts and hemosiderin deposits in the proximal convoluted tubules. The hyaline droplet degeneration was seen in all test groups and in the controls. Hemolysis, characterized by reduced red blood cell counts nad reduced hemoglobin concentrations were present at all dose levels. The NOAEL for the test chemical was reported as < 195 mg/kg bw/day, the lowest dose level tested.