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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:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is scientifically valid and followed the principles of OPPTS Test Guideline 870.8700 for subchronic oral toxicity.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.8700 (Subchronic Oral Toxicity Test)
Deviations:
not applicable
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Prop-2-yn-1-ol
EC Number:
203-471-2
EC Name:
Prop-2-yn-1-ol
Cas Number:
107-19-7
Molecular formula:
C3H4O
IUPAC Name:
prop-2-yn-1-ol
Details on test material:
Test substance: propargyl alcohol (> 99% pure)

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
no details available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Test Item was given as aqueous solution.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 15 or 50 mg/kg bw/day
Basis:
nominal in water
No. of animals per sex per dose:
20 rats/sex/dose and control group
Control animals:
yes
Details on study design:
- 40 Animals (20/sex/dose group) were used
- Interim sacrifice of animals was peformed (10/sex/dose group)
- Recovery group was not included
Positive control:
no

Examinations

Observations and examinations performed and frequency:
- CLINICAL SIGNS AND MORTALITY: yes

- BODY WEIGHT AND WEIGHT GAIN: yes

- OPHTHALMOSCOPIC EXAMINATION: yes

- CLINICAL CHEMISTRY / HAEMATOLOGY: yes

- ORGAN WEIGHTS: yes

- GROSS PATHOLOGY: yes

- HISTOPATHOLOGY: NON-NEOPLASTIC: yes
Sacrifice and pathology:
Rats were sacrificed on days 91 or 92 after dosing.
Gross pathology and histopathology was performed.
Other examinations:
none
Statistics:
not indicated

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY:
Treatment-related mortality was reported in the 50 mg/kg dosage group, although the precise cause was not identified.
4 male rats of the 50 mg/kg dose group died. Animals belonging to this dose group showed marked salivation.

BODY WEIGHT AND WEIGHT GAIN:
The body weight of males of the highest dose group were significantly lower compared to the control group. In case of the females there was only a tendency towards lower body weights compared to the controls.

OPHTHALMOSCOPIC EXAMINATION:
The ophtalmological examination was without findings.

HAEMATOLOGY:
No changes in haematological parameters were reported in the rats of the 5 mg/kg dose group. In males of the highest dose group reduced values for haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) were measured. In females of the highest dose group only reduced values for MCH and MCHC were observed. Neutrophil counts were significantly increased in males of the mid- and high-dose group (15 and 50 mg/kg bw/day). Hematological changes were seen in the mid- and high-dose animals and were considered to be treatment- related.

CLINICAL CHEMISTRY:
No changes in clinical pathology parameters were reported in the rats of the 5 mg/kg dosage group.
Enzyme changes characteristic of liver damage were seen in the mid- and high-dose animals. These changes included significantly increased ALAT, ASAT, LDH, and ALP serum activities. Moreover, decreased glucose, sodium, total cholesterol, total protein, albumin, globulin, and creatinine serum levels were seen, whereas inorganic phosphate and total bilirubin serum levels were significantly higher.

ORGAN WEIGHTS:
Treatment-related effects at the 15 mg/kg/day dose level included increased liver weights in both genders, increased kidney weights in females, and megalocytosis of the liver after 13 weeks of dosing.

GROSS PATHOLOGY
Macroscopic findings were confined to the liver (15 and 50 mg/kg bw) and the stomach (50 mg/kg bw).

HISTOPATHOLOGY: NON-NEOPLASTIC
Hepatocytic megalocytosis with a less prominent proliferation of the bile ducts and cytoplasmic vacuolation of hepatocytes was observed in all rats in the 50 mg/kg group dosed for 3 months, in all 15 mg/kg rats dosed for 3 months. In the low-dose group, megalocytosis was seen only in one rat treated for 3 months. Karyomegaly of renal tubular epithelial cells was reported to occur in a dose-response fashion in the mid- and high-dose groups, but not in the low-dosage group.

Effect levels

Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: effects on clinical chemistry, organ weight, histopathology at higher dose levels

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

Male and female Crl:CD(SD)BR rats (n=20/sex/group) were dosed orally (gavage) with 0, 5, 15 or 50 mg/kg bw of Propargyl alcohol (purity: >99%) (at 10 mL/kg in deionised water) daily for 13 weeks. Rats were sacrificed on days 91 or 92 after dosing. Parameters examined included clinical signs, body and organ weight changes, food consumption, ophthalmology, haematology, blood chemistry and histological evaluations. Treatment-related mortality was reported for 4/30 males in the high-dose group. The most prevalent clinical sign was salivation, occurring mainly at 50 mg/kg bw. Body weights were significantly lower in the high-dose animals. Haematological changes observed in the high-dose animals comprised decreased haemoglobin, MCV (also at 15 mg/kg bw), MCH, and mean corpuscular haemoglobin concentration (MCHC) values. Enzyme changes characteristic of liver damage were seen in the mid- and high-dose animals. These changes included significantly increased ALAT, ASAT, LDH, and ALP serum activities. Moreover, decreased glucose, sodium, total cholesterol, total protein, albumin, globulin, and creatinine serum levels were seen, whereas inorganic phosphate and total bilirubin serum levels were significantly higher. The haematological and blood chemistry changes were considered to be treatment-related. Absolute and relative liver and kidney weights were significantly increased in males and/or females at 15 and 50 mg/kg bw/day. At 5 mg/kg bw, mean absolute and relative liver weights were higher compared to controls, but statistical significance was not reached. Macroscopic findings were confined to the liver (15 and 50 mg/kg bw) and the stomach (50 mg/kg bw). Hepatocytic megalocytosis with a less prominent proliferation of the bile ducts and cytoplasmic vacuolation of hepatocytes was observed in the majority of rats in the mid- and high-dose groups. In the low-dose group, megalocytosis was seen only in one rat treated for 3 months. Karyomegaly of renal tubular epithelial cells was reported to occur in a dose-response fashion in the mid- and high-dose groups, but not in the low-dose group. Treatment-related effects at 15 mg/kg bw included increased liver weights in both genders, increased kidney weights in females, and megalocytosis of the liver after 13 weeks of dosing. The daily oral administration of 5 mg/kg bw/day of propynol produced no apparent treatment-related effects and hence this dose level was considered a NOAEL for subchronic oral exposure to Propargyl alcohol.