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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted according to guideline/s and GLP but the report contains sufficient data for interpretation of study results

Data source

Reference
Reference Type:
publication
Title:
2-week and 13-week inhalation studies of aerosolized glycerol in rats
Author:
Renne R.
Year:
1992
Bibliographic source:
Inhal Toxicol 4:95-111

Materials and methods

Principles of method if other than guideline:
Study design appears to follow intent of OECD 413 but publication does not indicate that OECD 413 was followed.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
purity >99.8% USP grade

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Rats were obtained from Charles River Breeding Laboratories. Animals were subjected to a 3-week quarantine, health screening five rats of each sex for viral and Mycoplasma infection at the beginning and toward the end of quarantine, physical examinations, body weight measurements, acclimation to the restraining tubes of the nose only exposure system, randomized assignment to exposure groups and individual identification.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: MMAD <2.0 um (respirable)
Details on inhalation exposure:
A viscous-liquid aerosol generator was used to generate aerosol.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
ANALYSES: target concentration and homogeneity of aerosol
- Method: sampling with aerosol monitor and gravimetric and GC analyses
- Sampling times: actual concentration 2 samples per exposure chamber; homogeneity and uniformity in mock exposure before start of the experiment (6 samples) and during animal exposure (20 samples/concentration)
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
33, 165 and 660 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
15/sex/dose level
Control animals:
yes, concurrent no treatment
Details on study design:
CLINICAL OBSERVATIONS AND FREQUENCY:
- Mortality/clinical signs: twice daily
- Body weight: weekly
- Food consumption: weekly
- Haematology: not specified (complete blood count included)
- Biochemistry: blood urea nitrogen, creatinine, glucose, protein, albumin, albumin/globulin, ASAT, ALAT, LDH, gamma glutamyl transferase, cholesterol, triglycerides and phospholipids

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Organ weights: lungs, liver, kidneys, brain and heart
- Macroscopic: not specified (complete necropsy).
- Microscopic: total of 40 tissues of high dose and control animals; lungs trachea and anterior nasal cavity were stained with hematoxylin and eosin and duplicate slides with Alcian blue/periodic acid Schiff (Goblet cell changes)

Three rats/sex of control and high dose group were killed during week 10, lung lobes were excised and 2 samples/rat were examined by transmission electron microscopy for abnormalities associated with the Clara cells. The same procedure was followed for 3 rats/sex of all groups during terminal necropsy

ANALYSES: target concentration and homogeneity of aerosol
- Method: sampling with aerosol monitor and gravimetric and GC analyses
- Sampling times: actual concentration 2 samples per exposure chamber; homogeneity and uniformity in mock exposure before start of the experiment (6 samples) and during animal exposure (20 samples/concentration)
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY:
- Mortality/clinical signs: twice daily
- Body weight: weekly
- Food consumption: weekly
- Haematology: not specified (complete blood count included)
- Biochemistry: blood urea nitrogen, creatinine, glucose, protein, albumin, albumin/globulin, ASAT, ALAT, LDH, gamma glutamyl transferase, cholesterol, triglycerides and phospholipids
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Organ weights: lungs, liver, kidneys, brain and heart
- Macroscopic: not specified (complete necropsy)
- Microscopic: total of 40 tissues of high dose and control animals; lungs trachea and anterior nasal cavity were stained with hematoxylin and eosin and duplicate slides with Alcian blue/periodic acid Schiff (Goblet cell changes)

Three rats/sex of control and high dose group were killed during week 10, lung lobes were excised and 2 samples/rat were examined by transmission electron microscopy for abnormalities associated with the Clara cells. The same procedure was followed for 3 rats/sex of all groups during terminal necropsy
Other examinations:
No additional information available.
Statistics:
STATISTICAL METHODS: ANOVA, least significant difference

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 examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
triglycerides decreased in males at 33 (34%) and 167 mg/m3 (22%) only.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
minimal squamous metaplasia of the epiglottis in 2/25, 1/19, 4/20 and 10/21 rats at 0, 33, 167 and 662 mg/m3; 1 male at 662 mg/m3 showed mild squamous metaplasia. No differences in morphology of the Clara cells in control and high dose rats
Histopathological findings: neoplastic:
not specified
Details on results:
ANALYTICAL ANALYSES:
- Actual dose level: 33, 167 and 662 mg/m3 (100-101% of target)
- Homogeneity (uniformity): relative standard deviation <1% of mean value

- Hematology: No differences between the exposed rats in any group of either sex when compared to their respective control group.
- Clinical chemistry: triglycerides decreased in males at 33 (34%) and 167 mg/m3 (22%) only.
- Gross lesions: few gross lessions observed with no evidence of changes attributed to exposure to glycerol.
- Histopathology: minimal squamous metaplasia of the epiglottis in 2/25, 1/19, 4/20 and 10/21 rats at 0, 33, 167 and 662 mg/m3; 1 male at 662 mg/m3 showed mild squamous metaplasia.
No differences in morphology of the Clara cells in control and high dose rats

STATISTICAL RESULTS: all effects mentioned showed statistical significance (squamous metaplasia only significant at high concentration)

Effect levels

Dose descriptor:
NOAEL
Effect level:
167 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on local irritant effects on the upper respiratory tract.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No additional information available.

Applicant's summary and conclusion

Conclusions:
The NOAEL was 167 mg/m3 based on local irritant effects on the upper respiratory tract..
Executive summary:

The subchronic toxicity of glycerol was examined following aerosol exposure. The NOAEL was 167 mg/m3 based on local irritant effects on the upper respiratory tract..