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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restrictions because it is an acceptable well-documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Four-week Inhalation Exposure of Rats to Aerosols of Three Lubricant Base Oils.
Author:
Dalbey, W., Osimitz, T., Kommineni, C., Roy, T., Feuston, M., and Yang, J.
Year:
1991
Bibliographic source:
Journal of Applied Toxicology, 11(4), 297-302.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Oily liquid
Details on test material:
Name of test material (as cited in study report): CAS#: 8042-47-5
Preparation: Severely hydrotreating a dewaxed feedstock followed by acid washing with fuming sulphuric acid.

Viscosity at 100 °F SUS: 85
Pour point (°F): 15
API Gravity: 34.6
Furfural ppm: 0

Composition (wt.%)
Paraffins 60.0
Monoaromatics 0
Diaromatics 0
Polyaromatics 0
Unidentified aromatics 0
Aromatics sulfur types 0

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories.
- Age at study initiation: approximately 12 weeks old.
- Housing: animal room
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22 degrees Celsius
- Humidity (%): 40% to 60%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/ 12 hours light.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: < 2 µm
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass 400-I Inhalation chamber
- Method of holding animals in test chamber: Not reported
- Source and rate of air: Not reported
- Method of conditioning air: Not reported
- System of generating particulates/aerosols:Drew et al., nebulizer
- Temperature, humidity, pressure in air chamber: 68 to 74 degrees F, 30% to 50% humidity.
- Air flow rate: Not reported
- Air change rate: 12 per hour
- Method of particle size determination: Cascade Impactor
- Treatment of exhaust air: Not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal Concentrations Measured Concentration
0 0
50 50 ± 10
210 210 ± 10
1000 980 ± 20
Duration of treatment / exposure:
4 weeks (total of 18 exposures)
Frequency of treatment:
6 hours per day/ 5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 210 and 1000 mg/m³.
Basis:
nominal conc.
No. of animals per sex per dose:
10 animals per sex per group (treated group or sham control group)
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Not provided
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to each exposure


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: not reported
- Anaesthetic used for blood collection: Yes sodium pentobarbitol
- Animals fasted: Yes
- How many animals: All animals
- Parameters examined were: hematology
Hematological Parameters: total blood cell counts including leukocytes, erythrocytes, hemoglobin, hematocrit, mean cell volume, mean cellular hemoglobin and mean cellular hemoglobin concentration. Differential cell count include enumerated eosinophils, polymorphonuclear neutrophils and lymphocytes.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: not reported
- Animals fasted: Yes
- How many animals: All animals
- Serum Chemistry Parameters: alanine aminotransferase, albumin, albumin/globulin ratio, alkaline phosphatase, aspartate aminotransferase, total bilirubin, calcium, chloride, cholesterol, creatinine, globulin, glucose, iron, lactate dehydrogenase, inorganic phosphorus potassium, protein, sodium, triglycerides, urea nitrogen and uric acid.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No data
Other examinations:
All animals were necropsied and the following organs were weighed: gonads, heart, kidneys, liver, spleen, and thymus. The right middle lobe of the lung was weighed immediately after removal and again after drying. H&E sections were prepared and examined of the following tissues from all control and high dose group animals: heart, kidney, liver, lung, four locations in the nasal turbinates, spleen, gonads, thymus and tracheobronchial lymph nodes. Sperm from the cauda epididymis of each control and high dose male was assessed for morphological effects.
Statistics:
Data was analyzed by one-way analysis of variance. A probability of Type I error oc < 0.5% (P<0.05) was considered to be statistically significant. Comparison of means was performed by Duncan's multiple range test or the Student-Neuman-Keuls multiple comparison.

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY - Apart from occasional loose stool there were no treatment related clinical observations.

BODY WEIGHT AND WEIGHT GAIN - Body weights were unaffected by exposure

OPHTHALMOSCOPIC EXAMINATION


HAEMATOLOGY - No treatment related effects were found in any of the hematological parameters that were measured

CLINICAL CHEMISTRY - No treatment related effects were found in any of the clinical chemical parameters that were measured

ORGAN WEIGHTS - With the exception of the lungs, there were no significant changes in organ weights. Wet and dry lung weights increased in a dose-related manner. The ratios of wet to dry lung weights were significantly increased for both sexes at the highest dose concentration. Morphologically, treatment related changes were only observed in the lungs and tracheobronchial lymph nodes. Foamy macrophages with numerous vacuoles of varying size were present in the alveolar spaces of the lungs of many of the exposed animals.

GROSS PATHOLOGY - There were no treatment-related observations at necropsy.


HISTOPATHOLOGY: See Table 5.14 Summary of histological changes in rats exposed by inhalation to white oil aerosols.

OTHER FINDINGS - The percent sperm with aberrant morphology, including breakage, was unaffected by exposure to any of the three base oils

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
50 mg/m³ air
Sex:
male/female
Basis for effect level:
other: based on increased lung weight, due to oil accumulation in the tissues; as such, the adversity of the effect is questionable and a NOEL is reported rather than a NOAEL
Dose descriptor:
LOEL
Effect level:
210 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: based on increased lung weight, due to oil accumulation in the tissues; as such, the adversity of the effect is questionable and a LOEL is reported rather than a LOAEL

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 5.14 Summary of histological changes in rats exposed by inhalation to white oil aerosols

No. of animals in each group with a given histopathological change

Tissue/change

Exposure Level (mg/m3)

50

210

1000

Lung

1-2 Foamy macrophages (FM)

20

20

20

3-6 FM

0

0

20

Thickened alveolar wall

0

0

0

FM in alveolar interstitium

0

0

0

Mild alveolar PMN infiltrate

0

0

19

Lymph nodes

Anterior mediastinal

-

-

-

Macrophage accumulation

Not Eval

Not Eval

0

Tracheobronchial

-

-

-

FM accumulation

Not Eval

Not Eval

0

Macrophage accumulation

Not Eval

Not Eval

19

Applicant's summary and conclusion

Conclusions:
The NOEL was considered to be 50 mg/m3 and LOEL was 210 mg/m3 due to the increase in lung weight.
Executive summary:

In an inhalation toxicity study, Highly refined base oil was administered to 10 male and 10 female Sprague-Dawley rats by dynamic whole body exposure at concentrations of 0, 50, 210 and 1000 mg/m³, for 6 hours per day, 5 days/ 4 weeks.

 

Apart from occasional loose stool there were no treatment related clinical observations and body weights were unaffected by exposure. No treatment related effects were found in any of the hematological or clinical chemical parameters that were measured. The percent sperm with aberrant morphology, including breakage, was unaffected by exposure to any of the three base oils. There were no treatment-related observations at necropsy and, with the exception of the lungs, there were no significant changes in organ weights. The NOEL was considered to be 50 mg/m3 and LOEL was 210 mg/m3 due to the increase in lung weight.

 

This study received a Klimisch score of 2 and is classified as reliable with restriction because it is an acceptable well-documented study report which meets basic scientific principles.