Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with out restriction because it was conducted according to OECD guideline 403.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

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): hydrotreated light naphthenic distillate (API 83-12)
- CAS number: 64742-53-6
- Substance type: lubricant base oil (insufficently refined IP346>3%)
- Storage condition of test material: stored at 4°C


- Physical state: liquid
- Viscosity, SSU:
53.5 at 100°F
33.3 at 210°F
- API Gravity: 26.2
- Flash Point: 255 °F
- Distillation range (°F) ASTM D86 Equiv: 533-713 (10-95%)
Initial Boiling Point (°F): 464
Final Boiling Point (°F): 796
- Pour Point (°F): 60
- Aniline Point (°F): 148.3
- Colour ASTM: 0.5

- Composition of test material ASTM D-2007, Wt. %:
Saturates: 61.6
Aromatics 36.1
Polar compounds: 2.3

Sulfur, Wt%: 0.019

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: 9 weeks (63 days)
- Weight at study initiation: males 292-310 grams, females 186-209 grams
- Fasting period before study: no
- Housing: individually housed in stainless steel hanging wire cages
- Diet (e.g. ad libitum): supplied Purina Certified Laboratory Chow # 5002 ad libitum
- Water (e.g. ad libitum): supplied water ad libitum
- Acclimation period: fourteen days


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark


Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: Air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: rats were individually housed in stainless steel and glass chambers
- Exposure chamber volume: 0.25 cubic meters
- Source and rate of air: the total air flow through the chamber was maintained at 2.0 cfm as measured by a calibrated orifice meter
- System of generating particulates/aerosols: aerosols were generated using a DeVilbiss No. 40 nebulizer
- Method of particle size determination: determined during each exposure by a Anderson Model 2000 cascade impactor
- Temperature and humidity chamber: temperature ranged from 23 to 25°C, and 32 to 70% humidity


TEST ATMOSPHERE
- Brief description of analytical method used: analytical samples were taken at least once per hour during each exposure by drawing a known volume of test atmosphere through tared Gelman A/E glass fiber filters. By knowing the amount of test material on the filter and the volume of air sampled the analytical exposure concentration was determined.


VEHICLE
air



GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
- Exposure chamber volume:
- Method of holding animals in test chamber:
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols:
- Method of particle size determination:
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber:


TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes/no


VEHICLE
- Composition of vehicle (if applicable):
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): ranges of 1.70 to 2.5 microns/1.50 to 1.61 microns


CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Phase 1, limit test: 5 mg/L
Phase 2: 0, 1.0, 1.5, 2.5, 3.5 (actual concentrations: 0, 0.02, 1.04, 1.51, 2.37, 3.49)
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: test animals were observed continuously for the first hour, hourly for the duration of the exposure, and once daily for the fourteen day post-exposure period. Weights were recorded prior to exposure and again on days 7 and 14 of the observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy, and histopathological examination

Results and discussion

Preliminary study:
Five male and five female rate were exposed to a concentration of 5 mg/L for four hours. All animals in this test died.
Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.18 mg/L air
95% CL:
1.8 - 2.55
Exp. duration:
4 h
Mortality:
No animals died in the control group. One male and one female died at a concentration of 1.0 mg/L, no animals died at a concentration of 1.5 mg/L, three males and three females died at a concentration of 2.5 mg/L, and all animals died at a concentration of 3.5.
Clinical signs:
The following clinical signs were observed: decreased activity, wet inguinal area, eyes partially closed, wet coat, loose stool, and oily coat. During the first week post-exposure all of these signs were exhibited in addition to signs of poor-condition, respiratory distress and death were observed. During the second week most survivors were considered of normal appearance.
Body weight:
No consistent dose related effect on body weight was observed
Gross pathology:
Animals exposed to concentrations of 5.0 and 3.5 mg/L consistently exhibited dark red lungs. They were also observed in three males and three females at 2.5 mg/L, one male and two females at 1.5 mg/L, and in one male and one female at 1.0 mg/L. This observation was present in all animals who died within a day or two of exposure.

A single skin lesion (scab) was observed in one male at 1.5 mg/L.
Other findings:
In histopathology observations affected animals presented moderate to marked diffuse pulmonary congestion and perivascular oedema, damage to alveolar walls. Necrosis and inflammation were seen in the walls of small blood vessels and there was spotty epithelial necrosis in small bronchioles.

Any other information on results incl. tables

Actual exposure concentrations and mortalities were as follows:      

Target level

Actual concentration

Mortality

(mg/l)

mg/l

±SD

Male

Female

0

0.02

0.01

0/5

0/5

1.0

1.04

0.1

1/5

1/5

1.5

1.51

0.15

0/5

0/5

2.5

2.37

0.31

3/5

3/5

3.5

3.49

0.36

5/5

5/5

5.0

5.05

0.18

5/5

5/5



Particle size measurements confirmed that mass median aerodynamic
diameter and geometric standard deviation values were in the ranges 1.7  to 2.5 µm and 1.5 to 1.61 respectively.  These measurements confirm that  the particles were within the respirable range.
The LC50 for combined sexes was estimated to be 2.18 with 95% confidence
  limits of 1.80 to 2.55 mg/l.

Body weight differences did not show a consistent dose related pattern.

At the highest concentration, the animals were obscured by a dense
  aerosol and observations could not be made during the exposure period. In  other groups, there was a decreased activity, wet inguinal area, eyes  partially closed, wet coat, loose stool and oily coat during exposure.
During the first week post-exposure, similar signs were observed as well
  as signs of poor condition, respiratory distress and some deaths  occurred.  During test week 2, most survivors were considered to be of  normal appearance.  The signs that were observed occurred in a dose  related manner.

At gross necropsy, dark red lungs were described for some animals. The
  incidence is shown below.



Dose Group

Male

Female

0

0/5

0/5

1.0

1/5

1/5

1.5

0/5

0/5

2.5

3/5

3/5

3.5

5/5

5/5

5.0

5/5

5/5



At histology, affected animals exhibited diffuse pulmonary congestion and
  perivascular oedema that were mostly moderate or marked in degree. Less  consistently spotty alveolar edema was also seen. There was widespread  damage to alveolar walls resulting in fibronecrotic debris resembling  hyaline membranes in more marked cases and extravasation of RBCs and  PMNs. Necrosis and inflammation were seen in the walls of small blood  vessels and there was spotty epithelial necrosis in small bronchioles,  but the most severe damage seemed to be centroacinar. The larger airways  were relatively unaffected.

None of the surviving animals exhibited the above acute changes.
   However, most of the surviving animals exposed to 2.5 or 1.0 mg/l and  above exhibited chronic inflammatory changes that were not seen in the  controls and only occasionally in animals exposed at the 1.5 mg/l level,  and then to a lesser degree of severity. Other findings were considered sporadic or unrelated to exposure to the test material.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC50 for males and females was 2.18 mg/L with 95% confidence limits at 1.80 to 2.55 mg/L for insufficiently refined lubricant base oil.
Executive summary:

A group of five male and five female rats were exposed for 4 hours to an aerosol of the test material at a target concentration of 5 mg/L. Four additional groups of rats were then exposed for 4 hours to target aerosol concentrations of 1, 1.5, 2.5 and 3.5 mg/L. A control group exposed, in the chamber, to air only was also included. Animals were observed continuously during the first hour of exposure, hourly for the remainder of the exposure and once daily for the 14-day post exposure period. Mortalities were recorded and body weights were measured prior to exposure and again 7 and 14 days after exposure. On the 14th day post-exposure, necropsies were performed on all surviving animals. For all animals, including animals found dead, the lungs and any other abnormal tissues were removed and fixed for subsequent histopathological examination.

At 5.0 mg/L, the animals were obscured by a dense aerosol and observations could not be made during the exposure period. In other groups, there was a decreased activity, wet inguinal area, eyes partially closed, wet coat, loose stool and oily coat during exposure. During the first week post-exposure, similar signs were observed as well as signs of poor condition, respiratory distress and some deaths occurred. During test week 2, most survivors were considered to be of normal appearance. The signs that were observed occurred in a dose related manner. At gross necropsy, dark red lungs were described for some animals. No animals died in the control group. One male and one female died at a concentration of 1.0 mg/L, no animals died at a concentration of 1.5 mg/L, three males and three females died at a concentration of 2.5 mg/L, and all animals died at a concentration of 3.5 mg/L.

The LC50 for males and females was 2.18 mg/L with 95% confidence limits at 1.80 to 2.55 mg/L for insufficiently refined lubricant base oil.

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was conducted according to OECD guideline 403.