Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 2.9 - <= 3.1 µm
Geometric standard deviation (GSD):
>= 2 - <= 2.4
Details on inhalation exposure:
aerosol and nose only
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5mg/l and 1mg/l
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Assessment of acute inhalation toxicity with GR-86-6599 in the rat (nose-only)
The study was carried out based on the guidelines described in:
• OECD Guidelines, Section 4, Health Effects. No.403, "Acute Inhalation Toxicity", Sep 2009.
• Commission Regulation (EC) No 440/2008, B.2. Acute Toxicity (inhalation), L142, May 2008.
• EPA OPPTS 870.1300, Acute inhalation Toxicity. EPA 712-C-98-193, August 1998.
• JMAFF Guidelines (2000), including the most recent revisions.
GR-86-6599 was administered as an aerosol by nose-only inhalation for 4 hours to two groups of five male and five female Wistar rats. Mortality and clinical signs were observed daily during the observation period and body weights were determined on Days 1, 2, 4, 8 and 15 and at death. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).
For the 5 mg/L exposure group, the time-weighted mean actual concentration was 5.1 ± 0.1 mg/L. The nominal concentration (amount of test item used divided by the volume of pressurized air used) was 6.9 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 74%. For the 1 mg/L exposure group, the time-weighted mean actual concentration was 1.2 ± 0.03 mg/L. The nominal concentration (amount of test item used divided by the volume of pressurized air used) was 1.7 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 67%. The concentration measurements equally distributed over time showed that the item was sufficiently stable.
The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the exposure period. At 5 mg/L, the MMAD was 3.0 μm (gsd 1.9) and 3.0 μm (gsd 2.1). At 1 mg/L, the MMAD was 2.9 μm (gsd 2.0) and 3.1 μm (gsd 2.4)

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 - < 5 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Acute inhalation toxicity of >1mg/l <5mg/l in rats via aerosol nose only route.
Executive summary:

Assessment of acute inhalation toxicity with GR-86-6599 in the rat (nose-only)

The study was carried out based on the guidelines described in:

• OECD Guidelines, Section 4, Health Effects. No.403, "Acute Inhalation Toxicity", Sep 2009.

• Commission Regulation (EC) No 440/2008, B.2. Acute Toxicity (inhalation), L142, May 2008.

• EPA OPPTS 870.1300, Acute inhalation Toxicity. EPA 712-C-98-193, August 1998.

• JMAFF Guidelines (2000), including the most recent revisions.

GR-86-6599 was administered as an aerosol by nose-only inhalation for 4 hours to two groups of five male and five female Wistar rats. Mortality and clinical signs were observed daily during the observation period and body weights were determined on Days 1, 2, 4, 8 and 15 and at death. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

For the 5 mg/L exposure group, the time-weighted mean actual concentration was 5.1 ± 0.1 mg/L. The nominal concentration (amount of test item used divided by the volume of pressurized air used) was 6.9 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 74%. For the 1 mg/L exposure group, the time-weighted mean actual concentration was 1.2 ± 0.03 mg/L. The nominal concentration (amount of test item used divided by the volume of pressurized air used) was 1.7 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 67%. The concentration measurements equally distributed over time showed that the item was sufficiently stable.

The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the exposure period. At 5 mg/L, the MMAD was 3.0 μm (gsd 1.9) and 3.0 μm (gsd 2.1). At 1 mg/L, the MMAD was 2.9 μm (gsd 2.0) and 3.1 μm (gsd 2.4)

At 5 mg/L, one male was found dead and one male and one female were sacrificed for humane reasons on Day 3. Two males were sacrificed between Days 7 and 9. No further mortality occurred in any of the other animals assigned to the study.

At 5 mg/L, slow respiration was noted during exposure. After exposure, lethargy, hunched posture, slow breathing, labored respiration, rales, piloerection and ptosis were seen for the animals up to Day 9. Scales were seen on the back of the females between Days 10 and 13. At 1 mg/L, no abnormalities were noted during exposure. After exposure, hunched posture and rales were seen for the animals between Days 1 and 4.

At 5 mg/L, body weight loss was noted for all surviving animals during the first week post exposure. All animals regained weight during the second week. At 1 mg/L, the body weight gain shown by the animals over the study period was considered not indicative of toxicity.

At 5 mg/L, macroscopic post mortem examination of the animals that were found dead or sacrificed for ethical reasons during the study revealed abnormalities of the lungs (pale with many dark red or black), stomach and intestines (distended with gas) and thymus (many dark red foci). No abnormalities were seen for the surviving animals. At 1 mg/L, no abnormalities were found at macroscopic examination of the animals.

The inhalation LC50, 4h value of GR-86-6599 in Wistar rats was established to be within the range of 1 – 5 mg/L.