Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 June - 3 August 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: brown mushy solid
Details on test material:
RH-573 Technical, (Lot No. SW 1029), 97.8% pure was used.

Test animals

Species:
rat
Strain:
other: Crl: CD®BR
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Crl: CD®BR, Charles River, Kingston (Stone Ridge, NY, USA)
- Age: Males: 7-8 weeks; females: 9-10 weeks
- Weight at study initiation: males: 201-329 g; females: 200-257 g
- Number of animals: 60 (24/sex)
- Controls: Not described.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: water
Details on inhalation exposure:
- Type of exposure: 4 hour nose-only inhalation
- Concentrations: 0.046, 0.012, 0.150, 1.07 and 2.09 mg/L air
- Particle size: 3.5, 3.1, 3.8, 5.2 and 5.3 um
- Type or preparation of particles: aerosol and vapor
Analytical verification of test atmosphere concentrations:
yes
Remarks:
HPLC analysis of captured airborne concentration in impingers
Duration of exposure:
4 h
Concentrations:
Analytical concentrations were 0.046, 0.012, 0.150, 1.07 and 2.09 mg RH-573 Technical/L air
No. of animals per sex per dose:
6 males and 6 females
Control animals:
not specified
Details on study design:
Observations and Evaluations
All animals were weighed just prior to exposure (day 0), and again on days 7 and 14 post-exposure. The animals were observed for signs of toxicity during the exposure, upon removal from the chamber, and 3 to 4 hours after termination of the exposure. For the remainder of the study, the animals were observed at least once daily for morbidity, mortality and clinical signs. At the end of the fourteen-day observation period, all surviving animals were anesthetized with sodium pentobarbital (50 mg/kg, ip), exsanguinated from the abdominal aorta, and necropsied. Visual examinations were made of external structures and body orifices. Thoracic and abdominal organs were also examined. In addition, although not specified in the protocol, the cervical lymph nodes, salivary glands and thyroids were examined.

In order to determine the airborne concentration of RH-573 Technical in the exposure chamber atmosphere, a two (Groups 1 and 2) or one (Groups 3,4 and 5) impinger train located outside the chamber was used for sampling. During the method development phase, it was determined for Groups 3, 4 and 5 that the concentrations were at a level where no break-through of the primary impinger would occur. Therefore, a single impinger was used for sampling for these groups. Each impinger (SKC, Inc., Eighty Four, PA) contained 12 ml of milli-Q water and was placed in an ice bath. The chamber atmosphere was drawn through the impingers at a flow rate of 0.7 L/min for 1 minute for Groups 1 and 2, 3 minutes for Groups 3 and 5, and 6 minutes for Group 4. Four samples were collected during each exposure.

After obtaining an impinger sample, the solution was transferred to a pre-weighed 20 ml scintillation vial and weighed again to determine the total material present. The solution was then sent to the Biocides Research Analytical Group for analysis by High Performance Liquid Chromatography (HPLC). The results of these analyses were reported in ug/ml of RH-573 Technical. Using the following equations, these results were converted to airborne concentrations in milligrams per liter (mg/L) of chamber atmosphere:

(1) mg of RH-573 a.i. = ug/ml a.i./1.0 g/ml* x (g of solution/1000)
(2) mg/L RH-573 in air = mg RH-573 (a.i.)/(sample duration x flow rate)
* density of Milli-Q water

In addition, gravimetric determinations of the aerosol concentration were made periodically during each exposure. A known volume of exposure chamber atmosphere was drawn through a pre-weighed glass fiber filter. The change in weight of the filter divided by the sample volume yielded the aerosol concentration. The gravimetric filters were used solely as a means of monitoring the total aerosol concentration during exposure, and not to determine an analytical concentration of RH-573 Technical in the chamber atmosphere. Therefore, these values were not reported.

Particle Size Determination
Particle size determination was determined at least once during each exposure by drawing samples of the chamber atmosphere through an 8-stage Anderson cascade impactor fitted with glass fiber collection disc (Anderson, 1966).
Statistics:
The calculation of mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) was performed by computer using a log-probit regression analysis program (Hagan, 1980). The respirable fraction was calculated from the MMAD and the GSD in the RFB program (Moss and Baldwin, 1983) on a programmable calculator. This program defines "respirable fraction" as that fraction of an aerosol that would pass a size-selector described by the American Conference of Governmental Industrial Hygienists (ACGIH), with the following characteristics: 90% of /=10 um particles will pass through the selector (Lippman, 1978).

References:
Hagan, J.V. (1980). SAS program. Copy retained in Rohm and Haas Co., Toxicology Department S.O.P. Section 19.8.2.a.

Lippman, M. (1978). Respirable Dust Sampling. Section G Sampling Dust Instruments. American Conference of Governmental Industrial Hygienists, Cincinnati, OH.

Moss, O. and Baldwin, R.C. (1983). Program written for an HP-97 calculator by O. Moss and modified for use on an HP-41C calculator by R.C. Baldwin. Program documented in Rohm and Haas Co., Toxicology Department S.O.P. Secion 19.8.2.b.

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.11 mg/L air
Based on:
test mat.
95% CL:
0.07 - 0.25
Exp. duration:
4 h
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
0.13 mg/L air
Based on:
test mat.
95% CL:
0.06 - 0.53
Exp. duration:
4 h
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
0.1 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other:
Remarks:
95% CL could not be calculated
Mortality:
* Time of death:
- 2.09 mg/L : 3 males & 1 female during exposure ; 2 males & 2 females by day 1 ; 1 male by day 2 (total 9 of 12 died)
- 1.07 mg/L : 6 males and 3 females during exposure (total 9 of 12 died)
- 0.15 mg/L : 2 males and 4 females during exposure and one male and one female died one day later (total 8 of 12 died)
- 0.046 mg/L : 1 male during exposure (total 1 of 12 died)
- 0.012 mg/L: (total 0 of 12 died

* Number of deaths at each dose:
9/12 (6 males & 3 females) at 2.09 mg/L
9/12 (6 males & 3 females) at 1.07 mg/L
8/12 (3 males & 5 females) at 0.15 mg/L
1/12 (1 female) at 0.046 mg/L
0/12 at 0.012 mg/L

Clinical signs:
other: Clinical signs seen in some, yet not all groups included gasping, rales, labored breathing, respiratory noise, salivation, red-stained eyes, muzzle and nasal exudate, passiveness and ataxia. Except for one male exposed to 0.15 mg/L that exhibited respi
Body weight:
With the exception of two females, one exposed to 1.07 mg/L (Group 2) and one exposed to 0.012 (Group 4), all surviving animals exceeded their pre-exposure body weight by day 7. Body weight gain was highly variable with no apparent exposure-related effects.
Gross pathology:
Slight to severe redness in lung, scattered incidences of red pinpoint foci on lungs, and gas-filled stomachs. These findings are consistent with the clinical signs of respiratory irritation.
POTENTIAL TARGET ORGANS: Lungs
Other findings:
Particle size distributions for Groups 1, 2, 3, 4 and 5 were characterized by mean mass median aerodynamic diameters (MMAD) of 5.3 +/- 0.3, 5.2 +/- 0.1, 3.8 +/- 0.3, 3.1 +/- 0 and 3.5 +/- 0.7 um, respectively. The mean geometric standard deviation for Groups 1, 2, 3, 4 and 5 were 2.4 +/- 0.1, 2.2 +/- 0.1, 2.0 +/- 0.1, 2.2 +/- 0 and 2.4 +/- 0.1, respectively. The mean respirable fraction for Groups 1, 2, 3, 4 and 5 were 33.5 +/-2.1, 33.5 +/-0.7, 46.5 +/- 3.5, 54.0 +/- 0 and 49.5 +/- 7.8%, respectively.

Any other information on results incl. tables

The four hour combined LC50 was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.

Applicant's summary and conclusion

Interpretation of results:
Category 2 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The four hour combined LC50 was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.
Executive summary:

The acute inhalation toxicity of RH-573 Technical to rats was examined. The four hour combined LC50 was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.