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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
06/25/91 - 11/17/92
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
OECD Guideline for Testing of Chemicals No. 403, Acute Inhalation Toxicity, 1981.
Deviations:
not specified
GLP compliance:
no
Remarks:
Internal Laboratory Quality Procedures followed.
Test type:
traditional method
Limit test:
no

Test material

Test material form:
solid
Details on test material:
The test substance was supplied by the sponsor as a white solid with a purity of >98.5%.
Specific details on test material used for the study:
No further details specified

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Young adult Crl:CD BR rats were obtained from Charles River Breeding Laboratories, Kingston, New York. The rats were approximately 44-46 days of age on arrival.
Rats have historically been used in safety evaluation studies for acute inhalation toxic! ty testing. The Crl:CD BR rat has been chosen based on consistently acceptable health status and extensive experience with the strain at this laboratory.

Animal Husbandry
Quarantine and Animal. Selection. Rats were quarantined after arrival for approximately 6 days prior to testing. They were housed individually in 5" x 11" x 7" suspended, stainless steel, wire-mesh cages. Rats were weighed and observed 3 times during the quarantine period. Rats used on this study were obtained from the general population of stock rats released from quarantine.
Housing. Rats were housed either singly Dr in pairs during the test period in 8" x 14ft X 8ft suspended, stainless steel, wire-mesh cages.
Animal Room Environment. The animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were within temperatures of 23 ~ 2°C and a relative humidity of 50 ~ 10%. Excursions outside these ranges were of small magnitude and/or brief duration and did not adversely affect the validity of the study.
Identification. Each rat vas assigned a unique 6-digit identification number which corresponded to a numbered card affixed to the cage. The rat assigned the lover number in each cage vas identified by a slash in the right ear. Prior to exposure, tails of the rats and cage cards were color-coded with water-insoluble markers so that individual rats could be identified.
Feed and Water. Except during exposure, Purina Certified Rodent Chow®*5002 and tap water from the Vilmington Suburban Vater Corporation were available ad-ibitum.

Administration / exposure

Route of administration:
inhalation: mixture of vapour and aerosol / mist
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 7 - <= 8 µm
Remark on MMAD/GSD:
Particles were often visible in the chamber as large flakes, and distributions were either skewed to the larger sizes, with mass median aerodynamic diameters 7-8 µm, or bimodally distributed.
Details on inhalation exposure:
Atmospheres of H-19056 were generated by heating the test substance in a three-necked flask encased in a temperature-controlled Brisk heater. Nitrogen vas passed through the flask. The H-19056 vapor passed from the flask to the chamber, where it was mixed with dilution air. Aerosol was formed when heated vapor combined with cooler dilution air in the exposure chamber. The resultant test atmosphere was a mixture of vapor and particulate H-19056. A baffle located inside the exposure chamber aided in the even dispersion material during the first and second exposures.
Test atmospheres were exhausted through water-filled impingers and MSA particulate filter, prior to discharge into the fume hood.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Remarks on duration:
As per the guideline.
Concentrations:
66.5, 156, 335, 381 or 820 mg/m3 of test substance.
No. of animals per sex per dose:
5 groups of 10 animals (5 male/5 female)
Control animals:
yes
Details on study design:
Five groups of 5 male and 5 female rats each were exposed nose-only for a 4-hour period to an atmosphere of H-19056 in air. Rats were approximately 52 to 57 days of age at the time of exposure and ranged in weight from 176 to 281 grams.
Rats from all the exposure groups were observed for mortality and clinical signs of toxicity during exposure and immediately following exposure.
During a 14-day, postexposure period, rats from all groups were observed each day for mortality. Rats were weighed and observed daily, weekends and holidays excluded, for clinical signs of toxicity, except when warranted by health status.

During each exposure, rats were individually restrained in cylinders with conical nose pieces. The restrainers were inserted into the face plate of the exposure chamber so that only the nose of each rat extended into the chamber. A 150-L stainless steel and glass exposure chamber vas used for the exposures to the two lowest concentrations. A 38-L glass, cylindrical chamber was used for the other three exposures.
Chamber airflow vas set at the beginning of each exposure and adjusted as needed throughout the 4-hour period. Chamber temperature was targeted at 23 ± 2°C. Temperature vas measured continually with a mercury thermometer and recorded twice during each exposure. Relative humidity was targeted at 50 ± 10%. Humidity in the exposure chamber vas measured once during each exposure with an Omega Hodel 5100 Digital Psychrometer. Chamber oxygen concentration was targeted to at least 19% and measured with a Biosystems Hodel 3100R Oxygen Analyzer once during each exposure.

The atmospheric concentrations of both particulate and vapor H-19056 were determined at least once per hour, and generally more frequently, during the exposure. Samples of a known volume of chamber atmospheres were drawn from the breathing zone of the rats through a 25 mm filter cassette that contained a preweighed Gelman glass fiber (Type A/E) filter in line with two midget impingers filled with dry toluene.
The concentration of particulate vas determined by gravimetric analysis of filter samples. The filters were weighed on a Cahn Model C-30 Automatic Microbalance. The atmospheric concentration of particulate H-19056 was calculated from the difference in the pre- and post-sampling filter weights.
Samples to determine the particle size distribution were taken with a Sierra Series 210 cyclone preseparator/cascade impactor and Sierrae Series 110 Constant Flow Air Sampler.
The concentration of vapor component of H-19056 in the exposure chamber was determined by gas chromatographic analysis of the impinger samples. A Hewlett Packard 5890A Gas Chromatograph with flame ionization detector fitted with SPB-5 fused silica glass column vas used for the analysis.
Statistics:
Not specified

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
other: ALC (approximate lethal concentration)
Effect level:
335 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
Rats exposed to 66.5, 156, 335, 381, or 820 mg/m3 total test substance had 0/10, 0/10, 2/10, 2/10, and 3/10 deaths, respectively. None of the mortalities occurred during exposures; all deaths were delayed, and they occurred 1 to 14 days after exposure. Due to the large, non-respirable particulate formed in the chamber at the higher concentrations, it was determined that a calculation of the LC50 would not appropriately predict lethality at higher concentrations. The results, however, provide a reasonable estimate of the approximate lethal concentration (ALC).
Clinical signs:
other: When rats were removed from restrainers immediately following exposure, the clinical signs of toxicity observed frequently in all exposure groups included colored discharge of the nose and eyes and lung noise. Additional signs seen frequently included col
Body weight:
Slight to severe body-weight losses occurred in all groups within 1 to 4 days following the exposure. Rats that died prior to the end of the recovery period generally continued to lose weight until death occurred. The severity and duration of the weight losses were dose related. These initial weight losses were followed by a normal weight gain, with intermittent weight losses, throughout the remainder of the post-exposure period.
Gross pathology:
Not examined

Any other information on results incl. tables

CONCENTRATION OF H-19056 IN CHAMBER ATMOSPHERES

Mean Vapor Concentration

Mean Particle Concentration

(mg/m3)

n

Total Concentration

(mg/m3)

(ppm)

(mg/m3)

Mean

S.D.

Range

4.85a

10.0

10.8

9.33

10.8

31.7a

65.65

70.5

61.1

70.6

34.8a

90.5

265

320

749

7

5

6

7

7

66.5a

156

335

381

820

7.83a

52.8

106

72.0

232

56.7 – 81.1a

88.0 – 210

200 – 459

289 – 489

618 – 1210

All values are expressed as 3 significant figures

aH-19056 was used for this exposure

 

PARTICLE SIZE DISTRIBUTION

Total H-19056 Concentration

(mg/m3)

MMADa

(µm)

% Particles by massb

<1 µm

<3 µm

<10 µm

66.5

156

335

 

381

 

820

7.0 ± 5.3c

7.6 ± 6.9c

0.35 ± 2.5d

9.6 ± 2.3

1.7 ± 7.1d

12.8 ± 1.9

1.9 ± 7.6d

14.5 ± 2.1

14

15

12

 

4

 

3

32

32

29

 

15

 

12

59

56

56

 

40

 

38

aMass median aerodynamic diameter ± geometric standard deviation

bBased on total distribution

cParticle distribution skewed

dBimodal distribution

 

CHAMBER ENVIRONMENT

Total H-19056 Concentration

(mg/m3)

Total Chamber Airflow

(L/min)

Temperature Range

(°C)

Relative Humidity

(%)

Oxygen

(%)

66.5

156

335

381

820

40.9

33.0

28.0

28.0

26.5

23 – 24

23 – 24

24

25 – 27

24 – 27

19.2

85.9

93.8

95.8

39.1

19.5

19.8

19.7

19.2

20.8

 

MORTALITY

Total H-19056 Concentration

(mg/m3)

# deaths/# exposed

Males

Females

Total

66.5

156

335

381

820

0/5

0/5

0/5

1/5

2/5

0/5

0/5

2/5

1/5

1/5

0/10

0/10

2/10

2/10

3/10

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The purpose of this study was to determine the median lethal concentration (LC50) of H-19056 in air. Due to the large, non-respirable particulate formed at high concentrations, it was apparent that an appropriate estimation of the LC50 could not be established from the data. Under the conditions of this study, the approximate lethal concentration (ALC) could be determined, and it was considered to be 335 mg/m3 total H-19056.
Executive summary:

Five groups of 5 male and 5 female Crl:CD®BR rats each were exposed to atmospheres of H-19056 for a single, 4-hour period. The test atmospheres were generated by heating the test substance and passing nitrogen through the heated vapor to carry the material to the exposure chamber. Due to cooler chamber temperatures, the exposure atmospheres were composed of both vapor and particulate H-19056. Particulate concentrations were measured by gravimetric analysis and vapor concentrations were determined by gas chromatography. After exposure, rats were observed for clinical signs of toxicity, and were then weighed and observed daily during a 14-day recovery period.

 

Rats were exposed to 66.5, 156, 335, 381 or 820 mg/m3of H-19056.

Chamber atmospheres were composed of both vapor and particulate. Particles were often visible in the chamber as large flakes, and distributions were either skewed to the larger sizes, with mass median aerodynamic diameters 7-8 µm, or bimodally distributed.

Rats exposed to 66.5, 156, 335, 381, or 820 mg/m3 had 0110, 0110, 2/10, 2/10 and 3/10 deaths, respectively. Frequently observed signs of toxicity visible following exposure included colored discharge of the nose, eyes, and mouth and signs of respiratory distress such as lung noise, irregular

respiration, and gasping. Lung noise was often apparent in rats that survived the 14-day recovery period. Rats that did not survive the recovery period tended to lose weight until death occurred. Surviving rats generally lost weight 1 to 3 days postexposure, followed by a normal weight-gain pattern.

 

Due to the large, non-respirable particulate formed at high concentrations, it was apparent that an appropriate estimation of the LC50 could not be established from the data. Under the conditions of this study, the approximate lethal concentration (ALC) could be determined, and it was considered to be 335 mg/m3 total H-19056.