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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Literature article of a non-GLP, non-guideline acute inhalation study with adequate details.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
Principles of method if other than guideline:
"The acute inhalation toxicity of TEB was determined not only as a function of concentration but also as a function of the time after initiation of oxidation as well. At various exposure concentrations animals were exposed for 1 h to TEB oxidation product vapors in which either 36 msec or 4.6 min had elapsed between the initiation of the oxidation process and delivery to the exposure apparatus." (Kimmel et al, 1990)
GLP compliance:
no
Test type:
other:

Test material

Constituent 1
Chemical structure
Reference substance name:
Triethylborane
EC Number:
202-620-9
EC Name:
Triethylborane
Cas Number:
97-94-9
Molecular formula:
C6H15B
IUPAC Name:
triethylborane
Test material form:
other: liquid
Details on test material:
"Two commercial sources of liquid TEB were used in the course of this investigation. One
hundred grams of TEB supplied by Aldrich Chemical Company, Inc. (Milwaukee, Wi - Lot No. 00S2SCP)
was used for initial attempts at analytical methods development. Triethylborane (1.2 kg) for
subsequent methods development, calibration standards, and exposure was supplied by Callery
Chemical Company, Inc. (Callery, PA - Lot No, 853-5). Both supplies of TEB were received in sealed
vessels containing a pure N2 headspace and precautions were instituted to ensure that all procedures
for transfer, use, and subsequent storage were conducted to maintain the integrity of this headspace." (Kimmel et al, 1990)

Physical properties provide by the authors are as follows:
Synonyms: Triethylboron, Triethlyborine, Trialkylborane
CAS No 97-94-9
Formula: (C2H5)3B
Molecular Weight: 98.0
Color and Form: Clear liquid
Melting Point: -93°C
Boilmg Point: 95 degC
Density: 068 gJmL at 25·C
Viscosity: 0.30 cP at 25 degC
Vapor Pressure: 42.6 mm Hg at 20 degC & 760 mm Hg
Solubility/H20 : Immiscible
Stability: PyrophortC - liquid autoignites on exposure to air, vapor autolgnites greater than or equal to 1150- to 1300 ppm
Conversion factors: 1 mg/m3 = 0.25 ppm

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
"Fischer 344 (F-344) rats of both genders, 12 to 13 weeks of age at exposure, were obtained from Harlan
Industries (indianapolis, IN) for the pilot investigation; and F-344 rats, 11 to 14weeks of age at
exposure, were purchased from Charles River Breeding Laboratories (Kingston, NY) for the second
phase of the investigation. Upon receipt all animals were quarantined for a two-week period and
were committed to study following observ(!tion and random selection of representative animals for
quality control analysis. Prior to the exposures and during a 14-day postt!xposure observational
period, animals were group-housed (two to three per unit) in clear plastic cages with wood chip
absorbent bedding. Housing Linits were maintained in sjngle-pass laminar flow facilities. Food and
water were provided ad libitum with the exception of withholding food for a 12-h period prior to
sacrifice. All animals were maintained on a 12 -hr diurnal cycle." (Kimmel et al, 1990)

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
"The animals were exposed to either fTEB or aTEB using a 48-port, nose-only exposure
apparatus described by Raabe et ai. (1973)."

"At concentrations below 1150 to 1300 ppm, TEB rapidly oxidizes
to diethylethoxyborane (DEEOB), then ethyldiethoxyborane (EDEOB), and ultimately to
triethoxyborane (TEOB) (Callery Chemical, 1978)"

"Because of the rapid oxidation of TEB in air and the possibility that TEB toxicity might be a
function of the extent to which this oxidation has progressed, the acute inhalation toxicity of TEB was
determined not only as a function of concentration but also as a function of the time after initiation
of oxidation as well. At various exposure concentrations animals were exposed for 1 h to TEB
oxidation product vapors in which either 36 msec or 4.6 min had elapsed between the initiation of the
oxidation process and delivery to the exposure apparatus. For the purpose of clarity, fresh TEB (fTEB)
refers, in actuality, to the mixture of TEB and its DEEDB, EDEOB, and TEOB oxidation derivatives
delivt'red to the exposure chamber 36 msec after initial mixing of pure TEB vapor with oxygen. Aged
TEB (aTE B) vapor refers to the atmosphere resulting from a 4.6-min delay between the initiation of
TEB oxidation and delivery to the exposure chamber." (Kimmel et al, 1990)

Analytical verification of test atmosphere concentrations:
yes
Remarks:
By IR and GC
Duration of exposure:
1 h
Concentrations:
approximately 370, 600, or 780 ppm
No. of animals per sex per dose:
six
Control animals:
yes
Details on study design:
"Animals were assigned to experimental groups using a body weight normalized random
selection procedure. For the pilot investigation, 12 animals of each sex were assigned to each of three
experimental groups. One group each was exposed to comparable concentrations (approximately
960 ppm) of either fTEB or aTEB and one group was exposed for approxirnately one hour to air to
serve as controls. Half of the animals in each group were designated for evaluation of acute toxicity
after a 14-day postexposure observation period and half of the animals were scheduled for serial
sacrifice to evaluate the development and recovery from pulmonary insult at 4 h, 24 h, and 7 days
postexposure. Six animals of each sex were assigned to each of seven experimental groups for the
second phase (LC50 determination) of the investigation. No provisions were made to include
subgroups for serial, postexposure pathologic evaluation of potential pulmonary or CNS lesions. In
addition to a control group, animals were exposed to either fTEB or aTES at one of three
concentrations (approxi mately 370, 600, or 780 ppm)." (Kimmel et al, 1990)
Statistics:
"Comparisons of mean body weights were performed using a multivariate analysis of covariance
for repeated measures test (Barcikowski, 1983). LCso determinations were made using a logistic
regression analysis (Bates and Watts, 1988). Histopathology data from the pilot investigation were
analyzed using a log-linear model, three-way contingency analysis (Dixon, 1990). Histopathology
data from the LC50 study were analyzed using a two-factor analysis of variance and Scheffe's multiple
comparison test (Barcikowski, 1983). Unless othenlVise specified, data reported are mean ±standard
deviation." (Kimmel et al, 1990)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
738 ppm
Remarks on result:
other: no further information
Mortality:
Pilot study: exposure durations were only 52 min because in the first (fTEB) exposure mortality at the time was 100%.
Of the 24 animals exposed to aTEB, a total of 10 died during the exposure and 2 died within 24 h.

LC50 Study: "The overall LC50 for TEB (both fTEB and aTEB, both genders; calculations did not include pilot
study data) was 738 ppm (692 to 806). The LC50 for fTEB only (both genders) was greater at 766 ppm
(699 to 779) and the LC50 for aTEB only (both genders) was less at 709 (629 to 798). The combined
(both fTEB and aTEB) LC50 for males was 676 ppm (591 to 719), whereas the combined LC50 for
females was >821 ppm. Numbers in parentheses are lower and upper 95% fiducial limits. The
general health of animals surviving exposures, as indicated by body weight maintenance, did not
demonstrate exposure concentration, type of TEB, or gender-specific effects." (Kimmel et al, 1990)


LC50 Determination
"No animals exposed to the lowest concentrations of fTEB and aTEB (33S and 399 ppm, respertively)
expired during the course of the investigation. One animal each expired after midlevel exposure to
fTEB or aTEB (617 and 575 ppm, respectively); interestingly, both were males. The animal exposed to
fTEB died during the exposure and the animal exposed to aTEB died within 24 h of exposure. At
higher levels of fTEB and aTEB (741 and 821 ppm, respectively), 5 of 12 animals expired from fTEB
exposure and 10 of 12 animals expired from aTEB exposure. All 5 animals that died from fTEB
exposure were male, 3 died during the exposure and 2 died within 24 h. Six of the 10 animals that
died from aTEB exposure were male. One male and 2 females died during exposure, 2 males and 2
females died on the day of exposure, and the 3 additional deaths occurred within 2 days of exposure
and all were males." (Kimmel et al, 1990)
Clinical signs:
other: Pilot Study: Abnormal breathing patterns, hyperactivity and broncospasms LC50 Study: "During exposures (all concentrations, either fTEBor aTEB), the majority of animals exhibited labored, shallow breathing which persisted for up to 24 h in animals surviv
Other findings:
Histopathology Pilot study:
Pulmonary edema was the most important histopathologic finding. No respiratory tract lesions
were present in rats exposed to aTEB at 7 and 14 days postexposure. Nasal and tracheal epithelial
necrosis occurred in a few of the rats that were exposed to fTEB and was primarily limited to the
ventral half of the tracheal circumference.

"Other significant findings were centrolobar hepatocytic, cytoplasmic, vacuolar degeneration,
and congestion in animals exposed to both fTEB and aTEB. The vacuoles frequently contained a
homogeneous eosinophilic material suggestive of a proteinaceous cell product. Acute to subacute
multifocal myocarditis was observed frequently in all exposure groups." (Kimmel et al, 1990)

Histopathology LC50 study:
"In this investigation gross observations of vascular engorgement and organ discolorations
suggestive of vascular congestion or hemorrhage were found in all TEB exposure groups, as well as in
some control animals. Hemorrhage was occasionally confirmed by histopathologic examination.
Congestion was histopathologically confirmed for the lung, liver, and kidneys of some animals.
Except for those tissues with concurrent diagnoses of edema (primarily lung), the vascular alterations
were considered agonal rather than exposure-related." (Kimmel et al, 1990)

Any other information on results incl. tables

"Mean concentrations of the fTEB and aTEB exposures in the pilot investigation were 956 ± 57.8 (n = 26) and 897 ± 14.6 (n = 29) ppm, respectively, and remained stable throughout the exposure with coefficients of variation (CV) of 6.0 and 1.7%, respectively. Pilot study exposure durations were only 52 min because in the first (fTEB) exposure mortality at the time was 100%." (Kimmel et al, 1990)

In the LD50 study:

"Mean fTEB and aTEB concentrations in the low-level exposure group were 335 ± 32.7 (n = 111) and 399 ± 27.8 (n + 111) ppm, respectively, and also were stable with CVs of 9.6 and 7.0 %. Mean concentrations of fTEB and aTEB in the midlevel exposures were 617 ± 133.1 (n = 111) and 575 ± 96.7 (n = 111) ppm, respectively, and were relatively variable with CVs of 16.9 and 21.6%. High-level exposure concentrations for fTES and alES were 741 ± 40.8 and 821 ± 56.9 ppm, and were stable with CVs of 5.5 and 6.9%, respectively. All of these exposures were 1 h in duration." (Kimmel et al, 1990)



Applicant's summary and conclusion

Interpretation of results:
Category 2 based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
According to the authors: The overall LC50 (males and females) of fTEB and aTEB was 738 ppm.
The combined (both fTEB and aTEB) LC50 for males was 676 ppm (591 to 719), whereas the combined LC50 for females was >821 ppm.
Executive summary:

This is a summary of a study conducted by Kimmel, E.C. et al. at the Harry G. Armstrong Aerospace Medical Research Laboratory at Wright-Patterson Air Force Base. Source: Govt Reports Announcements & Index (GRA&l), Issue 20, 1991 [NTIS]. The test article was described as a clear liquid with a 99% purity.

The study was conducted to determine the acute inhalation toxicity of TEB. It is reported that TEB rapidly oxidizes to diethylethoxyborane (DEEOB), to ethyldiethoxyborane (EDEOB) and to triethoxyborane (TEOB) at concentrations below 1150-1300 ppm. Since the oxidation occurs within milliseconds after initial contact of TEB with air and is complete within minutes, studies were conducted with fresh TEB (fTEB = mixture of TEB, DEEOB, EDEOB and TEOB oxidation derivaties delivered to the exposure chamber 36 msec after initial mixing of pure TEB vapor with oxygen) and with aged TEB (aTEB = vapor resulting from a 4.6 min delay between the initiation of TEB oxidation and delivery to the exposure chamber).

In the first study, groups of 24 rats were exposed to 956 (fTEB) ppm, 897 (aTEB) ppm or air for 1 hour. Mortality was 21/23, 12/24 0/24 for the fTEB, aTEB and control groups respectively. Clinical signs of toxicity included irregular respiration and hyperactivity. Survivors in the fTEB group exhibited abnormal breathing and were cyanotic following exposure. Pathology findings that were significantly different than control were: autolysis (self-digestion) of the trachea (fTEB males, and fTEB females); necrosis of the trachea, (male and female fTEB and male aTEB); lung edema and congestion (males and females fTEGB); liver cell degeneration (males and females fTEB and aTEB) and liver congestion (male and female fTEB).

In a second study to determine an LC50, 12 rats were exposed for 1 hour to either air, 335 or 399 ppm (fTEB and aTEB), 617 or 575 ppm (fTEB or aTEB) or 741 or 821 ppm (fTEB or aTEB). There were no mortalities in the low concentration group or in the control group. There was one mortality in each mid-fTEB and aTEB exposure group (both males), 5/12 (males only) mortalities in the 741 fTEB ppm group and 10/12 (6 males, 4 females) mortalities in the 821 aTEB ppm group.

The overall LC50 for TEB (both fTEB and aTEB of both genders) was 738 ppm. The LC50 (both genders) for fTEB and aTBE was greater than 766 ppm and 709 ppm, respectively. Female LC50 (fTEG and aTEB) was greater than 821 ppm and for males (fTEB and aTEB) the LC50 was 676 ppm. Clinical signs of toxicity included irregular breathing and tremors during exposusre, cyanosis and decreased activity. Lung congestion and edema were considered dose and gender related. Only high concentration females in the aTEB were effected while high concentration fTEB and aTEB males were effected and at a greater incidence. Significant degeneration of liver cells was observed in high concentration aTEB females and in high concentration fTEB and aTEB males. It should be noted that 50% of the control males also had liver cell degeneration in this portion of the study.

The lung edema due to TEB exposure was attributed to increased vascular permeability and tracheal lesions due to TEB dissolving in the tracheal mucus. The significance of the liver alterations was not known nor was the gender related response.