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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
GLP-compliant non-guideline study with 14 d of exposure. Otherwise similar to guideline and reported in sufficient detail.
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female CD(R) (Sprague-Dawley) rats (weighing approximately 100-185 g and 5-8 weeks of age) were purchased from Charles River Breeding Laboratories, Kingston, New York. Upon arrival at the TOxicology Department, all rats were quarantined for one week. Approved rats were weighed and randomized into 12 controls and test groups (5/sex/group) using the Xybion ASLECT program. Groups I-VIII were employed in the acute phase and Groups IX-XII were used in the repeat dose phase of the study. After randomization, test animals were ear tagged and color coded tags (listing the rat's sex, exposure level, ear tag, file and group numbers) were placed on the outside of each cage.

The rats were housed individually in suspended stainless steel, wire mesh bottom cages were designed to be placed within the exposure chambers. After each exposure, the rats were returned to their original housing. The rats were fed certified Purina rodent chow and water ad libitum except during exposures. The rats were housed during non-exposure periods in rooms designed to be maintained at 68-73°F and 30-70 percent relative humidity. A light cycle of alternating 12 hours light and 12 hours dark was maintained.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
Exposures were conducted in 2 m3 liter stainless steel whole body exposure chambers. The chambers were operated under dynamic conditions where the chamber air was room air, which had been filtered (hepa and charcoal filters). Airflows through the chambers were kept at approximately 12-15 air changes per hour. Chamber temperature, humidity, and airflow were monitored continuously and were recorded every five minutes by the Camile(R) Data Acquisition System during the exposure periods. The test material was introduced into the chambers through special designed glass J-tubes. The test material was metered into the J-tubes with harvard Apparatus syringe pumps. Instrument air which was filtered, flowed through the J-tubes at a controlled rate. The air/vapor mixture passed into the inlet port at the top of the chambers. During the exposure periods, attempts were made to keep the actual concentrations of the test material in the chambers as constant as possible.
The duration of each exposure period was six hours after equilibration of the chamber concentration. The equilibration time, which is a function of chamber airflow, was approximately 25 minutes. The amount of test material used during the exposure period was determined by pre- and post-measuring the weight of the test material in each syringe. The exposure duration (exposure period and equilibration time), test material used and airflows through the chambers were then used to calculate nominal concentrations.
Actual chamber concentrations were measured a minimum of once an hour by a Varian(R) 3400 Gas Chromatograph (GC) equipped with a flame ionization detector. The GC was calibrated before the start of the study and one bag standard was prepared and analyzed during each exposure period.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Concentrations:
0, 0.5, 1.0 and 2.0 ppm
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Eight groups of 5 rats/sex were exposed acutely for six hours to target concentrations of 0, 0.5, 1.0 and 2.0 ppm of the test material. Four groups, one from each concentration level, were sacrificed immediately following exposure. The remaining groups were scheduled to be sacrificed following a 14-day recovery period.
All surviving rats were observed daily during the post-exposure period for treatment-related signs of toxicity, in particular, any evidence of respiratory, dermal, behavioral, nasal and/or ocular changes.
Individual body weights were collected prior to exposure for animals in all groups. Body weights for rats in groups V-VIII (single exposure with 14 day post-exposure observation) were scheduled to be measured on days 1, 8 and 15.
A gross pathologic examination was conducted on all rats. The brain, kidneys, lungs, liver, spleen, adrenals and ovaries or testes were dissected free of fat and weighed from rats surviving until scheduled sacrifice. The lungs were removed intact, weighed and distended to their approximate normal inspiratory volume by tracheal infusion with 10% neutral buffered formalin.
Organs or samples of organs or tissues listed below for animals in all groups were preserved in 10% neutral buffered formalin. Hematoxylin and eosin stained paraffin sections of the organs and tissues were prepared using standard histologic methods:
Adrenal (2), Nasal Cavity (4 levels), brain (3 levels), eyes (2), heart, kidneys (2), larynx, liver (3 lobes), lymph nodes (mandibular, mediastinal), lungs (5 lobes), trachea (multiple levels, cervical and bifurcation), ovaries (2), pharyns, spleen, testes (2), thymus.
Histopathological examination was performed on the tissues specified above for all male and female animals in both the acute and repeated dose phases at all exposure concentrations by consulting pathologist Dr. Robert G. Geil, D.V.M., Diplomate, American College of Veterinary Pathologists.
Statistics:
Statistical analyses were conducted on terminal body weights, organ weights and organ weight ratios where appropriate. This data was analyzed by a two-sided Welch Trend test. If a significant overall trend was detected, then all follow-up tests were one-sided and in the same direction as the overall trend. Body weights, collected during the in-life phase of the study, were statistically analyzed by the Dow Corning HBS ANOVA program. All tests were conducted at the P<=0.05 level of significance.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 - < 2 ppm
Exp. duration:
6 h
Mortality:
All rats in the acute phase, which were scheduled for immediate sacrifice, survived the exposure. In the acute recovery phase, two males and one female in the 2.0 ppm group died and the remainder of the rats in this group were sacrificed in a moribund state two days after exposure. All rats in the 0.5 and 1.0 groups of the acute recovery phase survived to the scheduled sacrifice.
Body weight:
A statistically significant decrease in body weight was seen in males in the 0.5 and 1.0 ppm groups and the females in the 1.0 ppm group on study day 8. Recovery was seen in all groups except males in the 1.0 ppm group, however, a statistically significant decrease in mean body weights was still present on study day 15. Terminal body weights showed statistically significant decreases in males in the 0.5 and 1.0 ppm group.
Gross pathology:
Gross pathologic examination indicated that there were no test article-related lesions at necropsy in any of the rats from the experimental groups of the acute phase which were sacrificed immediately after exposure.
In the acute immediate sacrifice phase of the study, microscopic examination indicated test article-related necrosis of respiratory epithelium (with less involvement of the olfactory epithelium and no involvement of the squamous epithelium) of the nasal cavity in ratsin the 1.0 and 2.0 ppm groups. Test article-related necrosis of the tracheal epithelium was also noted. No test article-related microscopic changes were observed in the respiratory tract or other organs examined in rats in the 0.5 ppm group.
In the acute recovery phase, corneal opacity was observed in three rats in the 1.0 ppm group and four females had decreased size of the thymus in the 0.5 and 1.0 ppm groups. The macroscopic findings of corneal opacity correlated microscopically with corneal epithelial necrosis and desquamation and keratitis. One female in the 1.0 ppm group had a hypoplastic thymus. All other macroscopic findings which were observed during gross necropsy were considered spontaneous or agonal and not test article-related. Microscopically, several organs showed test article-related effects. These included eye (in which desquamation of corneal epithelium with occasional associate keratitis was found) and various levels of the respiratory tract, i.e., nasal cavity, pharynx, larynx, and trachea (in which epithelial necrosis of respiratory epithelium, ulcers, epithelial hypoplasia and inflammatory exudate were found). As in the acute immediate sacrifice phase of this study, necrosis of the respiratory epithelium of the nasal cavity was evident.
Other findings:
Statistically significant increases and/or decreases were seen in absolute and/or relative spleen, brain, liver, kidney, and lung weights in either male and/or female animals in the 0.5 and/or 1.0 ppm group. In the absence of histopathologic correlates the biological significance of absolute and relative organ weights differences is questionable.

The ranges for temperature and relative humidity were 24 -25°C and 38 -40%, respectively.

Good agreement was obtained between the actual and nominal concentrations. The actual exposure concentrations for the acute phases were 0.4, 0.9 and 1.9 ppm.

Daily actual and nominal chamber concentration during treatment period (mean +/- S.D.):

Target exposure concentration (ppm)

 

Study day

1

2

3*

4

0.5

Actual

0.3

0,5

0.4

0.5

 

S.D.

0.2

0.0

0.3

0.0

 

Nominal

0.5

0.4

0.4

0.5

1.0

Actual

0.9

1.0

0.9

-

 

S.D.

0.2

0.1

0.1

-

 

Nominal

1.3

1.2

1.2

-

2.0

Actual

1.9

2.0

1.9

-

 

S.D.

0.2

0.1

0.1

-

 

Nominal

2.2

2.2

2.2

-

*The acute phase exposures were conducted concurrently with the repeated dose exposures on study day three.

Interpretation of results:
study cannot be used for classification
Conclusions:
The results of this study indicate that the inhalation exposure of DOW CORNING® X1-6154A Additive at the concentrations and conditions of this study roduced significant toxicologic effects in rats. This study did not establish a no-observable-effect-level for the test material. It is recommended that further toxicologic studies be conducted to determine the LC50 and NOAEL.
Executive summary:

An acute and 14 -day repeated dose inhalation study was initiated to assess the inhalation toxicity and to determine the NOAEL of DOW CORNING® X1-6154A Additive in rats. The study consisted of both an acute and repeated dose phase. Eight groups of five rats/sex were exposed acutely for six hours to target concentrations of 0, 0.5, 1.0 and 2.0 ppm of the test material. Four groups, one from each concentration level, were sacrificed immediately following exposure. The remaining groups were scheduled to be sacrificed following a 14 -day recovery period. The repeated dose phase was scheduled to expose four grups of rats to the same target concentrations as the acute phase for six hours per day for two weeks.

The actual exposure concentrations of DOW CORNING® X1-6154A for the acute and repeated dose phases were 0.4, 0.9 and 1.9 ppm.

All rats in the acute phase, which were scheduled fro immediate sacrifice, survived the exposure. Three rats, two male and one female, fromt the acute recovery phase died in the 2.0 ppm group. The remaining animals in this group were sacrificed in moribund state two days post-exposure. All other rats in the acute recovery phase survived to the scheduled sacrifice.

Clinical signs of toxicity which were considered treatment-related included ocular and nasal discharge, facial soiling, rough coats, soft feces, lethargy and labored breathing.

A statistically significant decrease in body weights was seen in male rats in the 0.5 and 1.0 ppm groups of the acute recovery phase.

Gross pathologic examination indicated that there were no test article-related lesions at necropsy in any of the rats from the acute phase which were sacrificed immediately after exposure. Histopathologic examination of tissues, however, indicated necrosis of respiratory epithelium of the nasal cavity in rats in the 1.0 and 2.0 ppm groups. Test article-related necrosis of the tracheal epithelium was also noted in these groups. No test article-related microscopic changes were observed in the respiratory tract or other organs examined in the 0.5 ppm group.

In the acute recovery phase, corneal opacity and a decrease in thymus size was noted in some animals in the 0.5 and 1.0 ppm groups. Several organs had test article-related effects, these included the eye and various levels of the respiratory tract. As in the acute immediate sacrifice phase of this study, necrosis of the respiratory epithelium of the nasal cavity was evident.

In the repeated dose phase, two males and two females in the 2.0 ppm group died after the second exposure to DOW CORNING® X1 -6154A Additive. All surviving rats in the 1.0 and 2.0 ppm groups were sacrificed in a moribund state before the third exposure. Rats in the 0.5 ppm group were sacrificed in a moribund state after the fourth exposure along with the corresponding control animals. Test article-related gross findings in the repeated dose phase included corneal opacity and ulceration, nasal obstruction and failure of the lungs to collapse. These gross findings were correlated with histopathologic changes observed in these tissues. Microscopic examination of tissues and organs indicated that various levels of the respiratory tract had epithelial necrosis with associated fibrinopurulent exudate, olfactory epithelium was less severely involved and squamous epithelium was spared. Chemical related toxicity was also observed in the eye and lung.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
animals were exposed for 14 days only, some parameters like clinical chemistry and hematology were not reported
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
3,3,6,6-tetramethoxy-2,7-dioxa-3,6-disilaoctane
EC Number:
242-285-6
EC Name:
3,3,6,6-tetramethoxy-2,7-dioxa-3,6-disilaoctane
Cas Number:
18406-41-2
Molecular formula:
C8H22O6Si2
IUPAC Name:
3,3,6,6-tetramethoxy-2,7-dioxa-3,6-disilaoctane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female CD(R) (Sprague-Dawley) rats (weighing approximately 100-185 g and 5-8 weeks of age) were purchased from Charles River Breeding Laboratories, Kingston, New York. Upon arrival at the TOxicology Department, all rats were quarantined for one week. Approved rats were weighed and randomized into 12 controls and test groups (5/sex/group) using the Xybion ASLECT program. Groups I-VIII were employed in the acute phase and Groups IX-XII were used in the repeat dose phase of the study. After randomization, test animals were ear tagged and color coded tags (listing the rat's sex, exposure level, ear tag, file and group numbers) were placed on the outside of each cage.

The rats were housed individually in suspended stainless steel, wire mesh bottom cages were designed to be placed within the exposure chambers. After each exposure, the rats were returned to their original housing. The rats were fed certified Purina rodent chow and water ad libitum except during exposures. The rats were housed during non-exposure periods in rooms designed to be maintained at 68-73°F and 30-70 percent relative humidity. A light cycle of alternating 12 hours light and 12 hours dark was maintained.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
Exposures were conducted in 2 m3 liter stainless steel whole body exposure chambers. The chambers were operated under dynamic conditions where the chamber air was room air, which had been filtered (hepa and charcoal filters). Airflows through the chambers were kept at approximately 12-15 air changes per hour. Chamber temperature, humidity, and airflow were monitored continuously and were recorded every five minutes by the Camile(R) Data Acquisition System during the exposure periods. The test material was introduced into the chambers through special designed glass J-tubes. The test material was metered into the J-tubes with harvard Apparatus syringe pumps. Instrument air which was filtered, flowed through the J-tubes at a controlled rate. The air/vapor mixture passed into the inlet port at the top of the chambers. During the exposure periods, attempts were made to keep the actual concentrations of the test material in the chambers as constant as possible.
The duration of each exposure period was six hours after equilibration of the chamber concentration. The equilibration time, which is a function of chamber airflow, was approximately 25 minutes. The amount of test material used during the exposure period was determined by pre- and post-measuring the weight of the test material in each syringe. The exposure duration (exposure period and equilibration time), test material used and airflows through the chambers were then used to calculate nominal concentrations.
Actual chamber concentrations were measured a minimum of once an hour by a Varian(R) 3400 Gas Chromatograph (GC) equipped with a flame ionization detector. The GC was calibrated before the start of the study and one bag standard was prepared and analyzed during each exposure period.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 h, 10x over 14 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Dose / conc.:
0.5 ppm
Dose / conc.:
1 ppm
Dose / conc.:
2 ppm
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Four groups of animals were exposed for two weeks and sacrificed immediately following the last exposure.
All surviving rats were observed daily during the post-exposure period for treatment-related signs of toxicity, in particular, any evidence of respiratory, dermal, behavioral, nasal and/or ocular changes.
Individual body weights were collected prior to exposure for animals in all groups. Body weights for rats in groups V-VIII (single exposure with 14 day post-exposure observation) were scheduled to be measured on days 1, 8 and 15.
A gross pathologic examination was conducted on all rats. The brain, kidneys, lungs, liver, spleen, adrenals and ovaries or testes were dissected free of fat and weighed from rats surviving until scheduled sacrifice. The lungs were removed intact, weighed and distended to their approximate normal inspiratory volume by tracheal infusion with 10% neutral buffered formalin.
Organs or samples of organs or tissues listed below for animals in all groups were preserved in 10% neutral buffered formalin. Hematoxylin and eosin stained paraffin sections of the organs and tissues were prepared using standard histologic methods:
Adrenal (2), Nasal Cavity (4 levels), brain (3 levels), eyes (2), heart, kidneys (2), larynx, liver (3 lobes), lymph nodes (mandibular, mediastinal), lungs (5 lobes), trachea (multiple levels, cervical and bifurcation), ovaries (2), pharyns, spleen, testes (2), thymus.
Histopathological examination was performed on the tissues specified above for all male and female animals in both the acute and repeated dose phases at all exposure concentrations by consulting pathologist Dr. Robert G. Geil, D.V.M., Diplomate, American College of Veterinary Pathologists.

Examinations

Statistics:
Statistical analyses were conducted on terminal body weights, organ weights and organ weight ratios where appropriate. This data was analyzed by a two-sided Welch Trend test. If a significant overall trend was detected, then all follow-up tests were one-sided and in the same direction as the overall trend. Body weights, collected during the in-life phase of the study, were statistically analyzed by the Dow Corning HBS ANOVA program. All tests were conducted at the P<=0.05 level of significance.

Results and discussion

Results of examinations

Mortality:
mortality observed, treatment-related
Description (incidence):
Two males and two females in the 2.0 ppm group died after a second six-hour exposure. All surviving rats in the 1.0 or 2.0 ppm groups were sacrificed in a moribund state on study day three. On study day five, all rats in the 0.5 ppm group were sacrificed in a moribund state with the corresponding control group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test article related macroscopic findings included corneal opacity and ulceration, nasal obstruction and failure of the lungs to collapse. These findings correlated with microscopic changes. All other findings which were observed during gross necropsy were considered spontaneous or agonal and not test article-related.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic examination of tissues and organs indicated that various levels of the respiratory tract, i.e., nasal cavity, pharynx, larynx and trachea, had test-article-related epithelial necrosis with associated fibrinopurulent exudate. As with the acute phase of this study, the respiratory epithelium of the nasal cavity was most severely affected in the repeated dose phase animals; this change was most evident in rats from the 1.0 and 2.0 ppm groups. However, in contradistinction from the 0.5 ppm groups of the acute phases, rats from the 0.5 ppm group of the repeated dose phase had necrosis on the respiratory epithelium of the nasal cavity; olfactory epithelium was less severely involved and squamous epithelium was spared. As with the acute recovery phase, the eye also had test article-related effects which included desquamation, hyperplasia and keratitis of corneal epithelium. The lung had test article-related necrosis of bronchial epithelium. THere was no evidence of spontaneous diseases which would have had an effect on the validity of the study in any of the organs examined microscopically.

Effect levels

Dose descriptor:
NOAEC
Effect level:
< 0.5 ppm
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
mortality

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
0.5 ppm
System:
other: respiratory system
Organ:
bronchi
larynx
lungs
nasal cavity
trachea
Treatment related:
yes

Any other information on results incl. tables

Test article-related macroscopic findings in the repeated dose phase included corneal opacity and ulceration, nasal obstruction and failure of the lungs to collapse. These findings correlated with microscopic changes. All other findings which were observed during gross necropsy were considered spontaneous or agonal and not test article-related.

Microscopic examination of tissues and organs indicated that various levels of the respiratory tract, i.e., nasal cavity, pharynx, larynx and trachea, had test article-related epithelial necrosis with associated fibrinopurulent exudate. As with the acute phases of this study, the respiratory epithelium of the nasal cavity was mose severely affected in the repeated dose phase animals; this change was most evident in rats from the 1.0 and 2.0 ppm groups. However, in contradistinction from the 0.5 ppm groups of the acute phases, rats from the 0.5 ppm grou pof the repeated dose phase had necrosis of respiratory epithelium of the nasal cavity; olfactory epithelium was less severely involved and squamous epithelium was spared. As with the acute recovery phase, the eye also had test article-related effects which included desquamation, hyperplasia and keratitis of corneal epithelium. THe lung had test article-related necrosis of bronchial epithelium. There was no evidence of spontaneous disease which would have had an effect on the validity of the study in any of the organs examined microscopically.

Applicant's summary and conclusion

Conclusions:
The results of this study indicate that the inhalation exposure of DOW CORNING® X1-6154A Additive at the concentrations and conditions of this study roduced significant toxicologic effects in rats. This study did not establish a no-observable-effect-level for the test material.
Executive summary:

An acute and 14 -day repeated dose inhalation study was initiated to assess the inhalation toxicity and to determine the NOAEL of DOW CORNING® X1-6154A Additive in rats. The study consisted of both an acute and repeated dose phase. Eight groups of five rats/sex were exposed acutely for six hours to target concentrations of 0, 0.5, 1.0 and 2.0 ppm of the test material. Four groups, one from each concentration level, were sacrificed immediately following exposure. The remaining groups were scheduled to be sacrificed following a 14 -day recovery period. The repeated dose phase was scheduled to expose four grups of rats to the same target concentrations as the acute phase for six hours per day for two weeks.

The actual exposure concentrations of DOW CORNING® X1-6154A for the acute and repeated dose phases were 0.4, 0.9 and 1.9 ppm.

All rats in the acute phase, which were scheduled for immediate sacrifice, survived the exposure. Three rats, two male and one female, fromt the acute recovery phase died in the 2.0 ppm group. The remaining animals in this group were sacrificed in moribund state two days post-exposure. All other rats in the acute recovery phase survived to the scheduled sacrifice.

Clinical signs of toxicity which were considered treatment-related included ocular and nasal discharge, facial soiling, rough coats, soft feces, lethargy and labored breathing.

A statistically significant decrease in body weights was seen in male rats in the 0.5 and 1.0 ppm groups of the acute recovery phase.

Gross pathologic examination indicated that there were no test article-related lesions at necropsy in any of the rats from the acute phase which were sacrificed immediately after exposure. Histopathologic examination of tissues, however, indicated necrosis of respiratory epithelium of the nasal cavity in rats in the 1.0 and 2.0 ppm groups. Test article-related necrosis of the tracheal epithelium was also noted in these groups. No test article-related microscopic changes were observed in the respiratory tract or other organs examined in the 0.5 ppm group.

In the acute recovery phase, corneal opacity and a decrease in thymus size was noted in some animals in the 0.5 and 1.0 ppm groups. Several organs had test article-related effects, these included the eye and various levels of the respiratory tract. As in the acute immediate sacrifice phase of this study, necrosis of the respiratory epithelium of the nasal cavity was evident.

In the repeated dose phase, two males and two females in the 2.0 ppm group died after the second exposure to DOW CORNING® X1 -6154A Additive. All surviving rats in the 1.0 and 2.0 ppm groups were sacrificed in a moribund state before the third exposure. Rats in the 0.5 ppm group were sacrificed in a moribund state after the fourth exposure along with the corresponding control animals. Test article-related gross findings in the repeated dose phase included corneal opacity and ulceration, nasal obstruction and failure of the lungs to collapse. These gross findings were correlated with histopathologic changes observed in these tissues. Microscopic examination of tissues and organs indicated that various levels of the respiratory tract had epithelial necrosis with associated fibrinopurulent exudate, olfactory epithelium was less severely involved and squamous epithelium was spared. Chemical related toxicity was also observed in the eye and lung.