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EC number: 200-849-9 | CAS number: 75-21-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Specific investigations: other studies
Administrative data
- Endpoint:
- biochemical or cellular interactions
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The purpose of this study was to investigate the mode of action for ethylene oxide-induced lung mutations in male B6C3F1 mice. Inhalation is a probable route of human exposure during the use or manufacture of EO.
- GLP compliance:
- yes
- Type of method:
- in vivo
- Endpoint addressed:
- other: Mode of action
Test material
- Reference substance name:
- Ethylene oxide
- EC Number:
- 200-849-9
- EC Name:
- Ethylene oxide
- Cas Number:
- 75-21-8
- Molecular formula:
- C2H4O
- IUPAC Name:
- oxirane
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: ARC Specialty Products, New Hampton, New York, USA (Satellite Group), ARC Specialty Products, Belchem Corporation, Green Pond, South Carolina, USA (Experimental groups)
- Lot No.of test material: UTLX902827F10 (Satellite group); UTLX902111C11 (Experimental groups)
- Molecular weight: 44.1 g/mol
- Purity: 99.9%
Test animals
- Species:
- mouse
- Strain:
- B6C3F1
- Remarks:
- Tac and Big Blue hemizygous
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms (Germantown, New York, USA)
- Age at study initiation: Approximately 8 weeks
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1 (maximum permissible excursion 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12 h (5 am to 5 pm illumination)
OTHER SPECIFICS:
JUSTIFICATION FOR STRAIN SELECTION:
B6C3F1 mice were selected because of their general acceptance and suitability for toxicity testing, availability of hisorical gackground data, the reliability of the commercial supplier, and their use in previous studies on EO. Big Blue B6C3F1 mice were used for mutational analysis.
Administration / exposure
- Route of administration:
- inhalation: gas
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4 m³ stainless steel and glass exposure chambers. Whole body exposure
- Method of holding animals in test chamber: mice were housed singly
- Source and rate of air: Exposure atmospheres were generated by mixing Eo in nitrogen with HEPA-filtered breathing air
- Method of conditioning air: not specified
- Temperature, humidity, pressure in air chamber: 22 +/- 2°C, 40-60%, with the exception of the control chamber (slightly positive pressure), the exposure chambers were operated at a slightly negative pressure relative to the surrounding area.
- Air flow rate: 869.9 - 898.1 lpm (liters per minute)
- Air change rate: 12-15 per hour
TEST ATMOSPHERE
- Brief description of analytical method used: Test atmosphere concentration was determined approximately twice per hour with a Miran 1A infrared spectrometer
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Exposure chamber concentrations were assessed daily and the mean, standard deviation, a minimum and a maximum concentration were established.
- Duration of treatment / exposure:
- 4, 8, 12 weeks
- Frequency of treatment:
- 6 h/d, 5 d/w
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 ppm
- Remarks:
- 4 weeks exposure
- Dose / conc.:
- 50 ppm
- Remarks:
- 4 weeks exposure
- Dose / conc.:
- 100 ppm
- Remarks:
- 4, 8, and 12 weeks exposure
- Dose / conc.:
- 200 ppm
- Remarks:
- 4, 8, and 12 weeks exposure
- No. of animals per sex per dose:
- 356 total animals
- Control animals:
- yes
- Details on study design:
- PROBE STUDY:
A satellite group of 10 male B6C3F1/Tac mice were exposed 6 h/d for 3 consecutive days to 0 and 200 ppm EO (n = 5/concentration). Spleen, Liver, and lung from these animals were isolated, processed, and analyzed for biomolecular analyses (DNA adducts and isoprostates, in all three tissues and 8-OHdG and GSH/GSSG only in the lung).
MAIN STUDY:
Animales were assigned to one of the following test groups:
- Satellite group: Probe study
- Group 1: Histopathoogy, cell proliferation, micronucleus, and comet:
A total of 91 mice were used of which 86 were exposed resulting in 10 mice per exposure level (4-week exposure). Six mice per exposure level were used for weeks 8 and 12.
- Group 2: Bioanalytical assays
A total of 160 mice were used. 20 mice per exposure level were used (4-week exposure). 10 mice were used for each exposure level (8-and 12-week exposure).
- Group 3: cII and K-ras mutations
A total of 110 mice were used of which 10 mice per exposure level were utilized (4-, 8-, 12-week exposure).
Examinations
- Examinations:
- Cage-side examination was conducted at least once a day. Animals were observed for morbifity, mortality, and the availability of feed and water at least twice daily. A hands-on evaluation of skin, fur, mucous membranes, respiration, and nervous system
function (including tremors, convulsions, diarrhea, and animal behavior) were conducted twice during the first week of exposure and weekly thereafter. Animals were weighed and visually examined prior to exposure to EO. All mice were weighed during the pre-exposure period and at least weekly during the exposure period. Feed consumed was determined at least weekly for all animals by weighing feed crocks
at the start and end of a measurement cycle. - Positive control:
- Additional 5 mice were exposed to 300 mg/kg ethyl methanesulfonate in water by oral gavage and were used as a positive control.
Results and discussion
- Details on results:
- CHAMBER CONCENTRATIONS:
Mean analytically determined concentrations values were 0, 10.1 ± 0.4, 50.0 ± 1.6, 100.5 ± 4.6, and 199.2 ± 2.7 ppm,. The nominal concentrations were determined by the mass of EO divided by volume of gas delivered to each exposure chamber. Nominal concentrations for this study were 10.0 ± 0.2, 51.5 ± 0.4, 104.0 ± 7.7, and 206.5 ± 0.9 ppm,
MORTALITY:
No mortality was observed except for one mouse in the 50 ppm group which spontaneously died on the second day of exposure.
CAGE-SIDE OBSERVATIONS:
No effects observed
CLINICAL OBSERVATIONS:
No effect observed
BODY WEIGHTS7/BODY WEIGHT GAINS:
No effects observed except in one B6C3F1/Tac mice exposed to EO for 8 weeks at 200 ppm a treatment-related statistically-decreased mean body weight was observed when compared to the respective controls. In Big Blue B6C3F1 hemizygous mice, there were no statistically significant differences except in mice exposed to 100 ppm of EO for 12 weeks where a treatment-related statistically-decreased mean body weight when compared to the respective controls was observed.
FEED CONSUMPTION:
There was a statistically identified difference in feed consumption for the 200 ppm group of Big BLue B6C3F1 mice although there was an inconsistent temporal responsiveness to the alterations in feed consumption, i.e. not the same week in the three exposure periods was affected. A similar subtle and inconsistent increase in feed consumpion was noted in the B6C3F1/Tac mice.
ORGAN WEIGHTS:
In group 1, no consistent or remarkable changes were observed. The lung weight of the 200 ppm treated B6C3F1/Tac mice was statistically increased (after 8 weeks of exposure), this finding was not observed for the other two time periods.
In group 2, there was a consistent, statistically significant increase in the lung weights of the animals in the 8 and 12-week treatment group at an exposure concentration of 200 ppm. In addition, the liver weights were decreased at the 4-week treatment group at 200 ppm.
In Big Blue B6C3F1 mice, the only statistically increased change in organ weight was in the lungs at the 200 ppm exposure concentration treated for 12 weeks.
HISTOPATHOLOGY:
no effects observed.
CELL PROLIFERATION (KI-67) IN LUNG TISSUE:
Effects observed, non treatment-related.
Statistically identified decreases in labeling index and unit length labeling index were noted at 4 and 8 weeks at 200 ppm. A slight decrease was also observed in numeric density at 200 ppm at the 4 week exposure time only (B6C3F1/Tac mice), see table 1 in "any other information on results". Lung tissue from one control animal from the 4-week exposure group (animal #1877) was inadvertently not prepared for evaluation of proliferation in the terminal bronchioles. Another control animal in the 4-week exposure group (animal # 1876) as well as 200 ppm animal from the 4-week exposure group (animal # 2143) did not have any terminal bronchioles present in the prepared slide and hence were not available for evaluation. Two control animals (animal # 1876 and 1878), one 10 ppm animal (animal # 1921), two 50 ppm animals (animal # 1959 and 1960), three 100 ppm animals (animal # 2047, 2054, and 2055), and three 200 ppm animals (animal #2139, 2141, and 2143) from the 4-week exposure group did not have any terminal bronchioles present in the prepared slide and hence were not available for evaluation.
MICRONUCLEATED PERIPHERAL BLOOD RETICULOCYTES:
no effects observed
IN VIVO COMET ASSAY IN LUNG TISSUE:
effects observed, treatment-related.
A statistically significant increase in the percent tail DNA intensity in lung tissue of animals treated for 4 weeks with EO at concentrations of 50, 100, or 200 ppm was observed when compared to control values (B6C3F1/Tac mice). Sections of the lung tissues were evaluated in order to determine whether the response was due to cytotoxicity or genotoxicity revealing no evidence of necrosis or apoptosis.
BIOANALYTICAL ASSAYS:
EO did not cause detectable ROS induction. Alkylated DNA adducts were substantially increased and were clear biomarkers of exposure. Specifically, in the lung N7-HEG was increased 499-, 1553-, 2296-, and 8692-fold at 10, 50, 100, and 200 ppm, respectively. Similarly, this biomarker of exposure was increased at least 10,800-fold in the spleen and at least 12,700-fold in the liver at 200 ppm. N1- and N6-HEdA were both qualitatively increased in a concentration-dependent manner. Analysis of the GSH-related biomarkers also indicated a concentration-related increase in biomarkers of exposure, i.e., HESG.
Any other information on results incl. tables
TABLE 1. Summary of Proliferation Observations (Ki-67) in Lung Tissue (B6C3F1/Tac Male Mice), Control and High Dose (4-,8-, and 12-week)
|
4 Weeks |
8 Weeks |
12 Weeks |
|||
|
0 ppm |
200 ppm |
0 ppm |
200 ppm |
0 ppm |
200 ppm |
Labeling Index |
0.50 ± 0.31 |
0.21 ± 0.21 |
0.14 ± 0.06 |
0.03 ± 0.03 |
0.28 ± 0.12 |
0.35 ± 0.12 |
Unit Length Labeling Index |
0.84 ± 0.53 |
0.32 ± 0.31 |
0.25 ± 0.11 |
0.05 ± 0.06 |
0.45 ± 0.19 |
0.58 ± 0.22 |
Numeric Density |
166.7 ± 17.3 |
149.7 ± 9.5 |
172.4 ± 14.8 |
171.2 ± 8.1 |
164.7 ± 7.8 |
164.1 ± 9.8 |
Values are mean +/- standard deviation; bold values = significantly different than similarly exposed 0 ppm mice (p ≤ 0.05)
Table 2: Summary in vivo comet assay in lung tissue (B6C3F1/tac mice)
|
|
Lung |
Exposure (ppm) |
Na |
Mean % Tail Intensity |
0 |
10 |
4.066 |
10 |
10 |
4.298 |
50 |
10 |
7.971b |
100 |
10 |
14.734b |
200 |
10 |
39.594b |
Positive Control (300 mg/kg EMSc) |
5 |
53.802b |
a N is the number of animals per dose group at the time of scheduled sacrifice. 100 cells were examined/animal for Comet analysis, and expressed as mean % tail intensity.
b The values are significantly different from the negative control (alpha=0.05).
c EMS = Ethyl Methanesulfonate (positivecontrol).
Table 3: Summary of alkylated DNA adduct biomarkers
Biomarke rs |
Alkylate d DNA Adduct Biomarke rs |
|||||||
LC/MS-MS assay |
Assay 1 |
Assay 2 |
||||||
Biomarke r type s |
O6-HEdG |
N1-HEdA |
N6-HEdA |
N7-HEG |
||||
Biomarke r le vel units |
Adducts/dG [10 (e 6)] |
Adducts/dA[10 (e 6)] |
Adducts/NT [10 (e9)] |
|||||
Sample Name |
Ave rage |
SD |
Ave rage |
SD |
Ave rage |
SD |
Ave rage |
SD |
4W spleen (0 ppm) |
0.130 |
0.0690 |
<LLQ (0.431) |
NA |
<LLQ (0.431) |
NA |
<LLQ (4.83) |
NA |
4W spleen (10 ppm) |
0.129 |
0.0666 |
<LLQ (0.359) |
NA |
<LLQ (0.359) |
NA |
872 |
85.6 |
4W spleen (50 ppm) |
0.152 |
0.0918 |
<LLQ (0.335) |
NA |
<LLQ (0.335) |
NA |
4024 |
926 |
4W spleen (100 ppm) |
0.147 |
0.0329 |
0.412 |
0.103 |
<LLQ (0.360) |
NA |
8419 |
571 |
4W spleen (200 ppm) |
0.410 |
0.0635 |
1.47 |
0.149 |
0.596 |
0.0433 |
27112 |
5936 |
|
|
|
|
|
||||
4W liver (0 ppm) |
0.518 |
0.797 |
<LLQ (0.364) |
NA |
<LLQ (0.349) |
NA |
<LLQ (6.84) |
NA |
4W liver (10 ppm) |
0.611 |
0.761 |
<LLQ (0.340) |
NA |
<LLQ (0.340) |
NA |
606 |
49 |
4W liver (50 ppm) |
0.214 |
0.193 |
<LLQ (0.307) |
NA |
<LLQ (0.307) |
NA |
2547 |
553 |
4W liver (100 ppm) |
0.0936 |
0.0224 |
0.351 |
0.0384 |
<LLQ (0.306) |
NA |
9255 |
2825 |
4W liver (200 ppm) |
0.193 |
0.0696 |
1.70 |
0.119 |
0.680 |
0.0380 |
31807 |
7392 |
|
|
|
|
|
||||
4W lung (0 ppm) |
0.0977 |
0.0160 |
<LLQ (0.448) |
NA |
<LLQ (0.448) |
NA |
4.74 |
1.61 |
4W lung (10 ppm) |
0.183 |
0.125 |
<LLQ (0.410) |
NA |
<LLQ (0.410) |
NA |
2342 |
1651 |
4W lung (50 ppm) |
0.140 |
0.0339 |
<LLQ (0.383) |
NA |
<LLQ (0.367) |
NA |
7285 |
3072 |
4W lung (100 ppm) |
0.234 |
0.0599 |
0.765 |
0.131 |
<LLQ (0.392) |
NA |
10769 |
1178 |
4W lung (200 ppm) |
0.848 |
0.540 |
2.84 |
0.330 |
1.19 |
0.0442 |
40766 |
1950 |
|
|
|
|
|
||||
8W lung (0 ppm) |
0.111 |
0.0251 |
<LLQ (0.585) |
NA |
<LLQ (0.585) |
NA |
|
|
8W lung (100 ppm) |
0.279 |
0.0207 |
2.03 |
0.163 |
1.02 |
0.132 |
Not Analyzed |
|
8W lung (200 ppm) |
1.02 |
0.0989 |
5.64 |
0.502 |
2.90 |
0.254 |
|
|
|
|
|
|
|||||
12W lung (0 ppm) |
0.179 |
0.164 |
<LLQ (0.403) |
NA |
<LLQ (0.403) |
NA |
|
|
12W lung (100 ppm) |
0.467 |
0.365 |
1.96 |
0.152 |
1.39 |
0.0897 |
Not Analyzed |
|
12W lung (200 ppm) |
0.743 |
0.118 |
6.97 |
1.79 |
4.27 |
0.540 |
|
LLQ = Lower limit of quantitation
Table 4: Summary of GSH-related biomarkers
Biomarke rs |
GSH Relate d Biomarke rs |
|||||||
LC/MS-MS assay |
Assay 3 |
|
||||||
Biomarke r types |
GSH |
GSSG |
HESG |
Ratio |
||||
Biomarke r level units |
µg/g tissue |
|||||||
Sample Name |
Average |
SD |
Ave rage |
SD |
Average |
SD |
GSH/GSSG |
HESG/GSH |
4W spleen (0 ppm) |
1001 |
84.2 |
35.8 |
7.75 |
LLQ< (8.37) |
NA |
28.0 |
NA |
4W spleen (10 ppm) |
958 |
100 |
27.8 |
4.47 |
5.24 |
0.975 |
34.5 |
0.0055 |
4W spleen (50 ppm) |
882 |
67.0 |
28.1 |
4.24 |
14.8 |
3.65 |
31.4 |
0.0168 |
4W spleen (100 ppm) |
894 |
37.3 |
26.4 |
2.33 |
39.7 |
16.6 |
33.9 |
0.0444 |
4W spleen (200 ppm) |
824 |
74.7 |
23.8 |
6.40 |
67.3 |
15.6 |
34.6 |
0.0817 |
|
|
|
|
|
|
|||
4W liver (0 ppm) |
2006 |
352 |
57.3 |
8.03 |
LLQ< (4.87) |
NA |
35.0 |
NA |
4W liver (10 ppm) |
1776 |
88.1 |
46.0 |
3.35 |
12.1 |
4.08 |
38.6 |
0.00683 |
4W liver (50 ppm) |
1879 |
219 |
52.7 |
11.4 |
57.7 |
13.1 |
35.7 |
0.0307 |
4W liver (100 ppm) |
1438 |
146 |
33.9 |
8.01 |
102 |
56.7 |
42.4 |
0.0710 |
4W liver (200 ppm) |
935 |
435 |
25.8 |
11.7 |
351 |
178 |
36.2 |
0.376 |
|
|
|
|
|
|
|||
4W lung (0 ppm) |
702 |
59.0 |
53.4 |
4.78 |
LLQ< (5.53) |
NA |
13.2 |
NA |
4W lung (10 ppm) |
717 |
29.5 |
41.8 |
3.16 |
14.3 |
3.75 |
17.1 |
0.020 |
4W lung (50 ppm) |
687 |
38.1 |
49.0 |
6.23 |
84.6 |
23.8 |
14.0 |
0.123 |
4W lung (100 ppm) |
590 |
40.6 |
38.8 |
6.15 |
206 |
69.8 |
15.2 |
0.349 |
4W lung (200 ppm) |
432 |
222 |
27.3 |
4.37 |
440 |
75.5 |
15.9 |
1.02 |
|
|
|
|
|
|
|||
8W lung (0 ppm) |
850 |
115 |
50.5 |
16.6 |
LLQ< (5.39) |
NA |
16.8 |
NA |
8W lung (100 ppm) |
661 |
114 |
51.3 |
19.4 |
131 |
27.6 |
12.9 |
0.198 |
8W lung (200 ppm) |
489 |
83.8 |
31.0 |
9.4 |
338 |
95.5 |
15.8 |
0.691 |
|
|
|
|
|
|
|||
12W lung (0 ppm) |
758 |
35.8 |
65.5 |
9.01 |
LLQ< (5.35) |
NA |
11.6 |
NA |
12W lung (100 ppm) |
603 |
54.9 |
49.6 |
6.67 |
107 |
20.1 |
12.2 |
0.177 |
12W lung (200 ppm) |
368 |
51.0 |
33.0 |
6.10 |
263 |
100 |
11.1 |
0.715 |
LLQ = Lower limit of quantitation
Applicant's summary and conclusion
- Conclusions:
- The test substance, when administered by inhalation (6 hours/day, 5 days/week) at exposure concentrations of 0, 10, 50, 100, or 200 ppm (4 weeks) or 0, 100, or 200 ppm (8 or 12 weeks), did not result in significant phenotypic apical alterations of the lung. This was demonstrated by a lack of both histopathological alterations and altered cell proliferation in terminal bronchioles as measured by Ki-67 nuclear antigen. Furthermore, reactive oxygen species-related adducts (i.e., biomarkers of effect: 8-OHdG, Croton dG, M1dG) were only minimally affected, whereas alkylated DNA adducts (i.e., biomarkers of exposure: O6-HEdG, N1-HEdA, N6-HEdA, and N7-HEG) were increased more robustly. There were no treatment-related changes in the MN-RET frequency or % RET. Comet analysis revealed a dose-dependent, statistically significant increase in %DNA in tail at 50 ppm and above. While a clear NOEL was identified for all apical endpoints examined, the molecular analyses reveal a complex biological outcome of inhalation
exposure to EO. - Executive summary:
The test substance, a reactive industrial chemical, is known to induce alveolar/bronchiolar adenomas and carcinomas in the lungs of B6C3F1 male mice at atmospheric concentrations of 50 and 100 ppm. Previous work has identified a specific mutation in the K-ras oncogene that appears to be associated with the tumors. The purpose of the current study was to investigate the mode of action (MoA) of these test substance-induced lung mutations in male B6C3F1 mice. Mice were exposed via whole body inhalation for 6 hours/day, five consecutive days/week, for 4, 8, or 12 weeks (a total of 20, 40, or 60 days of exposure, respectively) to target concentrations of 0, 10, 50, 100, or 200 ppm (4 weeks) or 0, 100, or 200 ppm (8 or 12 weeks). Tissues from these animals were examined for incidence of micronuclei in the
peripheral blood (MNT), DNA damage (Comet assay), histopathology of the lung, and characterization of DNA- and glutathione-adducts and lipid peroxidation in the tumor target and non-target tissues. In general, reactive oxygen species-related adducts (8-OHdG, CrotondG, M1dG) were only minimally affected, whereas alkylated DNA adducts (O6-HEdG, N1-HEdA, N6-HEdA, and N7-HEG) were increased more robustly. There was a dose-dependent increase in glutathione adducts (HESG) in all tissues, although severe GSH depletion was not noted. There were no treatment-related changes in the MN-RET
(reticulocyte) frequency or % RET. Comet analysis of the lung revealed a dose-dependent, statistically significant increase in DNA damage at 50 ppm and above. There were no treatment-related alterations in the lung at any concentration or exposure duration, and there was no consistent change in the proportion of Ki-67 positive cells in the terminal bronchioles of the animals examined. In summary, these observations revealed a complex sequela of biomarkers of exposure and effect following inhalation exposure to the test substance with a clear no observable effect level (NOEL) for all apical endpoints studied.
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