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Target Organs and Levels of Evidence for TR-440

Toxicology and Carcinogenesis Studies of Ozone (CASRN 10028-15-6) and Ozone/NNK (CASRN 10028-15-6/64091-91-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies)

Chemical (Study Title) CASRN	Peer Review Date	Route/Exposure Levels	Study Laboratory
Ozone 10028-15-6	11/16/1993	Inhalation R&M: 0, 0.12, 0.5, OR 1.0 PPM (50/SEX/SPECIES/GROUP)	Battelle Northwest Laboratory

Levels of Evidence

Male Rats: No Evidence

Type	Organ/Tissue (Lesion)
Non-Neoplastic Lesions	NOSE: (2 YR. STUDY) GOBLET CELL AND LATERAL WALL HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (2 YR. STUDY) SQUAMOUS METAPLASIA LUNG: (2 YR. STUDY) METAPLASIA; INTERSTITIAL FIBROSIS

Female Rats: No Evidence

Type	Organ/Tissue (Lesion)
Non-Neoplastic Lesions	NOSE: (2 YR. STUDY) GOBLET CELL AND LATERAL WALL HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (2 YR. STUDY) SQUAMOUS METAPLASIA LUNG: (2 YR. STUDY) METAPLASIA; INTERSTITIAL FIBROSIS

Male Mice: Equivocal Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Lung: (2 YR. STUDY) AVEOLAR/BRONCHIOLAR ADENOMA 6/50 9/50 12/50 11/50 OR ALVEOLAR/BRONCHIOLAR CARCINOMA 8/50 4/50 8/50 10/50 COMBINED 14/50 13/50 18/50 19/50
Non-Neoplastic Lesions	NOSE: (2 YR. STUDY) HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (2 YR. STUDY) HYPERPLASIA LUNG: (2 YR. STUDY) HISTIOCYTIC INFILTRATION; METAPLASIA

Female Mice: Some Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Lung: (2 YR. STUDY) ALVEOLAR/BRONCHIOLAR ADENOMA 4/50 5/50 5/49 8/50 OR ALVEOLAR/BRONCHIOLAR CARCINOMA 2/50 2/50 5/49 8/50 COMBINED 6/50 7/50 9/49 16/50
Non-Neoplastic Lesions	NOSE: (2 YR. STUDY) HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (2 YR. STUDY) HYPERPLASIA LUNG: (2 YR. STUDY) HISTIOCYCTIC INFILTRATION; METAPLASIA

Chemical (Study Title) CASRN	Peer Review Date	Primary Uses	Route/Exposure Levels	Study Laboratory
Ozone 10028-15-6	11/16/1993	Pollution control, waste treatment, chemical synthesis, sterilization where residuals of other chemicals would be objectionable, odor control, bleaching waxes, clay, textiles, paper pulp, oils, control of algae, mold, and bacteria. Associated with tobacco: reported either as a natural component of tobacco, pyrolysis product (in tobacco smoke), or additive for one or more types of tobacco products.	Inhalation R&M: 0, 0.5, OR 1.0 PPM (50/SEX/SPECIES/GROUP)	Battelle Northwest Laboratory

Levels of Evidence

Male Rats: No Evidence

Type	Organ/Tissue (Lesion)
Non-Neoplastic Lesions	NOSE: (LIFETIME STUDY) GOBLET CELL AND LATERAL WALL HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (LIFETIME STUDY) SQUAMOUS METAPLASIA LUNG: (LIFETIME STUDY) METAPLASIA; HISTIOCYTIC INFILTRATION; INTERSTITIAL FIBROSIS

Female Rats: No Evidence

Type	Organ/Tissue (Lesion)
Non-Neoplastic Lesions	NOSE: (LIFETIME STUDY) GOBLET CELL AND LATERAL WALL HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (LIFETIME STUDY) SQUAMOUS METAPLASIA LUNG: (LIFETIME STUDY) METAPLASIA; HISTIOCYTIC INFILTRATION; INTERSTITIAL FIBROSIS

Male Mice: Equivocal Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Lung: (LIFETIME STUDY) ALVEOLAR/BRONCHIOLAR ADENOMA 8/49 8/49 9/50 OR ALVEOLAR/BRONCHIOLAR CARCINOMA 8/49 15/49 18/50 COMBINED 16/49 22/49 21/50
Non-Neoplastic Lesions	NOSE: (LIFETIME STUDY) HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (LIFETIME STUDY) HYPERPLASIA; SQUAMOUS CELL METAPLASIA LUNG: (LIFETIME STUDY) HISTIOCYTIC INFILTRATION; METAPLASIA

Female Mice: Some Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Lung: (LIFETIME STUDY) ALVEOLAR/BRONCHIOLAR ADENOMA 3/50 3/49 11/50 OR ALVEOLAR/BRONCHIOLAR CARCINOMA 3/50 5/49 2/50 COMBINED 6/50 8/49 12/50
Non-Neoplastic Lesions	NOSE: (LIFETIME STUDY) HYPERPLASIA; SQUAMOUS METAPLASIA LARYNX: (LIFETIME STUDY) HYPERPLASIA; SQUAMOUS CELL METAPLASIA LUNG: (LIFETIME STUDY) HISTIOCYTIC INFILTRATION; METAPLASIA

Chemical (Study Title) CASRN	Peer Review Date	Primary Uses	Route/Exposure Levels	Study Laboratory
Ozone/NNK OZONNNKCOMB	11/16/1993	Byproduct of tobacco smoke. Associated with tobacco: reported either as a natural component of tobacco, pyrolysis product (in tobacco smoke), or additive for one or more types of tobacco products.	Inhalation MALE RATS ONLY: 0, 0.5 PPM OZONE WITH 0, 0.1, 1.0 MG/KG NNK BY S.C. INJECTION (20 WEEKS ONLY)	Battelle Northwest Laboratory

Levels of Evidence

Type	Organ/Tissue (Lesion)
Note	IN A COCARCINOGENICITY STUDY, OZONE DID NOT ENHANCE NNK-INDUCED PULMONARY NEOPLASMS IN MALE RATS