{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:00:37Z","timestamp":1777914037492,"version":"3.51.4"},"reference-count":21,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2018,7,22]],"date-time":"2018-07-22T00:00:00Z","timestamp":1532217600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>Benzonatate is a peripheral oral antitussive that dampens the activity of cough stretch receptors. Rodent carcinogenicity studies were performed in Tg.rasH2 mice and Wistar Han rats. Mice were orally gavaged benzonatate at 10, 30, 75, and 100 mg\/kg\/day for males and 5, 15, and 50 mg\/kg\/day for females. Rats were gavaged at 10, 30, and 90 mg\/kg\/day for males and 5, 15, and 50 mg\/kg\/day for females. Higher doses in males were due to differences in maximum tolerated doses in dose-ranging studies. In both species, benzonatate was not detected in plasma because of rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol polymer. This metabolism was similar in human plasma; therefore, plasma BBA was used to show systemic exposure. Both species had no evidence of a benzonatate-related increase in any neoplasm. A slight increase in nasal cavity exudative inflammation was present in benzonatate-dosed male mice. Retinal atrophy was observed in male rats at \u226530 mg\/kg\/day, but the incidence was within historical control data range and not related to benzonatate. In conclusion, benzonatate and its 2 major metabolites were not carcinogenic in rodent carcinogenicity studies at BBA exposures of \u226532 and 70 times a 200 mg human benzonatate dose, respectively.<\/jats:p>","DOI":"10.1177\/0192623318789130","type":"journal-article","created":{"date-parts":[[2018,7,23]],"date-time":"2018-07-23T01:01:53Z","timestamp":1532307713000},"page":"683-692","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["The Antitussive Benzonatate Is Not Tumorigenic in Rodent Carcinogenicity Studies"],"prefix":"10.1177","volume":"46","author":[{"given":"Steve","family":"Teo","sequence":"first","affiliation":[{"name":"Pfizer Inc., Madison, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhav","family":"Paranjpe","sequence":"additional","affiliation":[{"name":"MilliporeSigma BioReliance\u00ae Toxicology Services, Rockville, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Mckeon","sequence":"additional","affiliation":[{"name":"MilliporeSigma BioReliance\u00ae Toxicology Services, Rockville, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Mann","sequence":"additional","affiliation":[{"name":"Experimental Pathology Laboratories, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Lee","sequence":"additional","affiliation":[{"name":"Covance Labs, Madison, Wisconsin, USA"},{"name":"TaiGen Biotechnology, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"LaRock","sequence":"additional","affiliation":[{"name":"Covance Labs, Madison, Wisconsin, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Brown","sequence":"additional","affiliation":[{"name":"Pfizer Inc., Drug Safety Research and Development, Groton, Connecticut, USA"},{"name":"Clemson Veterinary Diagnostic Lab, Columbia, South Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2018,7,22]]},"reference":[{"key":"bibr1-0192623318789130","doi-asserted-by":"publisher","DOI":"10.2174\/187231209788654081"},{"key":"bibr2-0192623318789130","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0022-3565(25)03614-6","volume":"94","author":"Brodie B.","year":"1948","journal-title":"J Pharmacol Exp Ther"},{"key":"bibr3-0192623318789130","first-page":"94","volume":"86","author":"Bucher K.","year":"1956","journal-title":"Schweizerische Medizin Wochen"},{"key":"bibr4-0192623318789130","unstructured":"CFR. 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