{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:40:43Z","timestamp":1779932443926,"version":"3.53.1"},"reference-count":12,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T00:00:00Z","timestamp":1566864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Amphastar Pharmaceuticals Inc."}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Epinephrine HFA (Primatene<jats:sup>\u00ae<\/jats:sup> Mist) is a newly formulated asthma metered dose inhaler developed to replace the previous Primatene<jats:sup>\u00ae<\/jats:sup> Mist CFC. The formulation of Epinephrine HFA contains thymol, a substance recognized to be safe by the FDA. Although the content of thymol contained in Epinephrine HFA is much lower compared to many common foods and medications available, there are no known nonclinical data about the <jats:italic>chronic toxicity<\/jats:italic> of thymol through inhalation. Two sequential 6\u2010month studies of identical design were conducted to assess the chronic toxicity of inhaled thymol in mice. Four treatment groups, (a) Air; (b) vehicle control; (c) Article\u20101 (thymol 0.1%); and (d) Article\u20102 (thymol 0.5%) were assessed in 128 mice for 26\u00a0weeks. The mice were sacrificed at the end of the treatment period and a histopathologic evaluation was performed with respect to lungs, bronchial lymph nodes, nasal passages\/nasopharynx, and trachea. Forty\u2010five pathologic assessment parameters (PAPs) were evaluated. In total, 5591 data points from 487 mouse organs were assessed. Chronic toxicity index was calculated for 16 PAPs that had multiple histopathologic abnormal observations. The <jats:italic>t<\/jats:italic> tests were conducted for these 16 PAPs (Articles\u20101 and 2 versus Air and vehicle control, respectively), and all <jats:italic>P<\/jats:italic>\u2010values were greater than .05 indicating no significant differences between all treatment groups. An evaluation was also conducted for 25 PAPs that had only a very small number of pathologic abnormalities. No significant differences for chronic toxicity were found when comparing mice under long\u2010term repeated exposure of high doses of inhaled thymol and mice that inhaled no thymol.<\/jats:p>","DOI":"10.1002\/prp2.516","type":"journal-article","created":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T13:27:12Z","timestamp":1566912432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Chronic toxicity of inhaled thymol in lungs and respiratory tracts in mouse model"],"prefix":"10.1002","volume":"7","author":[{"given":"Kevin","family":"Xie","sequence":"first","affiliation":[{"name":"Amphastar New Drug Research Center (NDRC) Chino CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald P.","family":"Tashkin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine University of California at Los Angeles Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Z.","family":"Luo","sequence":"additional","affiliation":[{"name":"Amphastar Pharmaceuticals, Inc. Rancho Cucamonga CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2524-5074","authenticated-orcid":false,"given":"Jack Y.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Amphastar Pharmaceuticals, Inc. Rancho Cucamonga CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,27]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"The Montreal Protocol on Substances that Deplete the Ozone Layer.http:\/\/ozone.unep.org\/new_site\/en\/montreal_protocol.php. (Accessed April 29 2015)."},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-6264(64)80192-9"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-6264(67)82961-4"},{"key":"e_1_2_11_5_1","unstructured":"Federal Register.January 18 2006. Thymol; Exemption from the Requirement of a Tolerance. Rules and Regulations.71(11):2891."},{"key":"e_1_2_11_6_1","volume-title":"Assessing Toxic Risk: Student Edition","author":"Trautmann NM","year":"2001"},{"key":"e_1_2_11_7_1","unstructured":"EPA.1993.RED facts: Thymol. EPA-738-F-93\u2013011. Washington (DC): Office of Prevention Pesticides and Toxic Substances United States Environmental Protection Agency.https:\/\/archive.epa.gov\/pesticides\/reregistration\/web\/pdf\/3143fact.pdf. (Accessed June 8 2015)."},{"key":"e_1_2_11_8_1","unstructured":"USEPA; Biopesticide Registration Action Document THYMOL 5-methyl-2-isopropyl-1-phenol (PC Code080402) March 23 2006.https:\/\/www3.epa.gov\/pesticides\/chem_search\/reg_actions\/registration\/decision_PC-080402_23-Mar-06.pdf. (Accessed August 9 2019)."},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13059"},{"key":"e_1_2_11_10_1","volume-title":"Animal Models in Toxicology","author":"Gad SC","year":"1992"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2003.01893.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200410-1414OC"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000363390"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fprp2.516","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.516","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.516","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.516","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T12:41:12Z","timestamp":1694263272000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.516"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,27]]},"references-count":12,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1002\/prp2.516"],"URL":"https:\/\/doi.org\/10.1002\/prp2.516","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,27]]},"assertion":[{"value":"2019-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00516"}}