title: Comparison of the maximum tolerated dose (MTD) dermal response in three strains of mice following repeated exposure to acrylic acid.
abstract: The dermal response of three strains of mice (ICR, C3H and B6C3F1) exposed to repeated doses of 0, 1 or 4% acrylic acid was examined over 13 wk. Microscopic and gross changes to the skin were classified as being indicative of exceeding the maximum tolerated dose (MTD), reaching the MTD, or tolerating the dose based on proposed MTD guidelines established in US Environmental Protection Agency (EPA) Workshops on dermal carcinogenesis bioassays. A significant number of animals in all three strains with repeated exposure to 4% acrylic acid experienced skin irritation that was classified as having reached or exceeded the MTD compared with animals exposed to either 1% acrylic acid or the 0% acrylic acid acetone control. These results were observed within the first 3 wk of exposure, but there was some accommodation to irritation by 8 wk of exposure. Microscopic findings provided a more sensitive index for exceeding MTD than gross observations taken only at autopsy, but generally correlated well for MTD if gross observations were taken at regular intervals during treatment. That is, to set MTD, gross observations could be used if taken over the entire course of the exposure, but using microscopic findings was generally a more reliable or sensitive measure. EPA guidelines suggest that it is inappropriate to conduct a dermal bioassay at concentrations that exceed the MTD. Acrylic acid at 4% in acetone clearly exceeded the MTD based on microscopic or gross observation criteria. At 4%, strain differences were evident by gross observation only, with the ICR strain being less susceptible to irritation than C3H or B6C3F1 strains. These strain differences were not apparent with microscopic examination. Acrylic acid at 1% in acetone, although demonstrating signs of minimal irritation, was fairly well tolerated by all mice in all strains. Thus, acrylic acid at 1% in acetone, one-quarter of the concentration that was in clear excess of the MTD, would be the appropriate dose concentration for lifetime skin studies based on MTD criteria.
authors.affiliation: Rohm and Haas Company, Spring House, PA 19477-0904, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: McLaughlin
authors.forename: J
authors.initials: J
authors.lastname: Parno
authors.forename: F M
authors.initials: FM
authors.lastname: Garner
authors.forename: J J
authors.initials: JJ
authors.lastname: Clary
authors.forename: W C
authors.initials: WC
authors.lastname: Thomas
authors.forename: S R
authors.initials: SR
authors.lastname: Murphy
mesh_terms: D000179:Acrylates / Q000633:toxicity*; D000287:Administration, Topical; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012882:Skin Tests; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000179:Acrylates; C036658:acrylic acid