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. 2015 Jan;28(1):1-9.
doi: 10.1293/tox.2014-0021. Epub 2014 Aug 8.

Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats

Mikio Mitsuishi  1 , Takafumi Oshikata  1 , Shino Kumabe  2 , Azusa Kobayashi  1 , Koshiro Katoku  1 , Takeshi Kanno  1 , Masao Hamamura  1 , Minoru Tsuchitani  2
Affiliations

Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats

Mikio Mitsuishi et al. J Toxicol Pathol. 2015 Jan.

Erratum in

  • Errata (Printer's correction).
    [No authors listed] [No authors listed] J Toxicol Pathol. 2016 Jan;29(1):74. Epub 2016 Feb 17. J Toxicol Pathol. 2016. PMID: 26989306 Free PMC article.

Abstract

We reevaluated histological slides of dorsal skin in control animals from past percutaneous dose toxicity studies using dogs, rabbits and rats to provide background data concerning histological changes related to preparation and application procedures and vehicles or embrocations of every variety. Acanthosis, dermal or perifollicular inflammatory cell infiltration in dogs; hyperkeratosis, acanthosis, dermal inflammatory cell infiltration or hemorrhage in rabbits; and acanthosis, dermal inflammatory cell infiltration, crust or foreign body granuloma in rats were present as procedure-related underlying histological changes in the control animals. Four mechanical acts, (1) rubbing with gauze to remove an administered substance for reapplication, (2) use of a taut bandage to avoid slipping from the application site, (3) peeling a patch off as a preparation procedure for reapplication, and (4) clipping or shaving, were considered to cause injury to the skin. The degree of influence of the various application procedures was found to be as follows: sham, lotion < cream < ointment and tape in dogs; untreated control, sham < lotion < tape and poultice in rabbits; and sham, sodium carboxymethylcellulose < olive oil and lotion < ointment and tape in rats. The degree of ointment influence on rabbits is equivocal.

Keywords: acanthosis; dermal toxicity; dog; percutaneous dose toxicity; rabbit; rat.

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Figures

Fig. 1.
Fig. 1.
Photomicrographs showing the histopathology of the skin in dogs. A: Normal appearance of the epithelium in the dog of the sham group. Bar = 100 μm. B, C and D: Minimal (B), mild (C) and moderate (D) acanthosis of the dogs applied cream, tape and tape, respectively. The follicular epithelium is also hyperplastic (arrow). Bar = 100 μm. E: Normal appearance of the dermis in the dog of the sham group. Bar = 50 μm. F, G: Minimal (F) and mild (G) inflammatory cell infiltration in the dermis of the dogs applied ointment. The neutrophils are prominent. Bar = 50 μm. H: Normal appearance of the perifollicular area in the dog of the sham group. Bar = 50 μm. I, J: Minimal (I) and mild (J) perifollicular inflammatory cell infiltration of the dogs applied ointment. Bar = 50 μm.
Fig. 2.
Fig. 2.
Photomicrographs showing the histopathology of the skin in rabbits. A: Normal appearance of the epithelium in the rabbit of the sham group. Bar = 200 μm. B, C and D: Minimal (B), mild (C) and moderate (D) acanthosis of the rabbits applied tape, poultice and poultice, respectively. Bar = 200 μm. E: Normal appearance of the dermis in the rabbit of the sham group. Bar = 50 μm. F, G and H: Minimal (F), mild (G) and moderate (H) inflammatory cell infiltration in the dermis of the rabbits applied tape, poultice and poultice, respectively. The pseudoeosinophils are visible. Bar = 50 μm. I: Minimal hemorrhage in the dermis of the rabbit applied tape. Bar = 50 μm. J, K: Mild hemorrhage in the dermis of the rabbit applied tape. Photographs show the same area with low (J, Bar = 100 μm) and high (K, Bar = 50 μm) magnification.
Fig. 3.
Fig. 3.
Photomicrographs showing the histopathology of the skin in rats. A, D: Normal appearances of the epithelium in the male (A) and female (D) rats of the sham group. Bar = 100 μm. B, C: Minimal (B) and mild (C) acanthosis of the male rats applied tape. Bar = 100 μm. E, F: Minimal (E) and mild (F) acanthosis of the female rats of the sham and tape groups, respectively. Bar = 100 μm. G: Normal appearance of the dermis in the rat of the sham group. Bar = 50 μm. H, I: Minimal (H) and mild (I) inflammatory cell infiltration of the rats applied tape. Bar = 50 μm. J: Foreign body granuloma in the deep dermis of the rat applied ointment. Note the hair fragments (arrows) in the center of the granuloma. Bar = 100 μm.
Fig. 4.
Fig. 4.
Bar graphs showing the mean score of each finding in dogs (A), rabbits (B) and rats (C). The bars for the mean scores of each finding are stacked for each group. M, male; F, female; W, weeks; UC, untreated control; Sh, Sham treatment; Lo, lotion; Oi, ointment; Ta, tape; Po, poultice; CMC, CMC-Na; Ol, olive oil.
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