Integumentary System

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

“…In this study, it was confirmed that the preparation and application procedures employed in the percutaneous dose toxicity studies induced acanthosis and inflammatory cell infiltration in the dermis as the main change common to dogs, rabbits and rats. Application of irritant substances causes a variety of histological changes, such as erosion or ulcer, and inflammation that ranges in severity 3 , 10 . However, when the intensity of the irritant is mild or moderate, the epidermis does not erode but instead shows reactive changes including hyperkeratosis and acanthosis 3 .…”

“…In recent years, the forms of formulations of existing drugs have shifted to external preparations, as percutaneous administration of drugs has many advantages such as few adverse effects and convenience for medication and maintenance of blood concentrations 1 , 2 . As a part of the toxicological evaluation of pharmaceutical agents (external preparations) and cosmetics, repeated dose toxicity studies by percutaneous administration including cumulative skin irritation studies in rabbits are conducted to investigate general or local toxicity 3 . In skin irritancy studies, it is well known that inflammation may be seen focally in controls where skin abrasion techniques have been employed 3 .…”

“…As a part of the toxicological evaluation of pharmaceutical agents (external preparations) and cosmetics, repeated dose toxicity studies by percutaneous administration including cumulative skin irritation studies in rabbits are conducted to investigate general or local toxicity 3 . In skin irritancy studies, it is well known that inflammation may be seen focally in controls where skin abrasion techniques have been employed 3 . In nonclinical safety studies of developing pharmaceuticals, a few reports described the presence of cellular infiltration or squamous cell hyperplasia in the skin of control animals that have received percutaneous application of vehicle 4 , 5 , while some reports described the absence of lesions in the skin of controls 6 , 7 , 8 , 9 .…”

Injection-site Malignant Fibrous Histiocytomas in a Pegvisomant Carcinogenicity Study in SD Rats

“…Concentrated solutions of glucose, other sugars, sodium chloride, food colorings, carboxymethylcellulose, high molecular weight dextrans, iron dextran, and surfactants that are not considered carcinogenic in humans can produce injection-site sarcomas in rodents when injected subcutaneously over long periods of time. Materials such as pegvisomant that produce relatively low numbers of neoplasms at injection sites without producing neoplasia in other tissues following prolonged repeated SC administration often are attributed to injection-site inflammation, tissue damage, prominent macrophage response (histiocytic infiltrates), and fibrosis (Greaves 2012). It is also worth noting that in the 26-week SC toxicology study in rats, vacuolated macrophages were observed at injection sites with high incidences and this finding was considered to be a nonspecific inflammatory reaction caused by repeated SC injections of high concentrations of pegvisomant.…”

“…Other nongenotoxic chemicals, inert biomaterials, and plant extracts can produce mesenchymal neoplasms (fibrous histiocytoma and sarcomas) in rats at the site of SC injection or implantation (Greaves 2012;Greaves and Baroum 1990). Concentrated solutions of glucose, other sugars, sodium chloride, food colorings, carboxymethylcellulose, high molecular weight dextrans, iron dextran, and surfactants that are not considered carcinogenic in humans can produce injection-site sarcomas in rodents when injected subcutaneously over long periods of time.…”