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Dose-Response Assessment of the Dermal Toxicity of Virginia Cedarwood Oil in F344/N Rats and B6C3F1/N Mice

Catlin NR, Herbert R, Janardhan K, Hejtmancik MR, Fomby LM, Vallant M, Kissling GE, DeVito MJ.
Food Chem Toxicol. (2016) DOI: http:/dx.doi.org/10.1016/j.fct.2016.10.016 PMID: 27769849


Publication


Abstract

Virginia cedarwood oil is widely used as a fragrance material in household and personal products and as a naturally derived pesticide alternative. Due to conflicting literature on dermal exposures in animals and humans, concern for safe levels of human exposure remains. The present study evaluated the toxicity of cedarwood oil applied dermally to F344/N rats and B6C3F1/N mice for 13 weeks. Groups of 10 male and female rats and mice received no treatment (untreated control) or were administered cedarwood oil in 95% aqueous ethanol dermally at concentrations ranging from 0% (vehicle control), 6.25%, 12.5%, 25%, 50%, and 100% (undiluted). Rats and mice developed extensive skin lesions at the site of application. Benchmark dose modeling (BMD) was performed for the significantly increased skin lesions observed in the rat, to provide perspective for risk assessment applications. Benchmark dose modeling levels (BMDL) of 0.65 to 2.1% and 1.2 to 4.4% (equivalent to 13 to 42 mg/kg and 24 to 48 mg/kg, respectively) cedarwood oil were calculated for the most sensitive endpoint of epidermal hyperplasia in female rats and chronic active inflammation in male rats, respectively. These BMDL levels coincide with reported use levels in cosmetics and pesticides, raising the concern for human exposure.

Figures


Figure 1. Hematoxylin and Eosin stained histologic sections from F344/N rats

Hematoxylin and Eosin stained histologic sections showing the histopathology of lesions in the skin (site of application) from F344/N rats dermally administered 0%, 6.25%, 12.5%, 25%, 50% or 100% Virginia cedarwood oil for 3 months. A. Normal skin, vehicle control (95% ethanol) female. The epidermis (arrowheads) is composed of a 1 to 2 layers of epithelial cell; hair follicles (short arrows); sebaceous glands (sg); dermis (de); subcutaneous tissue (sc). B. Minimal epidermal hyperplasia (thickening) of the epidermis (arrowheads). C. Minimal hyperkeratosis (arrows); minimal sebaceous gland hyperplasia. Note that there is also mild epidermal hyperplasia. D. Moderate hair follicle hyperplasia (short arrows); moderate sebaceous gland hyperplasia (sg). Note that there is also moderate epidermal hyperplasia and also infiltrates of inflammatory cells within the dermis. E. Marked hyperkeratosis (arrows); marked hair follicle hyperplasia (short arrows); marked sebaceous gland hyperplasia. Note that there is also marked epidermal hyperplasia and marked fibrosis throughout the dermis (de). F. Marked hyperkeratosis (arrows); focal ulcers (ul); moderate sebaceous gland hyperplasia. All images, 5× original objective.

Figure 2. Hematoxylin and Eosin stained histologic sections from B6C3F1 mice

Hematoxylin and Eosin stained histologic sections showing the histopathology of lesions in the skin (site of application) from B6C3F1 mice dermally administered 0%, 6.25%, 12.5%, 25%, 50% or 100% Virginia cedarwood oil for 3 months. A. Normal skin, vehicle control (95% ethanol) female. Epidermis (arrowheads); dermis (de); subcutaneous tissue (sc). B. Mild epidermal hyperplasia (thickening) of the epidermis (arrowheads) and mild hair follicle hyperplasia (short arrow). C, D, E & F. Moderate epidermal hyperplasia (arrowhead) and hyperkeratosis (arrows); moderate hair follicle hyperplasia (short arrow); mild sebaceous gland hyperplasia (sg); moderate dermal (de) fibrosis; focal ulcer (ul). All images, 5× original objective.

Tables


Table 1. Survival and body weights of F344/N Rats and B6C3F1/N Mice in the 90 day dermal study

Survival and body weights of F344/N Rats and B6C3F1/N Mice in the 90 day dermal study of cedarwood oil.

Table 2. Time to first incidence of clinical observations at the skin site of observation

Time to first incidence of clinical observations at the skin site of observation in F344/N rats and B6C3F1/N Mice in the 90 day dermal study of cedarwood oil.

Table 3. Incidence and severity of non-neoplastic lesions at the Skin Site of Application

Incidence and severity of non-neoplastic lesions at the Skin Site of Application in F344/N Rats and B6C3F1/N Mice in the 90 day dermal study of cedarwood oil.

Table 4. Benchmark dose modeling (% cedarwood) of the final mean bodyweights

Benchmark dose modeling (% cedarwood) of the final mean bodyweights of male and female F344 rats and B6C3F1/N mice dermally administered cedarwood oil for 13 weeks.

Table 5. Benchmark dose modeling best-fit models (% cedarwood)

Benchmark dose modeling best-fit models (% cedarwood) of the most sensitive non-neoplastic dermal lesions in male and female F344 rats dermally administered cedarwood oil for 13 weeks.

Supplemental Materials


Supplemental Data