Preclinical safety assessment in rats after dermal exposure to acetylcarvacrol, a potential acaricide against the brown dog tick

Abstract

Carvacrol, a phenolic monoterpene found in essential oils of plants of the Lamiaceae family, emerges as an alternative acaricide of plant origin. Its acetylation was proposed to obtain a derivative compound with a better pharmacological profile and lower toxicity to non-target organisms. The present study aimed to assess the preclinical safety of acetylcarvacrol after dermal application in Wistar rats, through the examination of hematological and biochemical parameters, as well as histopathological analysis of the skin, liver and kidney. For this, twenty rats were distributed into four groups with five animals each. Three groups received treatment with different concentrations of the substance (26, 52, and 104 µL/mL) based on the lethal concentration for Rhipicephalus sanguineus ticks, and one group (Control) received only the vehicle. Acetylcarvacrol was applied daily to a trichotomized skin area for 21 days. No changes in hematological parameters were observed. Regarding biochemical analysis, a slight increase in urea and alanine transaminase levels was noted. No significant changes were observed in the kidney and liver, although the rats had developed cumulative irritant contact dermatitis at the application site, as corroborated by the histopathological analysis of the skin. In general, the results showed that the dermal application of acetylcarvacrol in the experimental conditions described here is safe. However, it can cause signs of mild systemic toxicity and skin irritation at high concentrations, suggesting that this product should be used in lower therapeutic doses and that the development of less aggressive formulations, including the combination with other acaricides, is desirable.

Keywords: Acaricide; Dermal toxicity; Semi-synthetic; Tick control.

Graphical abstract

Fig. 1

Appearance of the animals' skin at the conclusion of the experiment. It is noted that the occurrence of skin irritation was dose-dependent, compared to the control group. (A) Control Group (DMSO 5 %); (B) T1 Group; (C) T2 Group; (D) T3 Group.

Fig. 2

Photomicrographs of the skin of Wistar rats subjected to a repeated dose dermal toxicity test with acetylcarvacrol exposure over a 21-day period, stained with hematoxylin-eosin. (A-B) Control Group; (C-D) Treatment Group 1–26 µL/mL; (E-F) Treatment Group 2–52 µL/mL; (G-H) Treatment Group 3–104 µL/mL. Legends: (d) dermis; (eh) epidermal hyperplasia; (epi) epidermis; (hf) hair follicle; (hk) hyperkeratosis; (hsg) hyperplasic sebaceous gland; (pk) parakeratosis; (sc) stratum corneum; (sg) sebaceous gland. Scale bars: (A-H) 50 µm.

Fig. 3

Photomicrographs of the liver (A-D) and kidney (E-H) of Wistar rats subjected to a repeated dose dermal toxicity test with acetylcarvacrol exposure over a 21-day period, stained with hematoxylin-eosin. (A, E, F) Control Group; (B) Treatment Group 1–26 µL/mL; (C) Treatment Group 2–52 µL/mL; (D, G, H) Treatment Group 3–104 µL/mL. Legends: (bc) Bowman capsule; (cbv) congested blood vessel; (ct) convoluted tubules; (dct) distal convoluted tubule; (ds) dilated sinusoid; (dus) dilated urinary space; (gl) glomerulus; (hep) hepatocyte; (pct) proximal convoluted tubule; (rc) renal corpuscle; (sin) sinusoid; (us) urinary space. Scale bars: (A-D, F, H) 50 µm; (E, G) 200 µm.