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CLINIC AND SURGERY • Cienc. Rural 55 (4) • 2025 • https://doi.org/10.1590/0103-8478cr20240220 linkcopy

Open-access Cutaneous adverse drug reaction associated with topical use of benzyl benzoate in a dog

Reação cutânea adversa a fármaco associado ao uso tópico de benzoato de benzila em um cão

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

ABSTRACT:

Cutaneous adverse drug reactions (CADR) are unexpected dermatological reactions caused by medications. CADRs may mimic any type of dermatosis, including contact dermatitis (CD). This paper described a case of a CADR resulting from the topical use of benzyl benzoate in a dog. A two year old unneutered male Pit Bull was referred for a medical consultation due to skin lesions in the cervical region. The owner reported bathing this dog routinely using 10% benzyl benzoate (BB)-based scabicidal soap, without rinsing it off at the end. An ulcerative, draining maculopapular skin lesion was observed in the dorsal region of the neck extending to the interscapular region. A surgical skin biopsy was then performed and microscopically an area of ulcerated epidermis was observed with apoptosis of transepidermal keratinocytes associated with a mixed infiltrate. Interface dermatitis with a predominance of lymphocytes in the hair follicle region, multifocal areas of mild spongiosis, mild vacuolar degeneration of keratinocytes and sub-corneal pustule was also identified. Bathing with the BB-based scabicidal soap was discontinued and a new shampoo was introduced. Topical dexamethasone, neomycin sulfate, bacitracin zinc, griseofulvin, and benzocaine treatment was started. Within 48 hours of treatment, skin revitalization was already significant and total healing took place approximately three weeks after the first appointment. Considering the findings observed in this case, it can be concluded that prolonged topical exposure to BB, due to misuse of the product, may cause a CADR characterized by irritant CD in dogs.

Key words:
canine; dermatopathy; microscopy; sarnicidal soap; skin biopsy

RESUMO:

As reações cutâneas adversas a fármacos (RCAF) são manifestações dermatológicas inesperadas causadas por diferentes tipos de medicamentos. As RCAFs podem mimetizar qualquer tipo de dermatose, incluindo dermatite de contato (DC). Este relato tem como objetivo descrever um caso de RCAF resultante do uso tópico de benzoato de benzila em um cão. Um cão da raça Pit Bull, macho, não castrado, de dois anos de idade, foi encaminhado para consulta médica devido a lesões de pele na região cervical. O tutor revelou dar banho em seu cão, de forma rotineira, utilizando sabonete escabicida à base de benzoato de benzila a 10%, sem o enxaguar no final. No exame físico observou-se lesão cutânea maculopapular ulcerativa e drenante, na região dorsal do pescoço, estendendo-se até a região interescapular. Foi realizada biópsia incisional da pele e microscopicamente observou-se área de epiderme ulcerada com apoptose de queratinócitos transepidérmicos associada a infiltrado misto. Observou-se dermatite de interface com predomínio de linfócitos na região do folículo piloso, áreas multifocais de espongiose, leve degeneração vacuolar de queratinócitos e pústulas subcórneas. O banho com sabonete escabicida à base de BB foi descontinuado e um novo shampoo foi introduzido. Foi iniciado tratamento tópico com dexametasona, sulfato de neomicina, bacitracina-zinco, griseofulvina e benzocaína. Em 48 horas de tratamento, a revitalização da pele já era significativa e a cicatrização total ocorreu em aproximadamente três semanas após a primeira consulta. Pode-se concluir que a exposição tópica prolongada ao BB, devido ao uso indevido do produto, pode causar uma RCAF caracterizada por DC irritativa em cães.

Palavras-chave:
canino; dermatopatia; microscopia; sabonete sarnicida; biópsia cutânea

Cutaneous adverse drug reactions (CADR) are unexpected dermatological reactions caused by medications (SCOTT et al., 2013). These are present in different species of domestic animals and have been reported in dogs, cats and horses, as well as humans (SCOTT & MILLER, 1999; VOIE et al., 2012; TIAN et al., 2015; YOUNG et al., 2018; BRAGA et al., 2021). Its pathogenesis is diverse and may involve predictable not immune-mediated processes (irritative) or unpredictable immune-mediated responses (idiosyncratic, allergic and intolerance) that depend on previous sensitization and individual response (TEO & WALSH, 2016). CADR may be caused by any drug, whether systemic or topical, and are rare in dogs, with an incidence rate of approximately 2% (SCOTT et al., 2013; HOETZENECKER et al., 2016). CADR may mimic any type of dermatosis, including contact dermatitis (CD), erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, among others, which vary based on epidemiological, clinical-pathological and pathogenetic aspects (HO et al., 2015; MURAYAMA et al., 2008; YAGER, 2014).

Reports of CADR are scarce, and definitive diagnosis of CADR is often complex, especially when epidemiological and clinical information is limited. It is usually necessary to exclude other etiologies, and there is little information on specific tests for a definitive diagnosis, which makes its therapeutic management quite challenging (ROYAUX et al., 2016; SIMPSON et al, 2020; BRAGA et al., 2021; THAM et al., 2022). No reports were found in the literature about CADR resulting from the use of benzyl benzoate (BB) in dogs. This paper described a case of a CADR resulting from the topical use of benzyl benzoate in a dog.

A two year old unneutered male Pit Bull was referred for a medical consultation for dull coat and coarse skin in the cervical region. The patient had a previous history of skin lesions, with no definitive diagnosis, most of which were treated by the owner at home with recurring baths of varying frequency and a healing spray when skin lesions were observed. During the consultation, it was mentioned that no other type of oral or topical medication was used on an ongoing basis and that the dog was routinely bathed with a 10% benzyl benzoate (BB)-based scabicidal soap, without rinsing it off afterwards, leaving the product to dry in the open air. According to the owner, the patient was uncomfortable and restless after this procedure. Approximately two weeks before consultation, small sores on the skin of the dog’s back were observed, in association with redness and itching, which encouraged the owner to bathe the dog again. The soap was used again without further rinsing and left on the patient until it dried. Since the dog immediately began to feel itchy and uncomfortable, the owner decided to wash the skin lesions with water only and locally apply a healing, repellent and antiparasitic spray based on silver sulfadiazine (0.1%), cypermethrin (0.4%) and dichlorvos (1.6%). Afterwards, small wounds with secretions were observed, which evolved in two weeks to intense hair loss, ulceration and itching in the affected region

On the day of the appointment, in addition to the skin lesions, the patient had an episode of vomiting and was less active. During the consultation, no abnormalities were observed on physical examination and it was confirmed that the dog was adequately vaccinated and dewormed and was fed with commercial food. Additionally, the owner reported that his dog had received a sarolaner-based acaricide and insecticide two months earlier.

After the initial assessment, a trichotomy and a careful cleaning of the region was performed with saline solution and gauze, allowing us to observe an extensive area of maculopapular lesions with circular shapes, sometimes coalescing, and with signs of ulceration in the center. These lesions were located in the dorsal portion of the neck, extending to the interscapular region (Figure 1). The complete blood and the serum biochemistry parameters were all normal. Subsequently, material was collected from the site of the lesion using a fine needle for cytopathological examination, which showed neutrophilic inflammation with bacteria. A biopsy was suggested to confirm the diagnosis of an inflammatory lesion and exclude possible neoplastic changes. Secondary bacterial pyoderma was considered as a differential diagnosis due to the appearance of the lesion and the cytology results, which led to a biopsy to diagnose the primary cause.

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Figure 1
Irritant contact dermatitis due to cutaneous adverse drug reactions secondary to topical exposure of benzyl benzoate in an adult Pit Bull dog. Extensive area of focal maculopapular lesions in circular shapes, sometimes coalescing, with ulceration in the center, in the dorsal region of the neck extending to the interscapular region.

On the same day an incisional surgical skin biopsy was then performed, using a 6mm punch, and the sample was packed in 10% formalin and histopathologically examined. Microscopically, an area of ulcerated epidermis was observed with apoptosis of transepidermal keratinocytes associated with a mixed infiltrate (Figure 2A e B). Interface dermatitis with a predominance of lymphocytes in the hair follicle region was also observed (Figure 2C). Additionally, multifocal areas of mild spongiosis, mainly in the basal layers of the epidermis, and mild vacuolar degeneration of keratinocytes was seen. A focal area of the epidermis showed neutrophilic inflammatory infiltrates in its subcorneal layers, which were compatible with pustules (Figure 2D). Mild neutrophilic perivascular dermatitis was also observed in the superficial dermis. Based on the clinical aspects and histopathological findings, CADR, because of topical use of BB, was diagnosed.

thumbnail of Figure 2
Figure 2
(A) An area of ulcerated epidermis with apoptosis of transepidermal keratinocytes associated with a mixed infiltrate. HE, 200X. (B) Apoptosis keratinocytes (arrow) with lymphocyte exocytosis. HE, 400X. (C) Hair follicle with interface dermatitis with a predominance of lymphocytes, plasma cells and eosinophils. Keratinocyte apoptosis marked with black arrowheads. HE, 400X. (D) Apoptosis of subepidermal keratinocytes with exocytosis of neutrophils, spongiosis and interface dermatites. HE, 400X.

Therefore, cleaning the affected region and applying an ointment (Crema 6A, Labyes), containing dexamethasone (0,025%), neomycine sulfate (0,25%), bacitracin (50.000 UI/100g), griseofulvin (0,18 %) and benzocaine (1%), were prescribed. Bathing with the BB-based scabicidal soap was discontinued and a new shampoo containing complex of ceramides and fatty, monosaccharides and polyglycosides (Allermyl®, Virbac) was introduced for weekly baths at home. Within 48 hours of treatment, skin revitalization was already significant and total healing took place approximately three weeks after the first appointment.

The diagnosis of CADR due to topical exposure to BB was based on the history, characteristics of the lesion, histopathological changes, and clinical improvement after discontinuation of BB and topical treatment (HO et al., 2015; ROYAUX et al., 2016; SIMPSON et al., 2020). After taking the patient’s history and physical examination, some differential diagnoses were considered, such as allergic skin diseases, pyoderma, burns and CADR (HO et al., 2015). The location and characteristics of the lesion are not commonly observed in allergic diseases (HENSEL et al., 2015). Considering the main differential diagnoses, it was possible to establish the diagnosis of bacterial pyoderma by cytology, with a probable secondary cause, not requiring microbiological examination for confirmation at this time (HENSEL et al., 2015). After the cytology results, it was decided to start treatment with a topical anti-inflammatory, antibiotic, antimycotic, anesthetic, anti-allergic and antipruritic medication (Crema 6A, Labyes). Concomitantly with the treatment for pyoderma and skin revitalization, the primary cause was investigated through biopsy. Other causes were ruled out, as the patient had no alterations on physical examination or in laboratory tests and was up-to-date with deworming and vaccinations. With the results of the biopsy and the patient’s improvement after treatment and discontinuation of the use of BB soap, it was possible to confirm the diagnosis of CARD and secondary pyoderma (ROYAUX et al., 2016; LOEWINGER et al., 2022).

It is known that in humans BB may trigger irritant CD (ICD), a condition compatible with what was observed in this dog (LY et al., 2009; ISHII et al., 2017). As probably happened in this case, it has been reported that even patients with a previous history of dermatological disease can develop overlapping lesions because of drug reactions (GROSS et al., 2009; SCOTT et al., 2013; HO et al., 2015). BB is an active substance prescribed for humans at a recommended concentration of 12.5% in children and up to 25% in adults, effective and safe in the treatment of scabies, with adverse reactions considered to be mild. In humans, the pharmaceutical formulation used is lotion, which may remain on the patient for up to 24 hours without rinsing. However, there are reports of ICD-type CADR in up to 23% of patients, occurring more in patients who have had two applications of the drug (LY et al., 2009).

In the current patient report, two aspects need to be considered: the product was not rinsed off after bathing, and the use of BB was recurrent, which could contribute to greater skin sensitization over time, leading to the severe skin reaction observed (GROSS et al., 2009; LI & LI, 2021). It is possible that the previous skin lesions reported by the owner were caused by the misuse of BB; but although, it appears to be the main the cause of this condition, it cannot be ruled out that other components of the soap may have contributed to this (MURAYAMA et al., 2008). The other drug that could contribute to the lesion is the healing, repellent and antiparasitic spray which does not seem to be correlated to the case, as it was used by the owners after the appearance of the skin lesions and did not cause discomfort to the patient. Furthermore, silver sulfadiazine is indicated for topical use in burns (FULLER, 2009).

The clinical and histopathological findings of this condition were consistent with ICD, which typically results from direct skin contact with an irritating active ingredient, such as BB (GROSS et al., 2009; LY et al., 2009; HO et al., 2015). In contrast, allergic CD (AD), which is another type of contact dermatitis, requires prior, exposure to an active ingredient to sensitize the immune system and triggers a type IV hypersensitivity reaction. As most sensitizing drugs are irritating, it is common for both types of CD to occur simultaneously, which may also have happened in this patient (HO et al., 2015; LI & LI, 2021).

Ulcerative lesions and necrosis in the epidermis are related to ICD, while in ACD the lesions tend to be more vesicular, which was not observed in this case (HO et al., 2015). The localization of a CADR due to soap or shampoo occurs more frequently in a more generalized form (HO et al., 2015). The quantity, exposure time, product concentration, repetition of application and mechanical factors can should be considered for the development of the ICD (BAINS et al., 2019), and may have influenced the distribution of lesions in this canine patient. However, in ICD, skin lesions only appear in skin regions that came directly into contact with the irritant, as occurred in the case described (HO et al., 2015). Similar to the case presented here, necrotic superficial dermatitis may also occur in lesions frequently appearing on the trunk, when ICD is triggered by local application of shampoo. The reason for this peculiar distribution is not known, as it comes into contact with the shampoo throughout the body (MURAYAMA et al., 2008).

In cases of ICD-type CADRs, changes compatible with cytotoxic damage of keratinocytes, necrotic cells, ulceration areas, and varying degrees of spongiosis, are typically observed microscopically, as seen in this case. The perivascular dermatitis identified on histology can be seen in both ICD and ACD cases, while epidermal pustules can be seen in ACD cases, emphasizing that a concomitant course of ICD and ACD is likely (GROSS et al., 2009; HO et al., 2015; SCOTT et al., 2013).

In these cases, exposure tests with the suspected potentially irritating agent can be performed to establish the diagnosis of ICD. However, the test may be uncomfortable for the patient and expensive for the guardian; and therefore, it is not generally performed (HO et al., 2015). The diagnosis of pyoderma, in most cases, is secondary, and when the primary cause is not resolved, infections persist (SCOTT & MILLER, 1999). In cases of CARD, bacterial culture can be considered an additional test and positive tests do not rule out CARD (LOEWINGER et al., 2022). The diagnosis of a CADR may be confirmed when the cause of the lesion is removed and the patient shows improvement, some even evolving to spontaneous healing without treatment. However, in some cases, it is necessary to treat secondary complications, such as bacterial infection and, depending on the severity of the lesions, use steroidal anti-inflammatory drugs (BRAGA et al., 2021; ROYAUX et al., 2016; SIMPSON et al., 2020; THAM et al., 2022). The patient in this report was treated topically, and the owner was advised not to bathe his dog with a BB soap any longer (BRAGA et al., 2021; ROYAUX et al., 2016; THAM et al., 2022). The patient presented a satisfactory resolution with regression of the lesions and no recurrence.

Considering the findings observed in this case, it can be concluded that prolonged topical exposure to BB, due to misuse of the product, may cause a CADR characterized by ICD in dogs. Some of the evidence observed in this report suggested that ICD may occur concomitantly with clinical-pathological aspects characteristic of ACD, which makes it difficult to properly classify the injury.

ACKNOWLEDGEMENTS

The authors are thankful to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil - Finance Code 001.

REFERENCES

  • CR-2024-0220.R1

BIOETHICS AND BIOSECURITY COMMITTEE APPROVAL

  • The report was performed with an animal routinely treated in a veterinary hospital service and was not part of any project; it was simply a clinical case report.

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Publication Dates

  • Publication in this collection
    20 Jan 2025
  • Date of issue
    2025

History

  • Received
    16 Apr 2024
  • Accepted
    30 July 2024
  • Reviewed
    14 Oct 2024
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