Two-year dermal carcinogenicity bioassay of triclosan in B6C3F1 mice.

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups.

Preclinical determination of wound-healing activity of halibut oil cream in rat model of burn wound.

This study investigated the effects of halibut oil cream, containing omega-3 fatty acids, vitamins A and D, and hydroxyproline, on burn wound healing in rats. Acute dermal toxicity tests confirmed its nontoxicity. Wistar rats were divided into five groups: a control, a positive control treated with silver sulfadiazine 1% (SSD), and three groups treated with 3%, 9%, and 27% halibut oil cream Formulation (HBOF). The SSD and HBOF groups showed significant healing improvements compared to the control. Histopathological analysis indicated increased collagen production in the HBOF groups, suggesting halibut oil cream's potential as a topical treatment for burn wounds.

Investigating the effects of dermal exposure to in-vivo animal models on the riot-control properties of a powder formulation of Tragia involucrata leaf hair lining.

Purpose: Riot control agents (RCAs) such as CS, CN, CR, PAVA, and OC, etc., are already in use and has produced numerous health risks, including skin burns, dermatitis, gastrointestinal issues, impairment of respiratory variables, conjunctivitis, etc., and even prolonged and repeated exposure may cause death. Therefore, there is a demand and need for non-lethal, non-toxic RCAs that can effectively control riots without resulting in fatal outcomes. This study was carried out to evaluate the health risks related to a novel formulation made from isolated Tragia involucrata leaf hair lining, that can be used as the best suitable non-lethal RCAs.Methods: According to the OECD guidelines, studies on acute dermal toxicity, dermal irritation/corrosion, and skin sensitisation were carried out. Wistar rats were used in an acute dermal toxicity study, and the results indicated no mortality, morbidity, or abnormal food-and-water intake, biochemical parameters, or histopathological examination findings. A study on dermal irritation in Rabbits produced moderate erythema and the effect was instantaneous and resolved within 72 hrs of post-exposure. A skin sensitisation test was conducted on Guinea pig.Results: The results showed that the formulation had moderate skin-sensitizing properties after the application of the challenge dose. Patchy erythema was seen, and it went away 30 hrs after the gauze patch was removed.Conclusion: The preclinical results did not produce any indication of severe toxicity which supports it to be used as a natural RCAs in the future.

Toxicological evaluation of a nonlethal riot control combinational formulation upon dermal application using animal models.

Numerous adverse effects on human health have been reported in epidemiological studies of oleoresin capsicum (OC) and other riot control agents (RCAs). Importantly, the daunting risk of such RCAs can be neutralized by optimizing the desired concentration of such agents for mob dispersal. Hence, a nonlethal riot control combinational formulation (NCF) was prepared for dispersing rioters without imparting fatal outcomes. However, for desired utilization of NCF, it is essential to recognize its extent of potential toxicity. Therefore, the current investigation evaluated the dermal toxicity of NCF using experimental animals in compliance with the OECD guidelines. Additionally, few essential metal ions were analyzed and found non -significantly different in the test rats as compared to control rats. Moreover, abnormal dermal morphology and lesions ultrastructural tissue defects were not noticed as evinced by different studies like ultrasonography, histology, and scanning electron microscopy (SEM) respectively. Further, Doppler ultrasonography exhibited non-significantly different blood flow velocity in both groups, whereas miles test demonstrated a significantly increased Evans blue concentration in test rats compared to the control rats, which might be due to an initial increase in blood flow via an instant action of the NCF at the cutaneous sensory nerve endings. However, our results demonstrated NCF can produce initial skin irritating and sensitizing effects in guinea pigs and rabbits without the antecedence of acute toxicity (≤2000 mg/kg) in Wistar rats.

Use of alternative test methods in a tiered testing approach to address photoirritation potential of fragrance materials.

The safety assessment of fragrance materials for photoirritation utilized by The Research Institute for Fragrance Materials has recently been modified and is described in detail. Materials demonstrating significant absorbance in the ultraviolet and visible light (UV/VIS) range (290-700 nm) may present a concern for photoirritation and require further investigation. If there are no photoirritation data or data are insufficient, then data on read-across materials are considered before a tiered approach for testing begins. The hazard-based 3T3-Neutral Red Uptake (NRU) Phototoxicity Test (OECD TG 432) is used as a first-tier assay; if it predicts photoirritation, it is followed by the reconstructed human epidermis (RhE) phototoxicity assay (OECD TG 498). The RhE phototoxicity assay is used to determine a No Observed Effect Level (NOEL) for photoirritation that is used in a confirmatory human photoirritation test. Data are presented on 108 fragrance materials exhibiting significant UV/VIS absorbance and evaluated in the 3T3-NRU Phototoxicity Assay. Twenty-one materials were predicted to be phototoxic; twenty were evaluated in the RhE Phototoxicity Assay to establish a NOEL. Fourteen materials were then evaluated in a confirmatory human phototoxicity test. The tiered testing approach presented represents a scientifically pragmatic method to minimize the likelihood of photoirritation from fragrance materials.

Safety assessment of a novel, dietary pyrroloquinoline quinone disodium salt (mnemoPQQ®).

Pyrroloquinoline quinone (PQQ), a potent coenzyme antioxidant naturally occurring in foods, has been demonstrated to protect brain cells by enhancing the expression of nerve growth factors (NGF) and NGF receptors, and suppressing the fibril formation and aggression of amyloid ß. We developed mnemoPQQ®, a novel PQQ disodium salt and assessed its safety in GLP compliant toxicity studies. Acute toxicity studies of mnemoPQQ® in Wistar rats revealed that its LD50 was 1825- and 1410 mg/kg body weight (bw) in male and female rats, respectively, whereas its acute dermal LD50 was >2000 mg/kg bw. mnemoPQQ® was found to be nonirritant to the skin of rabbit in an acute dermal irritation/corrosion study, and classified mnemoPQQ® as a nonirritant to the eye of rabbit in an acute eye irritation/corrosion study. Ames bacterial reverse mutation assay and in vitro Mammalian cell gene mutation test exhibited its non-mutagenic potential. In mammalian in vivo erythrocyte micronucleus test, mnemoPQQ® was classified as non-clastogenic and non-mutagenic. A 90-day sub-chronic toxicity study, conducted at and up to the highest daily dose of 600 mg/kg body weight, revealed no evidence of systemic toxicity. All rats survived the treatment without any significant abnormal clinical signs and alterations in hematology, clinical chemistry, neurological evaluation, thyroid functions, reproductive hormone levels, sperm evaluations, vaginal cytology, endocrine functions, organ weight and gross and microscopic pathology findings. No observed adverse effect level (NOAEL) of mnemoPQQ® was found to be greater than 600 mg/kg body weight. These studies affirm that mnemoPQQ® has broad spectrum safety for human consumption.

Increasing confidence in waiving dermal toxicity studies: A comparison of oral and dermal acute data with alternative approaches for agrochemicals and products.

The refinement of OECD 402 study design and criteria under which the study can be waived has been welcomed in some regulatory regions but met with uncertainty in others. To address these human safety concerns, previously available in vivo acute oral and acute dermal toxicity data was evaluated from a total of 597 agrochemical active ingredients and products. It was identified that all active ingredients and 99.6% of products had an acute dermal classification equal to or less toxic than their acute oral classification, confirming that waiving the acute dermal study and basing the outcome on the acute oral toxicity result has no impact on human health assessment. Additionally, automated Acute Toxicity Estimate (ATE) calculations were conducted on 440 products to evaluate if the predicted dermal toxicity resulted in the same in vivo classification. 93% of ATE predictions provided excellent correlation to the in vivo result and 6.4% resulted in a more conservative prediction. It is therefore clear that the results of this investigation, should remove any regulatory concerns and that OECD 402 can be confidently eliminated in its entirety from testing requirements globally.

Optimization of the extraction conditions and dermal toxicity of oil body fused with acidic fibroblast growth factor (OLAF).

INTRODUCTION: Oil body (OB), a subcellular organelle that stores oil in plant seeds, is considered a new transdermal drug delivery system. With the increasing understanding of the OB and its main protein (oleosin), numerous studies have been conducted on OB as "carrier" for the expression of exogenous proteins. In our previous study, oil body fused with aFGF (OLAF) was obtained using a plant oil body expression system that had been preliminarily proven to be effective in accelerating the healing of skin wounds. However, no dermal toxicological information on OLAF is available. OBJECTIVE: To ensure the dermal safety of OLAF, a series of tests (the acute dermal toxicity test, 21-day repeat dermal toxicity test, dermal irritation test and skin sensitisation test) were conducted after optimising the extraction protocol of OLAF. MATERIALS AND METHODS: To improve the extraction rate of OLAF, response surface methodology (RSM) was first employed to optimise the extraction conditions. Then, Wistar rats were exposed to OLAF (400 mg·kg-1 body weight) in two different ways (6 hours/time for 24 hours and 1 time/day for 21 days) to evaluate the acute dermal toxicity and 21-day repeated dermal toxicity of OLAF. In the acute dermal toxicity test, clinical observations were conducted to evaluate the toxicity, behaviour, and health of the animals for 14 consecutive days. Similarly, the clinical signs, body weight, haematological and biochemical parameters, histopathological changes and other indicators were also detected during the 21 days administration. For the dermal irritation test, single and multiple doses of OLAF (125 mg·kg-1 body weight) were administered to albino rabbits for 14 days (1 time/day). The irritation reaction on the skin of each albino rabbit was recorded and scored. Meanwhile, skin sensitisation to OLAF was conducted using guinea pigs for a period of 28 days. RESULTS: Suitable extraction conditions for OLAF (PBS concentration 0.01, pH of PBS 8.6, solid-liquid ratio 1:385 g·mL-1) were obtained using RSM. Under these conditions, the extraction rate and particle size of OLAF were 7.29% and 1290 nm, respectively. In the tests of acute dermal toxicity and 21-day repeated dermal toxicity, no mortality or significant differences were observed in terms of clinical signs, body weight, haematological parameters, biochemical parameters and anatomopathological analysis. With respect to the dermal irritation test and skin sensitisation test, no differences in erythema, oedema or other abnormalities were observed between treatment and control groups on gross and histopathological examinations. CONCLUSIONS: The results of this study suggest that OLAF does not cause obvious toxicity, skin sensitisation or irritation in animals.

Dermal toxicity, dermal irritation, and delayed contact sensitization evaluation of oil body linked oleosin-hEGF microgel emulsion via transdermal drug delivery for wound healing.

Objective: The expression of therapeutic proteins in plant oil body bioreactors has attracted much attention. But its safety is not yet clear. This article determines the risk of safety after using the drug. Methods: The oil body-linked oleosin-hEGF microgel emulsion (OBEME) was prepared by mixing the xanthan gum with suitable concentrations in an appropriate proportion. Skin irritation and sensitization reaction were investigated in rats and guinea pigs using OBEME as test article.Results: The OBEME did not produce dermal erythema/eschar or oedema responses. The dermal subacute and subchronic toxicity of OBEME were evaluated in accordance with OECD guidelines. Compared with the control group, the basic physical signs, such as weight, feed, drinking, excretion, and behaviour of experimental animals, were not abnormal. In addition, no abnormality was found in haematological parameters, biochemical indexes, relative organ weight, and histopathological observation of organs, and there was no significant difference compared with normal saline treatment group. Therefore, we conclude that OBEME has no toxic effects and is safe and reliable to be used for topical application.

Subacute dermal toxicity of perfluoroalkyl carboxylic acids: comparison with different carbon-chain lengths in human skin equivalents and systemic effects of perfluoroheptanoic acid in Sprague Dawley rats.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are used in various fields but raise concerns regarding human health and environmental consequences. Among PFASs, perfluorooctanoic acid (PFOA) and short-chain perfluoroalkyl carboxylic acids (SC PFCAs) are detectable in skin-contact consumer products and have dermal absorption potential. Here, we investigated the effects of dermal exposure to PFOA and SC PFCAs using in vitro and in vivo models. Human skin equivalents were topically treated with 0.25 mM and 2.5 mM PFOA and SC PFCAs (perfluoropentanoic acid, PFPeA; perfluorohexanoic acid, PFHxA; and perfluoroheptanoic acid, PFHpA) for 6 days, and cell viability, interleukin (IL)-1α, oxidative stress markers (malondialdehyde, MDA; and 8-hydroxydeoxyguanosine, 8-OHdG), and histopathology were examined. MDA levels were significantly higher in the PFASs groups than in controls. Compared with SC PFCAs, 2.5 mM PFOA caused more IL-1α (p < 0.001) release, decreased skin thickness and microscopic abnormalities. To evaluate systemic effects, Sprague Dawley (SD) rats were dermally treated with 250 and 1000 mg/kg PFHpA for 2 weeks and clinical and anatomic pathology were assessed. At 1000 mg/kg, 83% of the rats died, with severe ulcerative dermatitis at the application site. Adverse PFHpA-treated systemic changes were observed in the kidney, liver and testes, and histopathologic lesions such as renal tubular necrosis, hepatocellular necrosis, and germ cell degeneration were seen at 250 and 1000 mg/kg. Our study suggests that SC PFCAs have fewer effects on the skin than PFOA, but SC PFCAs can have adverse effects on major organs with systemic exposure at high concentrations.

Assessment of dermal safety of oil extracted from Periplaneta americana: acute dermal toxicity, irritation, and sensitization.

INTRODUCTION: The American cockroach (Periplaneta americana) is used in traditional Chinese medicine. Periplaneta americana (P. americana) is rich in oil that has shown potential antioxidant and antibacterial activities in vitro. OBJECTIVE: To evaluate the safety of oil extracted from P. americana by conducting acute dermal toxicity, irritation, and sensitization tests. MATERIALS AND METHODS: In an acute dermal toxicity study, adult Sprague-Dawley rats were exposed to P. americana oil (2000 mg/kg body weight) for 24 h. Clinical observations were conducted to evaluate the toxicity, behaviour, and health of the animals every day after dermal exposure for 14 days. For the dermal irritation test, the oil was applied to rabbits in single and multiple doses. Multi-dose treatment was administered once per day for 14 days. Each rabbit served as its own left- and right-side control and the rabbits' irritation reactions in local intact and damaged skin were recorded and scored. The skin sensitization study of guinea pigs with the oil was conducted for a period of 28 days. RESULTS: The acute dermal median lethal dose (LD50) of P. americana oil was > 2000 mg/kg body weight in adult rats. There was no significant difference in mean irritation scores between the negative control and oil groups. The oil caused very little or no irritation in the intact and damaged skin rabbits treated with either single or multiple doses and it was non-sensitizing to the skin of guinea pigs. CONCLUSIONS: These results suggest that P. americana oil does not produce any significant acute toxic effects and is safe for use in animal models with almost no dermal irritation or sensitization. Therefore, it presents a low risk of provoking skin reactions in humans.

Non-relevance of acute dermal toxicity testing for assessing human health protection in the regulatory decision-making for agrochemical formulated products.

Compared to oral toxicity tests, dermal toxicity tests offer little or no additional scientific information or public health protection for agrochemical-formulated products (US EPA, 2016). Based on that, a retrospective analysis of the results of acute oral and dermal LD50 studies of agrochemical products registered in Brazil was carried out by the Technical Group on Toxicological Risk Assessment (GT-ART) of the Brazilian Crop Protection Association (ANDEF). The data were obtained from 6 agrochemical industries that are associated to ANDEF, following these considerations: only rat studies were selected; only paired studies were chosen; only studies performed with top doses ≥2,000 mg/kg were selected; biological products were excluded. The dataset includes 342 formulated products in 21 formulation types. Among these 342 formulated products, 228 have a single active ingredient, 107 have 2 and 7 have 3 or more. The comparison of acute oral to dermal toxicity studies of agrochemical-formulated products registered in Brazil corroborates the United States Environmental Protection Agency (US EPA) conclusion on waiving acute dermal toxicity tests, which will result in avoiding unnecessary use of time and resources, data generation costs and animal testing.

Expression of cytokines and chemokines in mouse skin treated with sulfur mustard.

Sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemokines in the ear skin. We found that SM caused an accumulation of macrophages and neutrophils in the tissue within one day which persisted for at least 7 days. This was associated with a 2-15 fold increase in expression of the proinflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor α at time points up to 7 days post-SM exposure. Marked increases (20-1000 fold) in expression of chemokines associated with recruitment and activation of macrophages were also noted in the tissue including growth-regulated oncogene α (GROα/CXCL1), monocyte chemoattractant protein 1 (MCP-1/CCL2), granulocyte-colony stimulating factor (GCSF/CSF3), macrophage inflammatory protein 1α (MIP1α/CCL3), and IFN-γ-inducible protein 10 (IP10/CXCL10). The pattern of cytokines/chemokine expression was coordinate with expression of macrophage elastase/MMP12 and neutrophil collagenase/MMP8 suggesting that macrophages and neutrophils were, at least in part, a source of cytokines and chemokines. These data support the idea that inflammatory cell-derived mediators contribute to the pathogenesis of SM induced skin damage. Modulating the infiltration of inflammatory cells and reducing the expression of inflammatory mediators in the skin may be an important strategy for mitigating SM-induced cutaneous injury.

Screening of acute and sub-chronic dermal toxicity of Calendula officinalis L essential oil.

The objective of the study is to access the safety of Calendula essential oil by studying acute and sub-chronic dermal toxicity. The dermal toxicities of Calendula essential oil were evaluated in accordance with OECD guidelines number 402 and 411 respectively. The animals were exposed to Calendula officinalis (CO) essential oil dose of 20 mL/kg body weight for acute dermal toxicity, whereas for dermal sub-chronic toxicity study, rats were exposed to CO oil 2.5, 5 and 10 mL/kg body weight, respectively, for 7 times in a week for 90 days. The parameters studies included CNS stimulation, depression, hematological parameters (RBC, WBC, Hb, Lymphocyte % etc), biochemical parameters (total protein, albumin, total bilirubin, ALP, AST, etc), relative organ weight, necropsy and histopathology. In toxicity studies, all animals exhibited normal behavior without any change in hematology, blood biochemistry, necroscopical and histopathology. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) of CO oil were 2.5 and 10 mg/kg/day, respectively. CO oil is under the herbal medicinal product according to the European Medicines Agency with the claim of an LD50 value of 20 mL/kg body weight. The result indicates that CO essential oil did not produce any significant toxic effects.

Exploration of toxicological impacts following acute and sub-chronic exposure to ethyl anthranilate-loaded mosquito repellent patch.

In the recent years, growing concern about the potential toxicity of synthetic repellents has led to the development of environmentally safe non-toxic insect control methods. Present investigation explores the toxicological impacts of ethyl anthranilate-loaded mosquito repellent patch (EAMRP) on respiratory system following acute and sub-chronic inhalation exposure in Wistar rats. Lungs parameters such as enhanced pause, tidal volume, respiration rate, inspiration time, and expiration time were determined using whole body plethysmograph. X-ray, scanning electron microscopy and histology were utilized to study the morphology and microscopical architecture of lungs. Hematological and serum biochemical markers were estimated. Cytokines such as IL-1ß, IL-2, and IL-12 were also estimated in bronchoalveolar lavage fluid using ELISA kits. Finally, acute oral and dermal toxicity studies were carried out to study the accidental or intentional poisoning due to the ingestion and skin contact of EAMRP, respectively. The findings demonstrate that inhalation exposure to EAMRP did not pose any significant dose related toxicity in above mentioned experiments. Further, no appreciable toxicity was observed in both acute oral and dermal exposure. Thus, these results revealed the non toxic nature of EAMRP in preclinical studies. Hence, EAMRP can be used successfully as an alternative to existing synthetic repellents without any potential health hazards.

Safety profile of silver sulfadiazine-bFGF-loaded hydrogel for partial thickness burn wounds.

In the present investigation, the safety of novel combinational silver sulfadiazine-bFGF-loaded hydrogel was assured by performing acute skin irritation, sensitization, acute dermal toxicity, and eye irritation in compliance with the Organization for Economic Co-operation and Development guidelines. In the skin irritation study, placebo, test, and positive control (0.8% w/v aqueous solution of formaldehyde) were applied on New Zealand rabbits and monitored for abnormal skin responses including erythema and edema. The placebo and test formulation did not induce any adverse reactions and were classified as nonirritating materials. In the skin sensitization test, guinea pigs were sensitized by positive control (0.1% w/v 1-chloro-2,4-dinitrobenzene in 10% of propylene glycol as a standard skin sensitizing agent), placebo, and test formulations. Weak sensitization was observed in the placebo and test formulation treated groups. Additionally, acute dermal toxicity test was performed in Wistar rats, where no signs of toxicity were observed in biochemical, hematological, and histopathological studies. Moreover, the acute eye irritation test was carried out in rabbits and no abnormal clinical signs were evident in the cornea or iris. As a whole, these findings suggest that the hydrogel formulation does not cause any skin irritation, skin sensitizationand dermal toxic effects, and eye irritation following dermal and ocular applications, respectively. Therefore, all the findings obtained from this preclinical study indicated that this hydrogel formulation is nontoxic and safe for use in animal models.

Biometrical evaluation of the performance of the revised OECD Test Guideline 402 for assessing acute dermal toxicity.

A comprehensive biometrical assessment was conducted to compare the performance of multiple test designs for acute dermal systemic toxicity to support the animal welfare update to the original OECD Test Guideline (TG) 402 for acute dermal toxicity. The test designs evaluated included: (1) two, three, or five animals per dose group (2) evident toxicity or lethality endpoints and (3) absence or presence of a one-animal sighting study. The revision of TG 402 respected the 3R principles (replace, reduce, refine) of animal testing. The results demonstrate that the TG 402 test design can be optimised with reduced animal numbers per test group, such that a scenario of two animals per group following a sighting study at a starting dose of 200 mg/kg bw (unless further information is available to better define the starting dose) would provide a classification which in most cases is conservative, without compromising both the statistical ability of the study to assess dermal toxicity, or the relevant classification outcome.

Cutaneous Phototoxicity: Clinical Observations versus Histopathological Findings.

Determination of test material-induced cutaneous phototoxicity for risk assessment has traditionally been based on visually observed skin reactions such as erythema, edema, and flaking. Because of its role in determining a toxic effect, the use of histopathological evaluation in this determination arises from time to time. However, there is little published information regarding the time course and types of histopathologic changes in the skin after test material-induced phototoxic insult nor any regulatory requirement or precedent for its use. This work evaluated both the visual and histopathological time course of the phototoxic response of the skin of the Long-Evans rat after oral administration of the phototoxins sparfloxacin and 8-methoxypsoralen (MOP) followed by a single exposure to solar-simulated ultraviolet radiation. Both sparfloxacin and 8-MOP elicited visual cutaneous reactions and microscopic changes consistent with a phototoxic response. The visually observed cutaneous time course and elicited histopathologic changes differed in response and extent for each phototoxin, but in both instances, microscopic evaluation did not alter the determination of a phototoxic response based on visual observations. These results indicate that, though histopathologic evaluations may have value for investigating mechanisms of phototoxicity, histopathologic evaluation of the skin is not warranted for determination of phototoxic potential in safety assessment intended for regulatory submission.

Recommended Diagnostic Approach to Documenting and Reporting Skin Findings of Nonhuman Primates from Regulatory Toxicity Studies.

Cutaneous adverse drug reactions (CADRs) in patients are not uncommon, and they are difficult to predict from nonclinical safety studies. Nonhuman primates (NHPs) are predestinated for a high predictivity of adverse drug reactions, and we postulate that this may also be true for CADRs, if skin findings in NHPs are thoroughly worked up, following the diagnostic approach in clinical veterinary dermatology. This article proposes a systematic approach to describe, analyze, and report skin findings that occur in NHP toxicity studies. Implementing this approach may increase the likelihood to differentiate between test item-related cutaneous findings and those that are independent of the test item. This will eventually result in increased relevance of skin findings identified in the scope of an NHP regulatory toxicity study for the risk assessment process to safeguard patients in clinical trials and beyond.

Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice.

Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.