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Altogen Labs provides acute dermal toxicity testing in alignment with OECD Test Guideline 402, ensuring accurate hazard classification while minimizing unnecessary rodent testing. Given the significant body of evidence demonstrating that acute dermal toxicity is rarely more severe than oral toxicity, we prioritize a weight-of-evidence approach before initiating in vivo testing. Our testing framework is designed to provide robust toxicological data for human health risk assessment while ensuring compliance with international regulatory requirements. Our approach integrates a weight-of-evidence assessment to determine the necessity of in vivo testing and employs a stepwise dosing strategy to minimize rodent use while obtaining definitive hazard classifications.
Initial Considerations
Prior to conducting in vivo acute dermal toxicity testing at Altogen Labs, a comprehensive assessment of available toxicological data is performed. This evaluation includes an analysis of the test chemical’s identity and structural characteristics, its physicochemical properties, and existing in vitro and in vivo toxicity data. Additionally, (Q)SAR modeling is utilized to predict potential toxicity based on chemical structure and known toxicological profiles of structurally related compounds. Consideration is also given to anticipated human exposure scenarios to determine the relevance and necessity of conducting in vivo testing. The objective is to justify the study based on scientific necessity, ensuring that only essential tests are conducted in accordance with regulatory requirements and ethical considerations. The study design is structured to avoid the administration of doses expected to be lethal, focusing instead on identifying toxicity thresholds that contribute to hazard classification.
Principle of the In Vivo Test
Acute dermal toxicity studies at Altogen Labs are conducted in a stepwise manner, exposing groups of rats of a single sex to a test compound at predetermined dose levels. Altogen Labs’ study aims to identify toxicity ranges and assess the systemic effects following a single dermal exposure. The results contribute to classification under the Globally Harmonized System (GHS) for chemical hazard assessment.
Description of the Method
Selection of Animal Species
At Altogen Labs, the selection of the appropriate animal species is determined based on standardized toxicological principles to ensure consistency and reliability in data interpretation. The adult rat is the species of choice due to its well-documented physiological responses, established baseline toxicology data, and extensive use in regulatory testing frameworks. The rat provides optimal dermal absorption characteristics, enabling accurate hazard classification.
Sex selection is guided by historical toxicological data, which generally indicate that there is minimal difference in sensitivity between males and females. However, when differences are observed, females have been shown to exhibit slightly greater susceptibility to toxic effects. Consequently, unless there is compelling toxicokinetic evidence suggesting that males are more sensitive to the test compound, females are typically utilized in acute dermal toxicity studies. All rats used in testing are young adults, typically between 8 to 10 weeks old, to ensure uniformity in physiological responses. Weight parameters are strictly controlled, with individual weights falling within ±20% of the mean weight of the study cohort. Only rats with healthy, intact skin are included in the study to ensure reliable dermal exposure and absorption assessments.
Test Compound Application and Exposure
The test compound is applied in a uniform layer over a defined area of exposed skin and secured with a porous gauze dressing and non-irritating tape for a 24-hour exposure period. Additional restraints are employed if necessary to prevent ingestion of the compound. After 24 hours, the residual test substance is removed with water or an appropriate solvent, and rats are returned to group housing unless individual isolation is deemed necessary due to toxicity-related concerns. The choice of dose levels follows a fixed-dose procedure, with adjustments based on prior toxicity data, when available.
Procedure
Altogen Labs houses the rats under controlled environmental conditions, with temperature maintained at approximately 22°C with a variance of ±3°C, relative humidity set between 30% and 70%, and a 12-hour light-dark cycle. They are provided with a standard laboratory diet and an unlimited supply of drinking water. On the day before test substance administration, fur is removed from the dorsal and flank areas, covering at least 10% of the body surface, without abrading the skin to avoid altering dermal absorption. Anesthetics are used to reduce handling stress during this process.
Dosing is conducted using a fixed-dose procedure, where a starting dose is selected based on available toxicological data. If no prior data exist, an initial range-finding study is conducted using a single rat at a dose level of 200 mg/kg body weight. Depending on the observed response, subsequent rats are dosed at lower or higher levels following a sequential design. This approach ensures that testing proceeds in a manner that minimizes rat use while still providing sufficient data to classify the test substance under the Globally Harmonized System (GHS). Testing continues until a dose that results in no more than one death or no evident toxicity is established, allowing for hazard classification without excessive testing.
Observations
Following exposure, rats are observed immediately after dosing, periodically during the first 24 hours with a particular focus on the first two to six hours, and then daily for a total of 14 days. Observations include assessments of skin and fur integrity, eye and mucous membrane conditions, respiratory and circulatory function, autonomic and central nervous system activity, somatomotor function, and behavioral responses. Specific signs such as tremors, convulsions, excessive salivation, diarrhea, lethargy, sleep disturbances, and coma are closely monitored. The treatment site is also examined at 24, 48, and 72 hours post-exposure to determine irritation potential, which may contribute to the assessment of skin irritation classification.
Body weights are recorded prior to dosing, at weekly intervals, and at study termination. Altogen Labs ensures that any deviations in body weight gain provide additional insight into systemic toxicity. Rats found in moribund condition or exhibiting signs of severe pain or distress are humanely euthanized, and the time of death is precisely recorded.
Pathological and Necropsy Evaluations
All Altogen Labs test rats, including those that succumb during the study or are euthanized for humane reasons, undergo gross necropsy to assess potential internal toxicological effects. Gross pathological changes are recorded, and microscopic examinations may be performed on organs displaying abnormalities or on the treatment site if deemed necessary. These evaluations contribute to a more comprehensive understanding of systemic and local toxicological effects.
Data Interpretation and Classification
Altogen Labs test results are compiled into individual rat data sets and summarized in tabular form to facilitate interpretation. Data summaries include the number of rats used per dose level, observed signs of toxicity, mortality rates, and time to onset of effects. Body weight changes, necropsy findings, and histopathological results are also recorded. The classification of the test compound is determined based on observed toxicity responses, following the criteria established by the GHS. The sequential testing flowchart is applied to determine whether additional dosing is required or if classification can be confidently established based on existing data.
Study Reporting and Documentation
Altogen Labs comprehensive study reports are generated for each acute dermal toxicity test. Reports include a detailed rationale for in vivo testing, including the weight-of-evidence analysis supporting the necessity of the study. They document relevant pre-existing toxicological data, justification for dose selection, and all procedural details related to chemical administration. Information on the test chemical, including source, lot number, stability, solubility, and physical characteristics, is provided alongside data on vehicle use when applicable.
Study reports also detail rat specifications, including species, strain, sex, age, microbiological status, housing conditions, and dietary parameters. Altogen Labs observational records, including clinical signs, body weight changes, and necropsy findings, are meticulously documented. Any deviations from standard procedures, if applicable, are justified, and all conclusions are drawn based on systematic toxicological assessment.
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