Dermal In Vivo Studies

Acute Dermal Limit Test

• One group of 5 male and 5 female rabbits
• A single 24-hr dermal exposure to the test substance
• Animals are weighed weekly and observed for clinical signs of toxicity and death for 2 weeks after treatment
• Gross necropsy is performed on all animals that die and on all survivors at the end of the 2-week study
• No tissues are preserved; necropsy findings are recorded

Acute Dermal Study (Rabbit)

• Groups of male and female rabbits will be submitted to the study
• A single 24-hr dermal exposure to 3 dose levels of the test substance
• Animals are weighed weekly and observed for clinical signs of toxicity and death for 2 weeks after treatment
• Necropsy is performed on all animals that die and on all survivors at the end of the 2-week study
• No tissues are preserved; necropsy findings are recorded

Primary Dermal Irritation Study

• The shaved intact skin of 6 rabbits is exposed to the test substance for 4 hours
• After the exposure period, the skin is graded for irritation at 1, 24, 48, and 72 hours
• Observation period may be extended for up to 21 days to evaluate the reversibility of the effects observed.

Ninety Day Dermal Toxicity Study (Mouse)

• Groups of 20 males and 20 females are treated with the test substance by dermal application at 3 dose levels for 90 days; a vehicle control group is included; an additional satellite toxicokinetic group of 6 males and 6 females is included for plasma drug evaluations.
• Study measurements include daily clinical observations, daily irritation scores at application site, weekly body weights.
• Plasma drug evaluations at approximately 4 time points on day 1 and on day 28.
• Hematology and serum clinical chemistry are performed at termination.
• Necropsies are performed on any animals that die or upon termination; weights are recorded for major organs.
• Full histopathological examinations are conducted on the control and high-dose groups and on any unscheduled deaths.
• Target organs are examined in the intermediate groups.

SKIN IRRITATION: Ratings corresponding to the following definitions are derived from data obtained from the test methods as described in 16 CFR 1500.41 and/or NAS Publication 1138, and categories of toxicity as described in 16 CFR 1500.3.

• Practically Non-Irritating: The undiluted product causes no noticeable irritation, or causes slight inflammation (edema and erythema skin reaction values of 0 or 1) of intact or abraded skin of rabbits during the study period. Primary Irritation Index of 0-1.9.
  
  
• Moderately Irritating: The undiluted product causes well-defined inflammation (edema and erythema skin reaction values of 2) during the study period. Primary Irritation Index of 2-4.9.
  
  
• Primary Skin Irritant: The undiluted product causes moderate to severe inflammation (edema and erythema skin reaction values of 3 or 4) of the intact or abraded skin of rabbits during the study period. Primary Irritation Index of 5 or more.
  
  
• Corrosive: The undiluted product causes visible destruction or irreversible alterations of the tissue structure at the site of contact on intact or abraded skin of rabbits during the study period.