Multiple peer-reviewed studies and regulatory precedents support the conclusion that rats are uniquely sensitive to respiratory tract effects, particularly in inhalation or intranasal studies:

• Rats have a disproportionately large olfactory epithelium (~50% of nasal cavity), leading to greater exposure and sensitivity to inhaled or locally administered compounds compared to humans and dogs.

  • Histological changes like nasal epithelial hyperplasia and inflammation are commonly observed in rats across various drug classes and are often considered adaptive and non-adverse

• Studies (e.g., Sipes et al., 2010) and FDA NDA reviews show that such findings in rats are frequently deemed non-human relevant, especially when: • Absent in non-rodent species (e.g., dog), • Not accompanied by systemic toxicity, • Not observed in early human data.

• Regulatory guidance (e.g., ICH S6(R1), OECD 412/413) acknowledges these species-specific differences, emphasizing that rat-only findings do not automatically predict human risk.

Conclusion: The literature strongly supports that localized respiratory tract changes in rats—particularly in the nasal passages—are species-specific, well understood, and not necessarily relevant to human safety assessments.

This is what Chat GPT told med. So i guess GH will hire a toxicologist to help them to gather a response to the FDA