# Presentation: 924295

## Environmental AssessmentsHuman and Animal Drugs

- Charles E. Eirkson III
- Environmental Safety Staff.
- FDA, CVM
- (Nancy Sager, CDER and Ron Bloom, CVM)
- U.S. EPA Region/ORD, Emerging Pollutants Workshop

## Statutory Framework

- Federal Food, Drug, and Cosmetic Act (FFDCA)
- 	FDA’s legal authority for assuring safety and effectiveness of drugs, food/feed additives, devices, biologics and cosmetics.
- National Environmental Policy Act (NEPA)
- FDA regulations implementing NEPA (21 CFR 25)
-  revised in 1997 (ReGO Initiative)
- Procedures for assuring the safety of drugs and food additives to the environment
- EPA’s Toxic Substances Control Act
- Premarket approval: drugs are specifically exempted

## National Environmental Policy Act

- NEPA requires of all Federal agencies to assess the environmental impacts of their “actions”
- Under NEPA, FDA considers the environmental impacts (use and disposal) due to the Federal “action” of approving a drug or food/feed additive application
- Environmental review incorporates environmental issues into FDA decision making

## National Environmental Policy Act

- “The NEPA process is intended to help public officials make decisions that are based on the understanding of environmental consequences, and take actions that protect, restore, and enhance the environment.”
- However, NEPA does not require that the most environmentally beneficial course of action be taken
- FDA must operate within the statutory framework of the FFDCA and NEPA

## NEPA Process

- Categorical Exclusions (CE)
- “Extraordinary circumstances” provision
- Environmental Assessments (EA)
- Environmental Impact Statements (EIS)

## Categorical Exclusions“Classes of actions that individually or cumulatively do not significantly affect the quality of the human environment are ordinarily excluded from the requirement to prepare an EA or EIS.”

- Investigational new (animal) drug applications (IND/INAD)
- Approval of natural substances when approval does not significantly alter the distribution of the substance, its metabolites, or degradation products in the environment

## Categorical ExclusionsExamples

- Approval of a drug when the approval will not increase the use of the drug
- Drugs for use in nonfood animals
- Drugs for minor species, including wildlife and endangered species, when previously approved  under similar animal management practices
- Therapeutics, under Veterinarian order or prescription
- EIC/EEC cutoff

## Extraordinary Circumstances

- An EA is required for an excludable action if _extraordinary circumstances_ indicate that the specific proposed action may significantly affect the quality of the environment
- Examples:
- Action for which available data establish that, at the expected level of exposure, there is the potential for serious harm to the environment.
- Adverse effects to species/critical habitat/endangered species

## Non-excluded Applications

- Therapeutics drugs used to treat whole herds/flocks (anthelmintics: ivermectin)
- Production drugs  (subtherapeutic antibiotics/synthetic hormonal growth promotants)
- Coccidiostats (anticoccidials and growth promotants: e.g., arsanilate)
- Aquaculture drugs
- Biotech products (including GMOs: e.g., transgenic salmon)
- Use of wild plants/animals (harvesting)

## Environmental Assessments

- “A concise document that provides sufficient information to determine whether an Environmental Assessment (EIS) or Finding of  No Significant Impact (FONSI) should be prepared.”
- Focus: Environmental fate and ecotoxicology based on drug use patterns/site specific
- Publicly available document

## Environmental Impact Statement A detailed statement on (i) the environmental impact of the proposed action, (ii) any adverse environmental effects which cannot be avoided, (iii) alternatives to the proposed action, (iv) the relationship between local short-term uses of the environment and maintenance and enhancement of long-term productivity, and (v) any irreversible and irretrievable commitments of resources which would be involved. 

- Selenium in Animal Feed
- Subtherapeutic Antibacterial Agents in Animal Feeds
- Taxol
- Chlorofluorocarbon Propellants

## Environmental Assessments

- Environmental Introduction/Hazards
- Environmental Fate and Effects
- Risk Characterization
- Mitigations
- Follows standard approaches/test methods (OECD/ASTM/EPA/VICH)

## Fate: Physical/Chemical Characterization

- water solubility
- dissociation constant
- octanol/water partition coefficient
- vapor pressure
- sorption/desorption properties

## Fate: Depletion Mechanisms

- photolysis
- hydrolysis
- biodegradation

## Effects

- Tiered approach:  Acute toxicity testing then chronic if data indicate
- Typical number of effects studies
- Human drugs: 2-4
- Animal drugs: 4-5
- Special studies: Antibiotic MICs, dung beetles, sediment toxicity, avian toxicity, wash-off studies, gene transfer

## Animal Drugs Effects Testing

- Aquatic Compartment
- Daphnia
- Algae
- Fish
- Terrestrial Compartment
- Plants
- Microbial function
- Earthworms
- Pasture parasiticides
- Dung insects (flies and beetles)

## Human and Animal DrugsDifferences:  Environmental Compartment

- EAs for human drugs normally focus on the aquatic environment
- EAs for animal drugs may evaluate fate and effects in the aquatic (fresh, salt), terrestrial environments, dung pats, and direct bird exposure

## Differences:  Cut-offs

- Human drugs are categorically excluded (CE) if the EIC in the aquatic environment is less than 1 ppb (absent extraordinary circumstances)
- Animal drugs do not have a CE based on an EEC.  However, less information can be provided if EECs are:
- less than 1 ppb at release from aquaculture facility
- less than 100 ppb in soil

## Human Drugs: 1 ppb (Aquatic)

- Data on human drugs routinely demonstrated no effects on relevant standard test organisms at concentration less than 1 ppb
- Approximately 90% of the toxicity results were 1 ppm or greater
- Approximately 10% of the toxicity results were between 1 ppb and 1 ppm
- Of those approximately 1/3 were antibiotics and 1/3 were central nervous system drugs

## Animal Drugs: 100 ppb (Soil)

- 	100 ppb is below the level shown to have effects in studies conducted with earthworms, microorganisms and plants

## Sources of Information

- 21 CFR Part 25 (FDA regulations implementing NEPA)
- 40 CFR Parts 1500-1508 (NEPA regulations)
*Retrospective Review of Ecotoxicity Data Submitted in Environmental Assessments:* available under FOI from Public Docket No. 96N-0057 (CDER)

## Sources of Information

- FDA’s guidance on *Environmental Assessment of Human Drug and Biologics Applications *(July 1998): available at http://www.fda.gov/cder/ guidance/index.htm
- FDA’s guidance on *Environmental Impact Assessments (EIAs) for  Veterinary Medicinal Products (VMPs)*; VICH GL6 (March 7, 2001): available at http://www.fda.gov/cvm/guidance/guide89.doc

## Sources of Information

- EAs available under Freedom of Information
- FOI summaries provide target animal, efficacy  and food safety data, ADIs, safe concentrations, regulatory methods
- CVM: EAs, FONSIs  & EISs posted at http://www.fda.gov/cvm/efoi/ea/ea.htm
- ceirkson@cvm.fda.gov
- sagern@cder.fda.gov
- rbloom@cvm.fda.gov

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## The Green Book

- The **FDA Approved Animal Drug Products**, (Green Book), is published by the Drug Information Laboratory; paper copies are available by subscription.
- Electronic copies of the Green Book are available on this website. The searchable database is maintained by the Drug Information Laboratory at Virginia Tech.
-  http://www.fda.gov/cvm/greenbook/elecgbook.html