Ocular Toxicity Regulatory Considerations for Nondrug Food and Drug Administration (FDA) Products and the Environmental Protection Agency (EPA)




FDCA (1938)

Department of Health and Human Services (FDA)

Pharmaceuticals and cosmetics

FIFRA (1947)



FHSA (1964) and TSCA (1977)

Department of Agriculture and EPA

Agriculture and industrial products

CPSA (1972)

Consumer Product Safety Commission

Household products

OSHA (1970)

Department of Labor (OSHA)

Occupational materials

8.2.1 Testing Guidelines

Several agencies, EPA, FDA, CPSC, and OSHA, have designated specific test guidelines for assessing ocular toxicity (Table 8.2). All of the testing guidelines provide standards for conducting the Draize eye test, but, due to variations in the nature of concern over the different regulated products, the guidelines for conducting the assay vary among the agencies. The Organization for Economic Cooperation and Development (OECD) has standardized methods for a number of toxicology tests, including the Draize eye test [8]. In general, 0.1 mL (liquid) or 0.1 g (solid) is placed on the conjunctival sac of one eye of the rabbit, and the other eye serves as an untreated control. Observations are made, and irritation is scored 1, 24, 48, and 72 h postexposure and daily thereafter until the lesion clears or for 21 days. Irritation is measured by observing corneal opacity, iritis, and conjunctival redness and swelling. Optional assessments can also be conducted using light microscopy or fluorescein, but in practice these assessments are rarely conducted [9].

Table 8.2
Current regulations that require ocular safety testing [9]


Authority created


Test guideline


FIFRA (1947), TSCA (1977)

40 CFR 156

OPPTS 870.2400


FHSA (1964)

16 CFR 1500

16 CFR 1500.42


FDCA (1938)

21 CFR 501–523

16 CFR 1500.42


OHSA (1970)

29 CFR 1910

16 CFR 1500.42

While all three testing guidelines that accompany current regulations are based on the Draize rabbit eye test [6], differences exist in the assay methodologies. OPPTS 870.2400 follows the OECD Test Guideline, TG 405 for Draize eye testing, more closely than 16 CFR 1500.42. EPA guidance requires studies to be carried out for 21 days to evaluate for reversible/irreversible effects, while FHSA only requires 3 days of observation. Other differences in the assay guidance are described in Table 8.3.

Table 8.3
Comparison summary of testing guidelines [9]

Test method component

EPA (TG OPPTS 870.2400)

FHSA (16 CFR 1500.42)

OECD (TG 405)

Number of animals used to make decision

1 to screen for corrosive, then n  ≥  2

1 Animal based on Maximum score in any animal on any day

1 Animal based on Maximum score in any animal on any day

Quantity in test eye

0.1 ml or 0.1 g

0.1 ml or 0.1 g

0.1 ml or 0.1 g

Observation times

1, 24, 48, 72 h, and daily thereafter until lesions clear or 21 days

24, 48, and 72 h

1, 24, 48, 72 h, and daily thereafter until lesions clear or 21 days

Post-dosing irrigation

24 h unless substance is shown to be irritating

24 h

Liquids: 24 h

Solids: 1 h

8.2.2 Hazard Classification Schemes and Labeling Requirements

The desired outcome of ocular toxicity testing based on the testing guidelines defined by regulatory agencies is to classify the ocular hazard of the substance. This allows for the material to be assigned to a group within the agencies’ hazard classification scheme and ensures proper labeling of a material and to provide instructions and warnings. As described above, the Draize eye test is still the test standard recommended by the different regulatory guidelines/guidances, but the interpretation of the results and the subsequent classification schemes vary among the agencies. The Draize eye test is necessary for materials like pesticides that require premarket authorization and hazard and labeling classification, while some industries like personal care products that do not require premarket approval or standardized classification and labeling have greater flexibility in substantiating ocular safety. While a push for alternative assays is ongoing and will be discussed in a later section, no alternative assays are used for hazard classification and labeling. Cosmetics

Cosmetics marketed in the United States are regulated by the FDCA and the Fair Packaging and Labeling Act (FPLA) [1]. Cosmetic products and ingredients are not subject to premarket approval with the exception of colorants, which must meet approved standards in CFR, and certain banned materials. Therefore, cosmetic firms are responsible for substantiating the safety of their products and ingredients prior to marketing. Failure by the cosmetic firm to substantiate safety prior to marketing puts them in violation of the FDCA and potentially subjects them to penalties or recalls. In addition to substantiating safety, the FPLA requires the cosmetic not be misbranded. The label must contain a complete ingredient list, proper warnings, and use instructions and must not contain false claims. Since substantiating the safety of cosmetic products prior to marketing is the responsibility of the cosmetic manufacturer and the specific methodology/approach is not mandated, manufacturers have the flexibility to use varying approaches. For example, many cosmetic firms have moved away from the standard Draize eye test to support ocular safety and have begun to use in vitro alternative assays like the EpiOcular assay to substantiate the safety of their products. Table 8.4 lists many of the common in vitro alternative assays currently in use.

Table 8.4
Ocular toxicity assays and regulatory conclusions


Test type

Assay endpoint

Prediction utility

Bovine corneal opacity and permeability

Isolated eye assay

Barrier function – fluorescein permeability

Conjuctival endpoints


3D epithelial cell models




Chicken egg membrane

Vascular effects

Corneal lesions and iritis Pesticides

As mentioned before, pesticides undergo registration prior to marketing. To ensure the safe use of pesticides, human health, environmental health, and efficacy data are required for submission to EPA. Part of the submission is an ocular toxicity test to determine the ocular hazard of the substance. Animals are tested according to the EPA test guidance OPPTS 870.2400. The conclusions drawn from the test result in classification of the substance and provide recommen­dations for the product label. In the EPA classification scheme, the most severe response seen in an animal is used for classification, which means that in a test with multiple animals, the classification is ultimately based on the most severe response by one animal. The classification scheme in Table 8.5 demonstrates how the results of the ocular toxicity test determine the hazard category of the substance.

Table 8.5
EPA classification scheme for ocular toxicity [9]

EPA category

In vivo effect observed


Corrosive; irreversible corneal involvement or irritation persisting more than 21 days


Corneal involvement or irritation clearing in 8–21 days


Corneal involvement or irritation clearing in ≤7 days


Minimal effects clearing within 24 h

Jul 28, 2016 | Posted by in EXOTIC, WILD, ZOO | Comments Off on Ocular Toxicity Regulatory Considerations for Nondrug Food and Drug Administration (FDA) Products and the Environmental Protection Agency (EPA)
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