The Federal Hazardous Substances Act (FHSA) is one of the laws administered by CPSC. One of the primary functions of the law is to require cautionary labeling on certain household products that contain a hazardous substance. Hazardous substances are those that are toxic, corrosive, an irritant, flammable, combustible, or a strong sensitizer and that may cause substantial personal injury or illness as a result of reasonably foreseeable use. In order to determine the appropriate cautionary labeling, it is necessary to have objective criteria by which the existence of a hazard can be determined. Neither the FHSA nor the regulations issued thereunder require animal testing to determine whether a hazard exists. Under the FHSA animal testing is one possible option that can be used to determine the biological response and appropriate cautionary labeling. The Commission's policy is to find alternatives to traditional animal testing that replace animals, reduce the number of animals tested, and decrease the pain and suffering in animals associated with testing household products. As such, the Commission and CPSC staff strongly encourage the use of scientifically validated alternatives to animal testing and the use of existing information, including expert opinion, prior human experience, and prior animal testing results, in the determination of hazard. The CPSC is a member of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and as such supports that Committee’s development and use of validated alternative test methods. ICCVAM test methods that have been approved by the CPSC for hazard determination under the FHSA are listed on this Web page.
The CPSC has codified its policy on animal testing at 16 C.F.R. § 1500.232 (77 Fed. Reg. 73,286). In addition, the CPSC has amended and updated its animal testing regulations to allow alternatives to animal testing, whenever possible, under 16 CFR part 1500 (77 Fed. Reg. 73,289). The information on this page is intended to supplement the CPSC's statement of policy on animal testing to help industry determine the alternative tests that are acceptable and available currently to determine the hazards addressed by the FHSA.
This page references alternative methods of testing that have been reviewed and approved by CPSC to identify specific hazards under the FHSA. If a manufacturer or other entity performs a hazard test for FHSA labeling purposes that has not been previously approved by the CPSC, that manufacturer may submit its data to the agency and CPSC staff will consider these data on a case-by-case basis. In particular, data generated using Organization for Economic Cooperation and Development (OECD) Guidelines may be considered by the CPSC in making a hazard determination as a result of the Mutual Acceptance of Data (MAD) agreement. The MAD agreement allows OECD member countries to mutually accept data that comply with OECD Test Guidelines and Principles of Good Laboratory Practice. Data from methods other than OECD that are scientifically supportable may be considered as well. However, neither the MAD agreement, nor CPSC staff’s decision to consider any test data, guarantees that CPSC staff will consider those data to be sufficient for purposes of FHSA classification and/or labeling. CPSC will review methods and data before using such data for FHSA labeling determinations.
This document provides guidance to stakeholders (i.e., method developers and product manufacturers) on the process by which CPSC staff assesses whether alternative toxicological methods, integrated approaches, and the resulting data are appropriate for use in hazard labeling under the FHSA.
The guidance includes sections that describe factors, based on current best practices, and provides definitions and discussion of key terms and concepts related to NAMs, IATAs, and the data produced using such methods.
Sections outlined in the guidance document are:
- Background Information
- Submission Process
- Technical Information Factors for Evaluating Alternative Toxicological Test Methods and Integrated Approaches
- Technical Information Factors for Evaluating Data from Alternative Toxicological Methods and Integrated Approaches
- New Approach Method (NAM) Application Form (Optional)
The following definitions are found in the FHSA and Chronic Hazard Guidelines.
FHSA
Chronic Hazard Guidelines
Acute Toxicity Testing
- For each of three exposure routes (oral, dermal, and inhalation), the FHSA distinguishes two levels of acute toxicity: “toxic” and “highly toxic.” These terms are defined in 16 CFR § 1500.3, along with a description of the traditional method for determining the acute toxicity endpoint, the LD50 or the LC50.
Oral acute toxicity testing
- 16 CFR § 1500.3(c)(1)(ii)(A) defines “highly toxic” by the oral exposure route, and § 1500.3(c)(2)(i)(A) gives the FHSA definition of “toxic” by the oral exposure route. These sections also contain guidelines for a traditional acute toxicity test. CPSC staff recommends the revised oral Up-and-Down Procedure (UDP) for determining acute oral toxicity to classify and label under the FHSA. The UDP was issued by U.S. Environmental Protection Agency's Office of Prevention, Pesticides and Toxic Substances (OPPTS) as OPPTS Harmonized Test Guideline 870.1100. The scientifically validated test guideline is referenced in CPSC staff's 2011 Response (pdf) to ICCVAM on Acute Toxicity Testing.
- In addition, CPSC staff has determined that in vitro basal cytotoxicity tests are appropriate for determining a starting dose for the oral LD50 test. The test guidelines are referenced in CPSC staff's 2008 Response (pdf) to ICCVAM on the Use of In Vitro Basal Cytotoxicity Test Methods for Estimating Starting Doses for Acute Oral Systemic Toxicity Testing.
Inhalation acute toxicity testing
- 16 CFR § 1500.3(c)(1)(ii)(B) defines “highly toxic” by the inhalation exposure route, and § 1500.3(c)(2)(i)(B) gives the FHSA definition of “toxic” by the inhalation exposure route.
Dermal acute toxicity testing
- 16 CFR § 1500.3(c)(1)(ii)(C) defines highly toxic by the dermal exposure route, and § 1500.3(c)(2)(i)(C) gives the FHSA definition of toxic by the dermal exposure route. Section 1500.40 of 16 CFR details an in vivo method for testing the acute dermal toxicity of substances. Currently, there are no Commission-approved non-animal methods for dermal toxicity testing.
Ocular Irritation Testing
The Commission has voted to accept the recommendations of ICCVAM on several in vitro alternatives to the Draize rabbit eye test. The strengths and limitations of each method with respect to FHSA labeling requirements are described below.
- In Vitro Ocular Irritation Testing Methods
- The isolated chicken eye (ICE) test can be used as a screening tool for severe irritants/corrosive substances. When the ICE test indicates a substance is a severe ocular irritant/corrosive, that substance can be labeled "irritant" or “corrosive” under FHSA with no additional testing. However, this assay cannot reliably distinguish all substances that require the FHSA irritant label (which includes mild and moderate irritants) from substances not requiring the label. Therefore, if this screening test indicates the substance is not a strong irritant/corrosive, additional testing (i.e., a Draize test) would be necessary for validation and subsequent determination of labeling. The ICE test cannot be used to distinguish substances not requiring the FHSA irritant label from those requiring it. The ICE test cannot be used with alcohols, surfactants, or solids.
- The Bovine Corneal Opacity and Permeability (BCOP) test can be used as a screening tool for severe irritants/corrosive substances. When the BCOP test indicates a substance is a strong irritant/ocular corrosive, that substance can be labeled irritant or corrosive under the FHSA with no additional testing. However, the BCOP test cannot reliably distinguish all substances that require the FHSA irritant label (which include mild and moderate irritants) from substances not requiring the label. If screening indicates the substance is anything but a strong irritant/corrosive, additional testing (i.e., a Draize test) would be necessary for validation and subsequent determination of labeling. The BCOP test cannot be used with alcohols, ketones, or solids.
- Cytosensor Microphysiometer (CM) test method can be used with water-soluble surfactant chemicals and certain types of surfactant-containing formulations (e.g., cosmetics and personal care product formulations, but not pesticide formulations) to distinguish substances not requiring the FHSA irritant label from those requiring the irritant label under FHSA. However, due to a substantial rate of false positive outcomes when the CM test method is being used for this distinction, a substance identified as an irritant would require additional testing in a valid test system (i.e., the Draize test) that can accurately characterize whether it requires hazard labeling.
In Vivo Ocular Irritation Testing Methods
The Commission has approved a modified version of the traditional Draize rabbit eye test for ocular irritants. The traditional test guidelines are outlined in 16 CFR § 1500.42. Modifications to this method comprise a balanced, three-part preemptive pain management strategy using topical anesthetics, systemic analgesics, and humane endpoints to avoid or minimize pain and distress associated with the traditional Draize method.
- Topical Anesthetics: Part one of the modified Draize eye test involves pretreatment of animals with a topical anesthetic and systemic analgesic before applying test substances. The ICCVAM-recommended protocol calls for administration of 0.01 mg/kg buprenorphine by subcutaneous injection 60 minutes before application of the test substance, plus 1 to 2 drops per eye of 0.5 percent proparacaine hydrochloride or 0.5 percent tetracaine hydrochloride 5 minutes before applying the test substance. This topical application can be repeated in 5-minute intervals, as needed, before test substance administration. However, ICCVAM qualified this recommendation with a warning that multiple applications could increase the severity or longevity of ocular lesions.
- Systemic Analgesics: The second part of the pain management strategy is adherence to a routine schedule of systemic analgesia after test substance administration. ICCVAM recommended a "rescue" dose of 0.03 mg/kg buprenorphine, given every 8 hours, and 0.5 mg/kg meloxicam every 12 hours following test substance administration for a distressed animal. If the test animal is not in distress, ICCVAM's protocol called for 0.01 mg/kg buprenorphine, plus 0.5 mg/kg meloxicam, to be delivered subcutaneously 8 hours after test article administration. If ocular lesions and/or clinical signs of pain and distress persist after this combination dose, another dose of buprenorphine could be given at 12-hour intervals and another dose of meloxicam at 24-hour intervals.
- Humane Endpoints: The third part of ICCVAM's recommended pain management strategy was scheduled observations, monitoring, and recording of the nature, severity, and progression of all eye injuries. (One recommended eye irritation scoring system is the U.S. EPA's Test Guideline, OPPTS 870.2400: Acute Eye Irritation) (pdf).
ICCVAM recommended maintaining a written record of all observations to facilitate decisions on the progression or resolution of ocular lesions. Specific methods emphasized by ICCVAM to help detect and measure ocular endpoints included fluorescein staining, slit-lamp biomicroscopy, and digital photography. ICCVAM also identified specific ocular lesions indicative of severity and irreversibility of damage that should warrant termination of studies before the end of the scheduled 21-day observation period, including:
- Draize corneal opacity score of 4 that persists for 48 hours;
- Corneal perforation or significant corneal ulceration, including staphyloma;
- Blood in the anterior chamber of the eye;
- Absence of light reflex that persists for 72 hours;
- Ulceration of the conjunctival membrane;
- Necrosis of the conjunctiva or nictitating membrane;
- Sloughing;
- Destruction of more than 75 percent of the limbus;
- Depth of injury to the cornea (routinely using slit-lamp and fluorescein staining)), in which corneal ulceration extends beyond superficial layers of the stroma;
- Vascularization of the corneal surface (i.e., pannus);
- No diminishment in area of fluorescein staining and/or increase in depth of injury over time; and
- Lack of re-epithelialization 5 days after application of the test substance.
- In Vitro Ocular Irritation Testing Methods
Dermal Irritation Testing
- The traditional in vivo method for testing primary irritants is described in 16 CFR § 1500.41.
- In vitro methods assessing skin irritation and corrosivity have not been assessed by CPSC staff. The Organization for Economic Cooperation and Development (OECD) has written guidelines outlining in vitro methods for determining skin irritation and corrosivity, which are described in OECD Test Guidelines 430 and 431. Data generated using OECD Guidelines can be considered by CPSC in making a hazard determination as a result of the Mutual Acceptance of Data (MAD) agreement. The MAD agreement allows OECD member countries to mutually accept data that comply with OECD Test Guidelines and Principles of Good Laboratory Practice.
Sensitization Testing
- 16 CFR § 1500.3(b)(9) and 16 CFR § 1500.3(c)(5)(i) define the term “strong sensitizer.” The supplemental definition at 16 CFR § 1500.3(c)(5)(ii) references testing on humans and animals, as well as indicates using other types of data to support the determination of a substance as a strong sensitizer.
Alternative methods for testing sensitization that have been approved by the Commission include:
- Murine local lymph node assay (LLNA), plus LLNA method updates;
- Reduced LLNA; and
- Two non-radioactive versions of the LLNA (BrdU-ELISA, LLNA:DA).
These methods have been approved for defined purposes, and are neither required, nor prescriptive. They do not require CPSC to accept data from these methods, nor is the public required to use these methods.
Basal Cytotoxicity Test
The neutral red uptake (NRU) assay in normal human epidermal keratinocytes (NHK) and mouse BALB/c fibroblast (3T3) cell lines
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The NRU test method using 3T3 and NHK cells was recommended by ICCVAM after the international workshop in 2000 for use in the cytotoxicity validation studies. To perform the NRU assay, cells are treated with the test substance, and cell death is measured following exposure to neutral red dye. The amount of dye retained by the cells is a measure of cell death because only viable cells take up and accumulate the neutral red dye.
Staff Recommendations:
The in vitro basal cytotoxicity tests evaluated in this validation study are based on sound science and are scientifically valid to be used as part of a weight-of-evidence approach to estimate the starting doses for acute oral in vivo toxicity test methods, but not to predict acute oral toxicity for the purpose of regulatory hazard classification. Although these test methods are not adequate to replace testing in animals, they can reduce the number of animals required for acute oral toxicity tests. Thus, CPSC staff believes they should be considered for use as part of a weight-of evidence approach before using animals.
Other potential uses, not listed here, may be acceptable. However, potential uses do not commit CPSC to accept any method or data.
Documents:
BG1LucERTA
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
The BG1LucERTA assay may be invaluable when determining whether a compound is a chronic toxicant in a weight-of-evidence approach.
Background:
On February 1, 2012, ICCVAM forwarded to the Commission for action, recommendations regarding the usefulness of the LUMI-CELL® estrogen receptor (BG1LucERTA) screening assay for identifying chemicals in vitro with the potential to activate (agonize) or inactivate (antagonize) the human estrogen receptor.
- The cell line endogenously expresses a large number of both ERα and Erβ.
- The assay uses a human cell line with a reporter gene in a more stable configuration and “natural” copy number.
- The assay does not use animals.
- The assay can identify both ER agonists and antagonists.
- The assay measures the biological response resulting from specific ER binding.
Staff Recommendations:
The BG1LucERTA assay may be invaluable when determining whether a compound is a chronic toxicant in a weight-of-evidence approach.
Documents:
Bovine corneal opacity and permeability (BCOP)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The BCOP test method is proposed as the initial test in a battery of tests to evaluate the ocular irritancy of substances. The BCOP assay uses isolated bovine cornea to predict irritation, as measured by corneal opacity and permeability. The BCOP test should closely model human response because the corneal tissue of the bovine eye is similar to the corneal tissue of the human eye.
Staff Recommendations:
The BCOP can be used as a screening test to identify severe ocular irritants and ocular corrosives as a part of a tiered testing strategy. This strategy calls for a follow-up in vivo study when a negative result is obtained via the BCOP. A positive result does not require further testing.
The BCOP is not recommended for identifying reversible eye irritants (i.e., EPA Category II and III; GHS Category 2A and 2B), as defined by the EPA and GHS classification systems.
Documents:
Corrositex
Contact the Office of Compliance or Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
Corrositex is an in vitro test method that measures the potential of chemicals to cause skin corrosion. The test is based on the ability of a corrosive chemical or chemical mixture to pass through, by diffusion and/or destruction/erosion, a biobarrier and elicit a color change in the underlying liquid Chemical Detection System (CDS).
Staff Recommendations:
The Corrositex assay, subject to the limitations described below, as an alternative to animal testing for evaluation the corrosivity of acids, bases, and acid derivatives that may require labeling under FHSA. A firm that elects to use this method to evaluate chemicals or chemical mixtures that are compatible with the assay must label any substance that tests positive as corrosive, unless the firm has data on animal testing or human experience that leads to a different conclusion. Those chemicals or chemical mixtures that are compatible with the assay and that yield a negative test result require animal testing or other evaluation to confirm the negative result before a decision not to label is made. Those chemicals and chemical mixtures not compatible with the assay, require alternative evaluation.
Documents:
Cytosensor Microphysiometer (CM) Test Method
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The Cytosensor Microphysiometer (CM) test method indirectly measures the metabolic activity of mouse L929 cells exposed to an increasing series of test substance concentrations. Decision criteria for ocular hazard classification for the CM assay are based on the concentration of test material that reduces cellular metabolic rate to 50 percent of the control rate (MRD50). A low value indicates a severe irritant, and a high value indicates a mild or nonirritant, because it takes less of a highly hazardous chemical to produce an adverse effect. An advantage of the CM test method is that its endpoint is a reversible cell change, which may be more appropriate for assessing ocular irritation potential than cell death.
Staff Recommendations:
The CM test method can be supported for its use as a screening test to identify water-soluble substances (water-soluble surfactants, surfactant-containing formulations, and nonsurfactants) as ocular corrosives and severe irritants (EPA Category I, EU R41, GHS Category 1) in a tiered-testing strategy as part of a weight-of-evidence approach.
The CM test method can be used as a screening test to distinguish water-soluble surfactant chemicals and certain types of surfactant-containing formulations that are not labeled as irritants (i.e., EPA Category IV; EU Not Labeled; and FHSA Not Labeled) from all other hazard categories (i.e., EPA Category I, II, III; EU R41, R36; FHSA Irritant) when results are to be used specifically for hazard classification and labeling purposes under the EPA, EU, and FHSA classification systems.
A substance that tests positive in a CM test identifying nonirritants would require additional testing in a valid test system that can characterize accurately whether it requires hazard labeling.
Documents:
Hen's egg test - chorioallantoic (HET-CAM)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The HET-CAM test method is proposed for identifying substances that are severely irritating or corrosive to the conjunctiva. This test method uses chorioallantoic membranes (CAM) from chicken embryos, a proposed model of the conjunctiva. CAMs are composed of blood vessels and proteins that are believed to mimic the response of exposures of test substances in the eye.
Staff Recommendations:
The HET-CAM assay is not a recommended test method for the identification of substances not labeled as irritants when results are to be used for EPA, FHSA, or GHS hazard classifications. Nor is it recommended for the identification of moderate and mild ocular irritants, or for the screening and identification of severe irritants and corrosive ocular irritants in a tiered-testing strategy as part of a weight-of-evidence approach.
Documents:
Isolated Chicken eye ICE
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The ICE test method is proposed as a screening assay to identify the ocular corrosive and severe irritation potential of chemicals or substances. The advantage of this test method is that it utilizes chicken eyes obtained from slaughterhouses.
Staff Recommendations:
The ICE test method is not recommended as a screening test to distinguish substances not labeled as irritants (i.e., EPA Category IV, FHSA Not Labeled, GHS Not Classified) from all other hazard categories (i.e., EPA Category I, II, III; GHS Category 1, 2A, 2B), nor to identify moderate and mild ocular irritants (i.e., EPA Category II, III; GHS Category 2A, 2B) when results are to be used specifically for hazard classification and labeling purposes under any of the hazard classification systems.
The ICE test method can be used as an in vitro alternative to the Draize rabbit eye test to identify ocular corrosives/severe irritants (i.e., EPA Category I, GHS Category 1) for some types of substances.
Documents:
Isolated Rabbit Eye (IRE)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The IRE test method is proposed for identifying substances that are severely irritating or corrosive to the cornea. To perform this assay, the test substance is applied to rabbit eyes mounted in specially designed holders, and the effects of the test substance on the eye are assessed. Four endpoints are scored for the evaluation of ocular irritancy and corrosivity: corneal swelling, corneal opacity, the area of corneal involvement, and permeability.
Staff Recommendations:
The IRE test should not be considered a replacement for the in vivo rabbit eye test and should not be used to classify substances by ocular irritancy.
Documents:
LLNA (all LLNA tests)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
LLNA
Background:
The LLNA is a test method developed to assess the potential of a test substance to induce allergic contact dermatitis in humans. The basic principle underlying the LLNA is that sensitizers induce a proliferation of lymphocytes in the lymph node draining the site of substance application. Under appropriate test conditions, this proliferation is proportional to the dose applied and provides a means of obtaining an objective measurement of sensitization. The LLNA was the first test method evaluated and recommended by ICCVAM.
Staff Recommendations:
LLNA should not be considered a standalone assay for skin sensitization potency classification. Based on the strength of the analysis and the expanding database of LLNA data, this assay can be a valuable tool in a weight-of-evidence evaluation for skin sensitization potency of a substance.
rLLNA
Brief Description:
In 2007, CPSC requested that ICCVAM evaluate several modifications of the traditional LLNA, including the “reduced LLNA” (rLLNA), also referred to as the “cut-down” or “limit dose” LLNA. In the traditional LLNA, three dose levels of each test substance are evaluated. The rLLNA evaluates only the highest dose of the test substance along with concurrent vehicle- and positive-control groups. The highest concentration, as it is for the traditional LLNA, is defined as the maximum soluble concentration that does not induce excessive local irritation and/or overt systemic toxicity.
Staff Recommendations:
Staff recommends that there is applicability for use of the rLLNA when dose-response information is not needed and when it is used in a weight-of-evidence approach. Staff also recommends acceptance of the internationally harmonized LLNA performance standards.
LLNA BrdU-ELISA and LLNA DA
Brief Description:
The LLNA is a test method developed to assess the potential of a test substance to induce allergic contact dermatitis in humans. The basic principle underlying the LLNA is that sensitizers induce a proliferation of lymphocytes in the lymph node draining the site of substance application. Under appropriate test conditions, this proliferation is proportional to the dose applied and provides a means of obtaining an objective measurement of sensitization.
The BrdU-ELISA method is mechanistically and functionally identical to the traditional LLNA. The sole difference is that the BrdU-ELISA assesses cell proliferation using the incorporation of BrdU into newly synthesized DNA, rather than by quantifying the incorporation of 3H-methyl thymidine or 125I-iododeoxyuridine, as is done in the traditional LLNA.
The mechanistic basis of the LLNA:DA is identical to that of the traditional LLNA. However, the LLNA:DA differs from the traditional LLNA in test substance treatment and sampling schedule. The LLNA:DA assesses cell proliferation by detecting increases in adenosine triphosphate (ATP) as an indicator of cell number at the end of cell proliferation rather than by quantifying the incorporation of 3H-methyl thymidine or 125I-iododeoxyuridine as is done in the traditional LLNA. The increase in ATP content in the lymph nodes is then quantified using bioluminescence (a luciferin-luciferase assay). The emitted light intensity is linearly related to the ATP concentration.
Staff Recommendations:
The nonradioactive versions of the LLNA would fit into a weight-of-evidence evaluation under the FHSA. Staff believes that the draft test method recommendations for the BrdU-ELISA and the LLNA:DA adequately address any false positive results, by giving cautionary and weight-of-evidence consideration to the positive substances.
Documents:
Staff Response to ICCVAM Recommendations on Revisions to the Murine Local Lymph Node Assay
Low-Volume Eye Test for Ocular Safety Testing (LVET)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
The low-volume eye test (LVET) is an in vivo test method that assesses the potential ocular irritancy of a test substance. It was developed as an alternative to the Draize rabbit eye test, which had been criticized for overpredicting actual hazard; in some instances, Draize results indicate that innocuous substances are severe ocular irritants or corrosives.
Staff Recommendations:
The LVET is not a complete replacement of the Draize eye test; it should be discontinued for use in regulatory ocular safety testing.
Documents:
OECD Test Guideline No. 496: “In vitro Macromolecular Test Method for Identifying Chemicals Inducing Serious Eye Damage and Chemicals not Requiring Classification for Eye Irritation or Serious Eye Damage.”
Contact the Office of Compliance and Field Operations or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
OECD Test Guideline 496 (OECD 496) is an in vitro method that can be used to identify potential eye irritants. This method is based on macromolecular damage following test chemical exposure. The OECD 496 protocol includes a pre-screen assessment to identify test chemicals that are outside the applicability domain of the test method, and therefore not suitable for evaluation using this method. Other preliminary tests are used to determine the optimal test procedure specific to the chemicals of interest. The test system contains a macromolecular reagent composed of a mixture of proteins, glycoproteins, carbohydrates, lipids, and low molecular weight components, that when rehydrated forms a complex macromolecular matrix which mimics the highly ordered structure of the transparent cornea of the eye. Test substances presenting an eye hazard will produce turbidity (cloudiness) of the matrix by causing disruptions in the proteins, as well as disruption and disaggregation of the matrix components.
Staff Recommendations:
Staff recommends that OECD 496 may be used as part of a tiered testing and risk assessment strategy. In this approach, negative responses are not sufficient for determining labeling under the FHSA. A positive response would require no further testing for FHSA labeling as corrosive to the eye, unless the testing party is concerned about a potential false positive response. The method is not sufficient for labeling as an eye irritant under the FHSA.
Documents:
Pyrogenicity
Determined irrelevant to consumer products and CPSC mission
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Up-and-Down Procedure (UPD)
Contact the Office of Compliance or the Directorate for Health Sciences for any clarification on use of this assay (AlternativeMethods@cpsc.gov).
Brief Description:
One of the alternative methods for in vivo oral acute toxicity testing is known as the UDP. This test method was originally adopted by the OECD (OECD, 1998a) as an alternative to OECD Test Guideline 401 (TG 401), a conventional LD50 assay. At about the same time, the OECD adopted two additional in vivo acute toxicity protocols (OECD TG 420 and 423; OECD 1999a and 1999b). After adopting these three new alternative methods, the OECD proposed deleting OECD Test Guideline 401. Since it was necessary to revise the three methods to conform with a new globally harmonized hazard classification scheme, the U.S. Environmental Protection Agency (EPA) agreed to organize a technical task force to revise the UDP.
Staff Recommendations:
Staff agrees with the peer-review panels and ICCVAM that the revised UDP test is an appropriate method for generating a point estimate for the LD50 for use in hazard classification. Limit-dose testing, as required by the FHSA, may be conducted at 5000 mg/kg using the revised UDP. In addition to providing the necessary information for the appropriate labeling of chemicals, the UDP also reduces the use of animals, and for those that remain, may help to decrease pain and distress.
Documents:
Recommended Response to ICCVAM on Acute Toxicity Testing, August 29, 2003
Frequently Asked Questions
- How do I find CPSC briefing packages on the various methods CPSC has reviewed?
- Go to the web link below and look up the briefing package by name or month and year of publication. https://www.cpsc.gov/Newsroom/FOIA/ReportList?month=all&year=all&nfr_type=commission&title=ICCVAM
- What should I do when I have questions regarding submitting a method or data to CPSC for evaluation?
- You can contact the Directorate for Health Sciences at: alternativemethods@cpsc.gov
- Is there guidance on how to submit methods and data for FHSA labeling purposes when using NAMs?
- Yes, go to the following link to download the CPSC “Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements”
- Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements.
- If a method is listed on CPSC’s Animal Testing web page, does that require the public to use these methods for FHSA labeling purposes?
- No, the public is under no obligation to use any particular method described here when testing to fulfill FHSA labeling requirements.
- If a method is listed on CPSC’s Animal Testing web page, does that require CPSC to accept the method and any data produced by those methods?
- No, the NAMs listed here have been reviewed and approved by CPSC for specific uses, but that does not obligate CPSC to accept or use any data produced under these methods.
- How do I nominate a method to be reviewed by CPSC?
- Information on this can be found if you download a copy of the CPSC “Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements”
- Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements
- This document contains useful information that may be used during the evaluation of any method or associated data.
- There is also an optional nomination form attached to the guidance document which will help gather information which could be helpful in the evaluation of the method.
- Information on this can be found if you download a copy of the CPSC “Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements”
- How do I find out about other federal agencies policies and guidance on NAMs?
- There are several good resources from other federal agencies that may help with NAM development and usage. Here is a list of some agencies web pages that may help.
- ICCVAM:
- FDA:
- EPA:
- There are several good resources from other federal agencies that may help with NAM development and usage. Here is a list of some agencies web pages that may help.