Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73289 

recommended before in vivo dermal 

irritation testing is considered to 

determine appropriate cautionary 

labeling. The weight-of-evidence 

analysis should incorporate any existing 

data on humans and animals, validated 

in vitro or in silico test results (valid 

tests are identified on the Commission’s 

animal testing Web site at: http:// 

www.cpsc.gov/library/ 

animaltesting.html), the substance’s 

dermal toxicity, evidence of corrosivity/ 

irritation of one or more structurally 

related substances or mixtures of such 

substances, data demonstrating low or 

high pH (≤2 or ≥11.5) of the substance, 

and any other relevant physicochemical 

properties that indicate the substance 

might be a dermal corrosive or irritant. 

If there is any indication from this 

analysis that the substance is either 

corrosive or irritating to the skin, the 

substance should be labeled 

appropriately. If the substance is not 

corrosive in vitro, but no data exist 

regarding its irritation potential, human 

patch testing should be considered. If in 

vitro data are unavailable, human patch 

testing is not an option, and there are 

insufficient data to determine the 

weight-of-evidence, a tiered in vivo 

animal test is recommended. 

(A) In a tiered in vivo dermal study, 

a single rabbit is tested initially. If the 

outcome is positive for corrosivity, 

testing is stopped, and the substance is 

labeled appropriately. If the substance is 

not corrosive, two more rabbits should 

be patch-tested to complete the 

assessment of skin irritation potential. 

(B) If a tiered test is not feasible, the 

Commission recommends the test 

method described in § 1500.41. Note 

that in any in vivo dermal irritation test 

method, the Commission recommends 

using a semiocclusive patch to cover the 

animal’s test site and eliminating the 

use of stocks for restraint during the 

exposure period, thereby allowing the 

animal free mobility and access to food 

and water. 

(iii) Ocular irritation. A weight-ofevidence analysis is recommended to 

evaluate existing information before any 

in vivo ocular irritation testing is 

considered. This analysis should 

incorporate any existing data on 

humans and animals, validated in vitro 

or in silico test data (identified on the 

Commission’s animal testing Web site 

at: http://www.cpsc.gov/library/ 

animaltesting.html), the substance’s 

dermal corrosivity/irritation (primary 

skin irritants and corrosives are also 

usually eye irritants and therefore do 

not need to be tested in the eye), 

evidence of ocular irritation of one or 

more structurally related substances or 

mixtures of such substances, data 

demonstrating high acidity or alkalinity 

of the substance, and any other relevant 

physicochemical properties that 

indicate the substance might be a 

dermal corrosive or irritant or ocular 

irritant. 

(A) When the weight-of-evidence is 

insufficient to determine a substance’s 

ocular irritation, a Commissionapproved in vitro or in silico assay for 

ocular irritancy should be run to assess 

eye irritation potential and determine 

labeling. Examples of Commissionvalidated in vitro assays are identified 

on the Commission’s animal testing 

Web site at: http://www.cpsc.gov/ 

library/animaltesting.html). If no valid 

in vitro test exists, the test strategy for 

determining dermal corrosion/irritation 

outlined in paragraph (b)(1)(ii)(B) of this 

section can be followed to determine 

ocular irritation. 

(B) If the dermal test strategy outlined 

in section paragraph (b)(1)(ii)(B) of this 

section leads to a conclusion of not 

corrosive, a tiered in vivo ocular 

irritation test should be performed, in 

which a single rabbit is exposed to the 

substance initially. If the outcome of 

this initial test is positive, testing is 

stopped, and the substance is labeled an 

eye irritant. If the outcome of this initial 

test is negative, one to two more rabbits 

are tested for ocular irritation, and the 

outcome of this test will determine the 

label. If a tiered test is not feasible, the 

Commission recommends the test 

method described in § 1500.42. 

(C) When any ocular irritancy testing 

on animals is conducted, including the 

method described in § 1500.42, the 

Commission recommends a threefold 

plan to reduce animal suffering: The use 

of preemptive pain management, 

including topical anesthetics and 

systemic analgesics that eliminate or 

reduce suffering that may occur as a 

result of the application process or from 

the test substance itself (an example of 

a typical preemptive pain treatment is 

two applications of tetracaine 

ophthalmic anesthetic, 10–15 minutes 

apart, prior to instilling the test material 

to the eye); post-treatment with systemic 

analgesics for pain relief; and 

implementation of humane endpoints, 

including scheduled observations, 

monitoring, and recording of clinical 

signs of distress and pain, and recording 

the nature, severity, and progression of 

eye injuries. The specific techniques 

that have been approved by the 

Commission can be found at: http:// 

www.cpsc.gov/library/ 

animaltesting.html. 

(iv) Dermal sensitization. An 

acceptable in vitro test method 

(examples of valid in vitro tests are 

identified on the Commission’s animal 

testing Web site at: http:// 

www.cpsc.gov/library/ 

animaltesting.html), or weight-ofevidence analysis is recommended 

before in vivo animal sensitization 

testing is considered to determine 

appropriate cautionary labeling. The 

weight-of-evidence analysis should 

incorporate any existing data on 

humans and animals, validated in vitro 

or in silico test results, and any relevant 

physicochemical properties that 

indicate the substance might be a 

dermal sensitizer. If there is any 

indication from this analysis that the 

substance is sensitizing to the skin, the 

substance should be labeled 

appropriately. 

(2) [Reserved]. 

Dated: November 29, 2012. 

Todd A. Stevenson, 

Secretary, Consumer Product Safety 

Commission. 

[FR Doc. 2012–29260 Filed 12–7–12; 8:45 am] 

BILLING CODE 6355–01–P 

CONSUMER PRODUCT SAFETY 

COMMISSION 

[CPSC Docket No. CPSC–2012–0036] 

16 CFR Part 1500 

Hazardous Substances and Articles; 

Administration and Enforcement 

Regulations: Revisions to Animal 

Testing Regulations 

AGENCY: Consumer Product Safety 

Commission. 

ACTION: Final rule. 

SUMMARY: The U.S. Consumer Product 

Safety Commission (CPSC or 

Commission) amends regulations on the 

CPSC’s animal testing methods under 

the Federal Hazardous Substances Act 

(FHSA). 

DATES: This rule is effective on January 

9, 2013. 

FOR FURTHER INFORMATION CONTACT: 

Leslie E. Patton, Ph.D., Project Manager, 

Office of Hazard Identification and 

Reduction, U.S. Consumer Product 

Safety Commission, 4330 East West 

Highway, Bethesda, MD 20814; 

telephone (301) 504–7848; 

lpatton@cpsc.gov. 

SUPPLEMENTARY INFORMATION: 

A. Background 

The Federal Hazardous Substances 

Act (FHSA), 15 U.S.C. 1261–1278, 

requires appropriate cautionary labeling 

on certain hazardous household 

products to alert consumers to the 

potential hazards that a product may 

present. Among the hazards addressed 


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73290 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

by the FHSA are products that are toxic, 

corrosive, irritants, flammable, 

combustible, or strong sensitizers. The 

FHSA and the Commission regulations 

at 16 CFR part 1500 provide certain 

definitions and test methods related to 

testing on animals to determine the 

existence of the hazards addressed by 

the FHSA. 

On June 29, 2012, the Commission 

issued a notice of proposed rulemaking 

to amend and to update regulations on 

the CPSC’s animal testing methods 

under the FHSA. 77 FR 38754. The 

Commission proposed amendments to 

the regulations that interpret, 

supplement, or provide alternatives to 

definitions of animal test methods used 

to aid in the classification of hazardous 

substances under the FHSA. 

In addition, on June 29, 2012, the 

Commission proposed to codify its 

statement of policy on animal testing to 

reflect new methods accepted by the 

scientific community as replacements, 

reductions, or refinements to animal 

tests including recommendations and 

test methods of the Interagency 

Coordinating Committee on the 

Validation of Alternative Methods 

(ICCVAM; http://iccvam.niehs.nih.gov/ 

home.htm) approved by the 

Commission. 77 FR 38751. The 

proposed codification at 16 CFR 

1500.232 would make the ICCVAM 

recommendations and the Commission’s 

animal testing policy more accessible 

and transparent to interested parties. 

The Commission has also established a 

Web page on the CPSC’s Web site at 

http://www.cpsc.gov/library/ 

animaltesting.html regarding the 

ICCVAM recommendations and new 

developments in test methods that avoid 

or further reduce or refine animal 

testing. The final statement on the 

CPSC’s animal testing policy is 

published elsewhere in this Federal 

Register. 

B. Response to Comments on the 

Proposed Rule 

In the Federal Register of June 29, 

2012, we published a proposed rule on 

revisions to the animal testing 

regulations (77 FR 38754). We received 

three comments on the proposed rule. 

Two of the comments were from 

individuals and the third comment was 

submitted jointly by the Alternatives 

Research and Development Foundation, 

American Anti-Vivisection Society, 

Humane Society of the United States, 

People for the Ethical Treatment of 

Animals, and the Physicians Committee 

for Responsible Medicine. 

1. Non-animal Testing Alternatives 

Comment: All three commenters urge 

the Commission to more strongly 

consider non-animal testing 

alternatives. One commenter suggests 

that the NPR underemphasizes in vitro 

and in silico alternatives to animal 

testing throughout relevant sections of 

16 CFR part 1500. The commenter gives 

examples of in vitro tests to support this 

assertion. 

Response: The Commission agrees 

that in vitro and in silico tests should be 

mentioned in the regulation as general 

options in a testing strategy and the rule 

has been revised accordingly. 

2. Alternatives 

Comment: One commenter notes that 

the Commission’s stated preference for 

human data/experience over animal 

testing results is not referenced in the 

relevant sections of 16 CFR part 1500. 

The commenter also provides a number 

of examples where in vivo test methods 

were detailed while the preference for 

alternatives was mentioned only briefly. 

Response: The FHSA direct that 

reliable human experience data take 

precedence over differing results from 

animal tests. 15 U.S.C. 1261(h)(2). 

Therefore, the Commission would 

always consider human experience with 

products and substances first, when it 

exists, followed by a thorough 

examination of the existing animal 

database. The Commission likewise 

recommends this approach to 

manufacturers who are labeling 

substances to indicate a hazard. 

Accordingly, the proposed rule has been 

revised to make the preference for 

human data clearer in the regulatory 

text. 

3. In Vivo Testing 

Comment: One commenter suggests 

that the regulations uncouple 

definitions of toxic effects from specific 

animal test results and that these animal 

tests are ‘‘enumerated with such detail 

as part of the definition [as to be] 

problematic.’’ The commenter urges the 

Commission to remove nearly all 

references to the in vivo tests that 

comprise the existing text of 16 CFR 

1500.3(c)(1–4), 1500.40, 1500.41, and 

1500.42. 

Response: The Commission disagrees 

that the hazard definitions using animal 

test methods are problematic. The test 

methods currently described in the 

FHSA and relevant sections of 16 CFR 

part 1500 are intended to show how the 

Commission would make a hazard 

determination in the absence of human 

experiential data, existing animal data, 

or another acceptable alternative, and 

are not mandatory or even necessarily 

recommended test methods for 

manufacturers. These methods set a 

baseline standard for hazard testing 

against which alternative tests can be 

compared for validity and reliability. 

They serve as the baseline because they 

have been used traditionally in hazard 

testing, not because they are considered 

superior to other methods. Therefore, 

while we understand the need to be 

clear on the discretionary nature of in 

vivo testing, these methods cannot be 

removed from the regulations altogether. 

However, the proposed rule has been 

revised to emphasize the use of in vitro 

and other alternative test methods and 

prior human experience throughout the 

relevant sections of 16 CFR part 1500. 

Other Comments 

Comment: One commenter states that 

CPSC’s animal testing guidelines Web 

site should not be limited to listing 

ICCVAM test methods, but should 

include new methods than can replace 

animal-based tests. In addition, this 

commenter requests that the Web site 

contain a process that would allow the 

public to propose changes to the test 

methods on the Web site. 

Response: We address these 

comments in further detail in response 

to the comments on the Final Statement 

on Animal Testing Policy published 

elsewhere in this Federal Register. In 

that policy statement we indicate that 

alternative test methods beyond those 

reviewed and recommended by 

ICCVAM may be acceptable. If a 

manufacturer or other entity performs a 

hazard test for FHSA labeling purposes 

that has not been previously approved 

by the Commission (i.e. an ICCVAMrecommended test method or one of the 

tests described in the current FHSA), 

the CPSC staff will review such data on 

a case-by-case basis before it will post 

any changes on the animal testing 

policy Web site. Although the 

Commission welcomes input from the 

public regarding new test methods, 

proposed changes to the test methods 

will be posted on the animal testing 

guidelines Web page only after review 

of the data regarding the proposed test 

method by CPSC staff. 

C. Revisions to Animal Testing 

Regulations 

1. Definition of highly toxic. 

Currently, the test methods in 

§ 1500.3(c)(1)(ii)(A) through (C), used in 

the definitions of oral, inhalation, and 

dermal toxicity, respectively, each 

describe a method for defining a 

substance as highly toxic. 

Because there are other Commissionapproved test methods that may be used 


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Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73291 

by CPSC staff or the public for toxicity 

testing and defining a substance as 

highly toxic, as reflected in the ICCVAM 

recommendations and outlined in the 

CPSC’s statement of policy on animal 

testing published elsewhere in this 

Federal Register, the proposed rule 

added language (in underline) under 

new § 1500.3(c)(1)(iii) as follows: A 

substance that produces a result of 

‘highly toxic’ in any of the approved test 

methods described in the CPSC’s animal 

testing policy set forth in 16 CFR 

1500.232. 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule provides additional 

language (in underline) to § 1500.3(c)(1) 

as follows: 

To provide flexibility as to the number of 

animals tested, and to emphasize in vitro 

testing methods, the following is an 

alternative to the definition of ‘‘highly toxic’’ 

in section 2(h) of the act (and paragraph 

(b)(6) of this section). 

In addition, the final rule provides 

additional language (in underline) to 

§ 1500.3(c)(1)(iii) as follows: 

A substance that produces a result of 

‘highly toxic’ in any of the approved test 

methods described in the CPSC’s animal 

testing policy set forth in 16 CFR 1500.232, 

including data from in vitro or in silico test 

methods that the Commission has approved; 

or a validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal data, 

structure activity relationships, 

physicochemical properties, and chemical 

reactivity data. 

2. Definition of toxic. Currently, the 

test methods in § 1500.3(c)(2)(i)(A) 

through (C) used in the definitions of 

oral, inhalation, and dermal toxicity, 

respectively, each describe a method for 

defining a substance as toxic. 

Because there are other Commissionapproved test methods that may be used 

by CPSC staff or the public for toxicity 

testing and defining a substance as 

toxic, as reflected in the ICCVAM 

recommendations, and outlined in the 

CPSC’s statement of policy on animal 

testing, the proposed rule added 

language (in underline) under new 

§ 1500.3(c)(2)(iii) as follows: 

Toxic also applies to any substance that 

can be labeled as such, based on the outcome 

of any of the approved test methods 

described in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232. 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule provides additional 

language (in underline) to § 1500.3(c)(2) 

as follows: 

To give specificity to the definition of 

‘‘toxic’’ in section 2(g) of the act (and restated 

in paragraph (b)(5) of this section), the 

following supplements that definition. 

‘‘Toxic’’ applies to any substance that is 

‘‘toxic’’ (but not ‘‘highly toxic’’) on the basis 

of human experience. The following 

categories are not intended to be inclusive. 

In addition, in the final rule, the 

Commission is moving the text from 

proposed section (iii) to section (i) to 

more accurately reflect that the text 

applies to the section on acute toxicity, 

rather than to create a separate section. 

Accordingly, the last sentence in 

§ 1500.3(c)(2)(i) has been revised (in 

underline) as follows: 

Toxic also applies to any substance that 

can be labeled as such, based on the outcome 

of any of the approved test methods 

described in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232, including data 

from in vitro or in silico test methods that the 

Commission has approved; or a validated 

weight-of-evidence analysis comprising all of 

the following that are available: existing 

human and animal data, structure activity 

relationships, physicochemical properties, 

and chemical reactivity data. 

3. Definition of corrosive. 16 CFR 

1500.3(c)(3) currently states that: 

Corrosive means ‘‘a substance that 

causes visible destruction or irreversible 

alterations in the tissue at the site of 

contact. A test for a corrosive substance 

is whether, by human experience, such 

tissue destruction occurs at the site of 

application. A substance would be 

considered corrosive to the skin if, 

when tested on the intact skin of the 

albino rabbit by the technique described 

in § 1500.41, the structure of the tissue 

at the site of contact is destroyed or 

changed irreversibly in 24 hours or less. 

Other appropriate tests should be 

applied when contact of the substance 

with other than skin tissue is being 

considered.’’ 

The proposed rule added the 

following text (in underline) to 16 CFR 

1500.3(c)(3): 

Corrosive means a substance that causes 

visible destruction or irreversible alterations 

in the tissue at the site of contact. A test for 

a corrosive substance is whether, by human 

experience, such tissue destruction occurs at 

the site of application. A substance would be 

considered corrosive to the skin if a weightof-evidence analysis suggests that it is 

corrosive or if, when tested by the in vivo 

technique described in § 1500.41, the 

structure of the tissue at the site of contact 

is destroyed or changed irreversibly in 24 

hours or less. Other appropriate tests should 

be applied when contact of the substance 

with other than skin tissue is being 

considered. A substance could also be 

labeled corrosive based on the outcome of 

any of the approved test methods described 

in the CPSC’s animal testing policy set forth 

in 16 CFR 1500.232. 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule provides additional 

language (in underline) to § 1500.3(c)(3) 

as follows: 

Corrosive means a substance that causes 

visible destruction or irreversible alterations 

in the tissue at the site of contact. A test for 

a corrosive substance is whether, by human 

experience, such tissue destruction occurs at 

the site of application. A substance would be 

considered corrosive to the skin if a weightof-evidence analysis suggests that it is 

corrosive, or validated in vitro test method 

suggests that it is corrosive, or if, when tested 

by the in vivo technique described in 

§ 1500.41, the structure of the tissue at the 

site of contact is destroyed or changed 

irreversibly in 24 hours or less. Other 

appropriate tests should be applied when 

contact of the substance with other than skin 

tissue is being considered. A substance could 

also be labeled corrosive based on the 

outcome of any of the approved test methods 

described in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232, including data 

from in vitro or in silico test methods that the 

Commission has approved; or a validated 

weight-of-evidence analysis comprising all of 

the following that are available: existing 

human and animal data, structure activity 

relationships, physicochemical properties, 

and chemical reactivity data. 

4. Definition of irritant, primary 

irritant, and eye irritant. Currently, 16 

CFR 1500.3(c)(4) provides that the test 

methods for irritant, primary irritant, 

and eye irritant reference 16 CFR 

1500.41 and 1500.42, which each 

describe a specific animal test method 

and outcome. For example, 16 CFR 

1500.41 states that primary irritation to 

the skin is measured by a patch-test 

technique on the abraded and intact 

skin of the albino rabbit, clipped free of 

hair. A minimum of six subjects are 

used in the skin tests. To test for eye 

irritants, 16 CFR 1500.42 requires the 

use of six albino rabbits. Such tests 

require the test material be placed in 

one eye of each animal, while the other 

eye remains untreated, to serve as a 

control to assess the grade of ocular 

reaction. 

The proposed rule added the 

following language (in underline) to 

§ 1500.3(c)(4): 

The definition of irritant in section 2(j) of 

the act (restated in paragraph (b)(8) of this 

section) is supplemented by the following: 

Irritant includes primary irritant to the skin, 

as well as substances irritant to the eye or to 

mucous membranes. Primary irritant means a 

substance that is not corrosive and that 

human experience data indicate is a primary 

irritant; and/or means a substance that results 


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73292 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

in an empirical score of five or more when 

tested by the method described in 1500.41; 

and/or a substance that can be considered a 

primary irritant based on the outcome of any 

of the approved test methods described in the 

CPSC’s animal testing policy set forth in 16 

CFR 1500.232. Eye irritant means a substance 

that human experience data indicate is an 

irritant to the eye; and/or means a substance 

for which a positive test is obtained when 

tested by the method described in 1500.42; 

and/or means a substance that can be 

considered an eye irritant based on the 

outcome of any of the approved test methods 

described in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232. 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule provides additional 

language (in underline) to § 1500.3(c)(4) 

as follows: 

The definition of irritant in section 2(j) of 

the act (restated in paragraph (b)(8) of this 

section) is supplemented by the following: 

Irritant includes primary irritant to the skin, 

as well as substances irritant to the eye or to 

mucous membranes. Primary irritant means a 

substance that is not corrosive and that 

human experience data indicate is a primary 

irritant; and/or means a substance that results 

in an empirical score of five or more when 

tested by the method described in § 1500.41; 

and/or a substance that can be considered a 

primary irritant based on the outcome of any 

of the approved test methods described in the 

CPSC’s animal testing policy set forth in 16 

CFR 1500.232, including data from in vitro 

or in silico test methods that the Commission 

has approved; or a validated weight-ofevidence analysis comprising all of the 

following that are available: existing human 

and animal data, structure activity 

relationships, physicochemical properties, 

and chemical reactivity data. Eye irritant 

means a substance that human experience 

data indicate is an irritant to the eye; and/ 

or means a substance for which a positive 

test is obtained when tested by the method 

described in 1500.42; and/or means a 

substance that can be considered an eye 

irritant based on the outcome of any of the 

approved test methods described in the 

CPSC’s animal testing policy set forth in 16 

CFR 1500.232, including data from in vitro 

or in silico test methods that the Commission 

has approved; or a validated weight-ofevidence analysis comprising all of the 

following that are available: existing human 

and animal data, structure activity 

relationships, physicochemical properties, 

and chemical reactivity data. 

5. Method of Testing Toxic 

Substances 

The method of testing toxic 

substances is set forth under 16 CFR 

1500.40. This method details an acute 

dermal toxicity assay using rabbits. The 

method is referenced in 

§ 1500.3(c)(1)(ii)(C) and (c)(2)(C). The 

proposed rule added the following text 

(in underline) to § 1500.40 immediately 

after the heading titled, ‘‘Method of 

testing toxic substances’’: 

Guidelines for testing the toxicity of 

substances, including testing that does not 

require animals, are presented in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232. A weight-of-evidence analysis is 

recommended to evaluate existing 

information before in vivo tests are 

considered. This analysis, when deemed 

necessary to carry out, should include any of 

the following: existing human and animal 

data, in vitro data, structure activity 

relationships, physicochemical properties, 

and chemical reactivity. When in vivo testing 

is necessary, a sequential testing strategy is 

recommended to reduce the number of test 

animals. 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule modifies the language (in 

underline) to § 1500.40 as follows: 

Guidelines for testing the toxicity of 

substances, including testing that does not 

require animals, are presented in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232. A weight-of-evidence analysis, 

including any of the following: existing 

human and animal data, structure activity 

relationships, physicochemical properties; 

and chemical reactivity, or validated in vitro 

or in silico testing are recommended to 

evaluate existing information before in vivo 

tests are considered. If in vivo testing is 

conducted, a sequential testing strategy is 

recommended to reduce the number of test 

animals. 

6. Method of Testing Primary Irritant 

Substances 

The method of testing primary irritant 

substances is set forth under 16 CFR 

1500.41. This method details an acute 

dermal toxicity assay using rabbits. The 

method is referenced in § 1500.3(c)(3) 

and (4). The proposed rule added the 

following text (in underline) to 

§ 1500.41 immediately after the heading 

titled, ‘‘Method of testing primary 

irritant substances’’: 

Guidelines for testing the dermal irritation 

and corrosivity properties of substances, 

including testing that does not require 

animals, are presented in the CPSC’s animal 

testing policy set forth in 16 CFR 1500.232. 

A weight-of-evidence analysis is 

recommended to evaluate existing 

information before in vivo tests are 

considered. This analysis should include all 

of the following that are available: human 

and animal data, structure activity 

relationships, physicochemical properties, 

and dermal toxicity. When in vivo testing is 

necessary, a sequential testing strategy is 

recommended to reduce the number of test 

animals. The method of testing the dermal 

corrosivity and primary irritation of 

substances referred to in § 1500.3(c)(3) and 

(4), respectively, is a patch-test technique on 

the abraded and intact skin of the albino 

rabbit, clipped free of hair* * * 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule modifies the language (in 

underline) to § 1500.41 as follows: 

Guidelines for testing the dermal irritation 

and corrosivity properties of substances, 

including testing that does not require 

animals, are presented in the CPSC’s animal 

testing policy set forth in 16 CFR 1500.232. 

A weight-of-evidence analysis or a validated 

in vitro test method is recommended to 

evaluate existing information before in vivo 

tests are considered. This analysis should 

include all of the following that are available: 

human and animal data, structure activity 

relationships, physicochemical properties, 

and dermal toxicity. If in vivo testing is 

conducted, a sequential testing strategy is 

recommended to reduce the number of test 

animals. The method of testing the dermal 

corrosivity and primary irritation of 

substances referred to in § 1500.3(c)(3) and 

(4), respectively, is a patch-test technique on 

the abraded and intact skin of the albino 

rabbit, clipped free of hair * * *. 

7. Test for Eye Irritants 

Section 1500.42 of 16 CFR provides a 

detailed animal test for eye irritation. 

The method is referenced in 

§ 1500.3(c)(4), which defines irritation. 

The proposed rule added the following 

text (in underline) to § 1500.42 

immediately after the heading titled, 

‘‘Test for eye irritants’’: 

Guidelines for in vivo and in vitro testing 

of ocular irritation of substances, including 

testing that does not require animals, are 

presented in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232. A weight-ofevidence analysis is recommended to 

evaluate existing information before in vivo 

tests are considered. This analysis should 

include any of the following: existing human 

and animal data on ocular or dermal 

irritation, structure activity relationships, 

physicochemical properties, and chemical 

reactivity. When in vivo testing is necessary, 

a sequential testing strategy is recommended 

to reduce the number of test animals. 

Additionally, the routine use of topical 

anesthetics, systemic analgesics, and 

humane endpoints to avoid or minimize pain 

and distress in ocular safety testing is 

recommended. (a)(1) In the method of testing 

the ocular irritation of a substance referred 

to in § 1500.3(c)(4), six albino rabbits are 

used for each test substance* * * 

In response to comments that request 

that the rule contain more references to 

human experience or in vitro or in silico 

tests as non-animal testing alternatives, 

the final rule modifies the language (in 

underline) to § 1500.42 as follows: 

Guidelines for in vivo and in vitro testing 

of ocular irritation of substances, including 

testing that does not require animals, are 

presented in the CPSC’s animal testing policy 

set forth in 16 CFR 1500.232. A weight-ofevidence analysis or a validated in vitro test 

method is recommended to evaluate existing 


srobinson on DSK4SPTVN1PROD with 
Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73293 

1EPA. 1998. Health Effects Test Guidelines, 

OPPTS 870.2400 Acute Eye Irritation. EPA 712–C– 

98–195. Washington, DC: U.S. Environmental 

Protection Agency. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/EPA/ 

EPA_870_2400.pdf) 

2OECD. 2002. OECD Guideline for the Testing of 

Chemicals 405: Acute Eye Irritation/Corrosion. 

Paris: Organisation for Economic Co-operation and 

Development. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/OECD/ 

OECDtg405.pdf) 

information before in vivo tests are 

considered. This analysis should include any 

of the following: existing human and animal 

data on ocular or dermal irritation, structure 

activity relationships, physicochemical 

properties, and chemical reactivity. If in vivo 

testing is conducted, a sequential testing 

strategy is recommended to reduce the 

number of test animals. Additionally, the 

routine use of topical anesthetics, systemic 

analgesics, and humane endpoints to avoid 

or minimize pain and distress in ocular 

safety testing is recommended. (a)(1) In the 

method of testing the ocular irritation of a 

substance referred to in § 1500.3(c)(4), six 

albino rabbits are used for each test 

substance* * * 

8. Editorial changes 

The proposed rule eliminates the 

reference in § 1500.42(c) to the 

‘‘Illustrated Guide for Grading Eye 

Irritation by Hazardous Substances,’’ 

and the accompanying note. The 

referenced guide is out of print, and 

photocopies are rare. Accordingly, the 

proposed rule amended § 1500.42(c) to 

reference guidelines from the U.S. 

Environmental Protection Agency (EPA) 

and the Organisation for Economic Cooperation and Development (OECD) as 

follows: 

To assist testing laboratories and others 

interested in interpreting ocular irritation test 

results, the CPSC animal testing policy Web 

page at http://www.cpsc.gov/library/ 

animaltesting.html will contain the scoring 

system defined in the U.S. EPA’s Test 

Guideline, OPPTS 870.2400: Acute Eye 

Irritation 1 or the OECD Test Guideline 405: 

Acute Eye Irritation/Corrosion.2

The only change made to this section 

was to update the Web page link for the 

CPSC animal testing guidelines. 

C. Impact on Small Businesses 

The Commission certifies that this 

rule will not a have a significant impact 

on a substantial number of small entities 

under section 605(b) of the Regulatory 

Flexibility Act (RFA), 5 U.S.C. 605(b). 

The Commission’s Directorate for 

Economic Analysis prepared an 

assessment of the impact of amending 

the regulations on animal testing. That 

assessment found that there would be 

little or no effect on small businesses 

and other entities because the 

amendments will not result in product 

modifications in order to comply, and 

they will not result in additional testing 

or recordkeeping burdens. 

D. Environmental Considerations 

Generally, CPSC rules are considered 

to ‘‘have little or no potential for 

affecting the human environment,’’ and 

environmental assessments and 

environmental impact statements are 

not usually prepared for these rules (see 

16 CFR 1021.5(c)(1)). The Commission 

does not expect the rule to have any 

adverse impact on the environment 

under this categorical exclusion. 

E. Executive Orders 

According to Executive Order 12988 

(February 5, 1996), agencies must state 

in clear language the preemptive effect, 

if any, of new regulations. The 

preemptive effect of regulations such as 

this proposed rule is stated in section 18 

of the FHSA. 15 U.S.C. 1261n. 

F. Paperwork Reduction Act 

This rule would not impose any 

information collection requirements. 

Accordingly, this rule is not subject to 

the Paperwork Reduction Act, 44 U.S.C. 

3501–3520. 

G. Effective Date 

The Administrative Procedure Act 

generally requires that a substantive rule 

be published not less than 30 days 

before its effective date, unless the 

agency finds, for good cause shown, that 

a lesser time period is required. 5 U.S.C. 

553(d)(3). The final rule will take effect 

30 days after publication in the Federal 

Register. 

List of Subjects in 16 CFR Part 1500 

Consumer protection, Hazardous 

substances, Imports, Infants and 

children, Labeling, Law enforcement, 

Reporting and recordkeeping 

requirements, and Toys. 

Accordingly, 16 CFR part 1500 is 

amended as follows: 

PART 1500—[AMENDED] 

■ 1. The authority citation for part 1500 

continues to reads as follows: 

Authority: 15 U.S.C. 1261–1278. 

■ 2. Section1500.3 is amended by: 

■ a. Revising paragraph (c)(1) 

introductory text; 

■ b. Adding paragraph (c)(1)(iii); 

■ c. Revising paragraph (c)(2) 

introductory text; 

■ d. Revising paragraph (c)(2)(i) and 

■ e. Revising paragraphs (c)(3) and (4). 

The revisions and addition read as 

follows: 

§ 1500.3 Definitions 

* * * * * 

(c) * * * 

(1) To provide flexibility as to the 

number of animals tested, and to 

emphasize in vitro testing methods, the 

following is an alternative to the 

definition of ‘‘highly toxic’’ in section 

2(h) of the act (and paragraph (b)(6) of 

this section); Highly toxic means: 

* * * * * 

(iii) A substance that produces a 

result of ‘highly toxic’ in any of the 

approved test methods described in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232, including data from in 

vitro or in silico test methods that the 

Commission has approved; or a 

validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal 

data, structure activity relationships, 

physicochemical properties, and 

chemical reactivity data. 

(2) To give specificity to the definition 

of ‘‘toxic’’ in section 2(g) of the act (and 

restated in paragraph (b)(5) of this 

section), the following supplements that 

definition. ‘‘Toxic’’ applies to any 

substance that is ‘‘toxic’’ (but not 

‘‘highly toxic’’) on the basis of human 

experience. The following categories are 

not intended to be inclusive. * * * 

(i) The number of animals tested shall 

be sufficient to give a statistically 

significant result and shall be in 

conformity with good pharmacological 

practices. Toxic also applies to any 

substance that can be labeled as such, 

based on the outcome of any of the 

approved test methods described in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232, including data from, 

including data from in vitro or in silico 

test methods that the Commission has 

approved; or a validated weight-ofevidence analysis comprising all of the 

following that are available: existing 

human and animal data, structure 

activity relationships, physicochemical 

properties, and chemical reactivity data. 

* * * * * 

(3) Corrosive means a substance that 

causes visible destruction or irreversible 

alterations in the tissue at the site of 

contact. A test for a corrosive substance 

is whether, by human experience, such 

tissue destruction occurs at the site of 

application. A substance would be 

considered corrosive to the skin if a 

weight-of-evidence analysis suggests 

that it is corrosive, or validated in vitro 

test method suggests that it is corrosive, 

or if, when tested by the in vivo 

technique described in § 1500.41, the 

structure of the tissue at the site of 

contact is destroyed or changed 

irreversibly in 24 hours or less. Other 

appropriate tests should be applied 

when contact of the substance with 


srobinson on DSK4SPTVN1PROD with 
73294 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

1EPA. 1998. Health Effects Test Guidelines, 

OPPTS 870.2400 Acute Eye Irritation. EPA 712–C– 

98–195. Washington, DC: U.S. Environmental 

Protection Agency. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/EPA/ 

EPA_870_2400.pdf) 

2OECD. 2002. OECD Guideline for the Testing of 

Chemicals 405: Acute Eye Irritation/Corrosion. 

Paris: Organisation for Economic Co-operation and 

Development. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/OECD/ 

OECDtg405.pdf) 

other than skin tissue is being 

considered. A substance could also be 

labeled corrosive based on the outcome 

of any of the approved test methods 

described in the CPSC’s animal testing 

policy set forth in 16 CFR 1500.232, 

including data from in vitro or in silico 

test methods that the Commission has 

approved; or a validated weight-ofevidence analysis comprising all of the 

following that are available: Existing 

human and animal data, structure 

activity relationships, physicochemical 

properties, and chemical reactivity data. 

(4) The definition of irritant in section 

2(j) of the act (restated in paragraph 

(b)(8) of this section) is supplemented 

by the following: Irritant includes 

primary irritant to the skin, as well as 

substances irritant to the eye or to 

mucous membranes. Primary irritant 

means a substance that is not corrosive 

and that human experience data 

indicate is a primary irritant; and/or 

means a substance that results in an 

empirical score of five or more when 

tested by the method described in 

1500.41; and/or a substance that can be 

considered a primary irritant based on 

the outcome of any of the approved test 

methods described in the CPSC’s animal 

testing policy set forth in 16 CFR 

1500.232, including data from in vitro or 

in silico test methods that the 

Commission has approved; or a 

validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal 

data, structure activity relationships, 

physicochemical properties, and 

chemical reactivity data. Eye irritant 

means a substance that human 

experience data indicate is an irritant to 

the eye; and/or means a substance for 

which a positive test is obtained when 

tested by the method described in 

1500.42; and/or means a substance that 

can be considered an eye irritant based 

on the outcome of any of the approved 

test methods described in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232, including data from in vitro or 

in silico test methods that the 

Commission has approved; or a 

validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal 

data, structure activity relationships, 

physicochemical properties, and 

chemical reactivity data. 

* * * * * 

■ 3. Amend § 1500.40 by revising the 

introductory text to read as follows: 

§ 1500.40 Method of testing toxic 

substances. 

Guidelines for testing the toxicity of 

substances, including testing that does 

not require animals, are presented in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232. A weight-of-evidence 

analysis, including any of the following: 

existing human and animal data, 

structure activity relationships, 

physicochemical properties; and 

chemical reactivity, or validated in vitro 

or in silico testing are recommended to 

evaluate existing information before in 

vivo tests are considered. If in vivo 

testing is conducted, a sequential testing 

strategy is recommended to reduce the 

number of test animals. The method of 

testing the toxic substances referred to 

in § 1500.3(c)(1)(ii)(C) and (c)(2)(iii) is as 

follows: 

* * * * * 

■ 4. In § 1500.41, add five sentences at 

the start of the introductory text to read 

as follows: 

§ 1500.41 Method of testing primary 

irritant substances. 

Guidelines for testing the dermal 

irritation and corrosivity properties of 

substances, including testing that does 

not require animals, are presented in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232. A weight-of-evidence 

analysis or a validated in vitro test 

method is recommended to evaluate 

existing information before in vivo tests 

are considered. This analysis should 

include all of the following that are 

available: human and animal data, 

structure activity relationships, 

physicochemical properties, and dermal 

toxicity. If in vivo testing is conducted, 

a sequential testing strategy is 

recommended to reduce the number of 

test animals. The method of testing the 

dermal corrosivity and primary 

irritation of substances referred to in 

§ 1500.3(c)(3) and (4), respectively, is a 

patch-test technique on the abraded and 

intact skin of the albino rabbit, clipped 

free of hair. * * * 

* * * * * 

■ 5. Amend § 1500.42 by adding 

introductory text, revising the first 

sentence of paragraph (a)(1), and 

revising paragraph (c) to read as follows: 

§ 1500.42 Test for eye irritants. 

Guidelines for in vivo and in vitro 

testing of ocular irritation of substances, 

including testing that does not require 

animals, are presented in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232. A weight-of-evidence analysis 

or a validated in vitro test method is 

recommended to evaluate existing 

information before in vivo tests are 

considered. This analysis should 

include any of the following: Existing 

human and animal data on ocular or 

dermal irritation, structure activity 

relationships, physicochemical 

properties, and chemical reactivity. If in 

vivo testing is conducted, a sequential 

testing strategy is recommended to 

reduce the number of test animals. 

Additionally, the routine use of topical 

anesthetics, systemic analgesics, and 

humane endpoints to avoid or minimize 

pain and distress in ocular safety testing 

is recommended. 

(a)(1) In the method of testing the 

ocular irritation of a substance referred 

to in § 1500.3(c)(4), six albino rabbits are 

used for each test substance * * * 

* * * * * 

(c) To assist testing laboratories and 

others interested in interpreting ocular 

irritation test results, the CPSC animal 

testing policy Web page at http:// 

www.cpsc.gov/library/ 

animaltesting.html will contain the 

scoring system defined in the U.S. 

EPA’s Test Guideline, OPPTS 870.2400: 

Acute Eye Irritation 1 or the OECD Test 

Guideline 405: Acute Eye Irritation/ 

Corrosion.2

Dated: November 29, 2012. 

Todd A. Stevenson, 

Secretary, U.S. Consumer Product Safety 

Commission. 

[FR Doc. 2012–29258 Filed 12–7–12; 8:45 am] 

BILLING CODE 6355–01–P 

CONSUMER PRODUCT SAFETY 

COMMISSION 

16 CFR Part 1700 

[CPSC Docket No. CPSC–2012–0005] 

Requirements for Child-Resistant 

Packaging: Products Containing 

Imidazolines Equivalent to 0.08 

Milligrams or More 

AGENCY: Consumer Product Safety 

Commission. 

ACTION: Final rule. 

SUMMARY: The Consumer Product Safety 

Commission (CPSC, Commission, or we) 

is issuing a rule to require childresistant (CR) packaging for any overthe-counter or prescription product 

containing the equivalent of 0.08 

milligrams or more of an imidazoline, a 

class of drugs that includes 

tetrahydrozoline, naphazoline, 

oxymetazoline, and xylometazoline, in a 


srobinson on DSK4SPTVN1PROD with