[Code of Federal Regulations]
[Title 16, Volume 2]
[Revised as of January 1, 2004]
From the U.S. Government Printing Office via GPO Access
[CITE: 16CFR1702.9]

[Page 753-755]
 
                     TITLE 16--COMMERCIAL PRACTICES
 
             CHAPTER II--CONSUMER PRODUCT SAFETY COMMISSION
 
PART 1702--PETITIONS FOR EXEMPTIONS FROM POISON PREVENTION PACKAGING 
ACT REQUIREMENTS; PETITION PROCEDURES AND REQUIREMENTS--Table of Contents
 
Sec.  1702.9  Relevant experimental data.

    Experimental data are generated in both animals and humans in 
controlled situations in order to evaluate the biological effects of a 
substance. Certain toxicological effects cannot generally be evaluated 
in human beings. This is especially true of those substances which are 
not normally intended to be used in or on the human body or animal body. 
Therefore, the Commission considers experimental data obtained in animal 
studies to be an important supplement to such data as may exist from any 
experimental studies conducted in humans. The minimum toxicological 
evaluation necessary for a particular household substance is 
proportional to the expected exposure of man to that substance. 
Household substances which are not expected, in normal use, to contact 
man are subject to less extensive studies than those substances, such as 
drugs, which are designed to be used in or on man. The Commission has, 
therefore, separated the requirements of this section into three 
subsections. Section 1702.9(a) lists minimum acute animal toxicity data 
which shall be submitted, if reasonably available, for all petitions; 
Sec.  1702.9(b) lists those additional data which shall be submitted, if 
reasonably available, for drug products and all other household 
substances which are normally intended to be used in or on the human 
body; and Sec.  1702.9(c) lists those additional data which shall be 
submitted, if reasonably available, by petitioners requesting exemption 
for substances not intended for use in or on the human or animal body. 
The Commission emphasizes that, while not absolutely necessary, the 
types of data outlined in Sec.  1702.9(c) may greatly expedite the 
Commission's evaluation of a particular exemption request.
    (a) General criteria applicable to all petitions. (1) Each petition 
for an exemption under this part shall include all reasonably available 
relevant experimental data relating to the petition regardless of 
whether such data are unfavorable to the petitioner's request. As used 
in this part, the term ``relevant experimental data'' includes, but is 
not limited to, all data, including animal and human studies revealing 
the nature and degree of the hazard associated with the particular 
substance. Generally, the hazard associated with the particular 
substance involves the risk of injury arising from the acute accidental 
ingestion of a product. Where a hazard different from the risk of injury 
arising from accidental ingestion is known to exist (e.g., potential for 
significant allergenicity, dermal or opthalmic injury from handling or 
using the product), the petitioner shall also submit all reasonably 
available relevant experimental data evaluating the nature and degree of 
any additional hazard(s).
    (2) All animal studies submitted in support of exemption requests 
should be performed in conformity with good pharmacological and 
toxicological practice which includes, as a minimum, complete 
descriptions of protocols used in experimental animal studies, and 
signed laboratory reports which include the following basic information:
    (i) An exact description of materials tested;
    (ii) A description of test animals employed in studies, including 
number, age, weight, sex and nutritional state of animals;
    (iii) Dosage level(s) and number of animals tested per dosage level;
    (iv) Basis upon which dosage was administered (e.g., as salt or 
base);
    (v) Route of administration and dosage volume; and

[[Page 754]]

    (vi) Appendices containing all raw data and any additional data 
generated subsequent to the completion of the original study (e.g., 
results of histopathological examinations, if performed).
    (3) Each petition shall include all reasonably available reports of 
Median Lethal Dosage (LD50) studies and shall include all raw data 
obtained in such studies. These studies should normally be conducted in 
both adult and weanling animals of the same species. The oral route of 
administration should be followed for studies involving substances 
subject to regulations promulgated under the Poison Prevention Packaging 
Act of 1970. Where a percutaneous toxicity hazard exists, the petition 
shall include reasonably available studies using the percutaneous route 
of administration. Sufficient dosage levels as well as adequate numbers 
of test animals per dosage level should be used to give statistical 
reliability to determined LD50 values.
    (4) In view of the fact that LD50 values in themselves do not 
necessarily reflect a true estimate of the overall toxic potential of a 
substance, LD50 determinations should, where an LD50 value may be 
calculated, include:
    (i) The LD50 value with 95 percent confidence limits;
    (ii) A slope determination for the dose response curve, including 95 
percent confidence limits; and
    (iii) A description of the statistical method employed in the 
analysis of such data (with proper citation) as well as the statistical 
analysis itself.
    (5) The Commission shall disregard any data which do not fulfill the 
strict requirements of the statistical method used in their analyses. 
Modifications of accepted statistical methods which have been published 
in the literature are acceptable to the Commission provided that a copy 
of the published work is submitted.
    (6) Acute toxicity studies submitted with petitions should have at 
least a seven day observation period of test animals. Good 
pharmacological practice provides that test animals are observed closely 
for several hours following test substance administration and less 
frequently on subsequent test days. Succumbing animals should be 
necropsied as soon as practicable following death, while surviving 
animals should be necropsied, and gross pathological alterations noted, 
at the end of the observation period. Documentation of non-lethal 
effects occurring during these observation periods should be submitted 
in conjunction with acute toxicity laboratory reports. Documentation of 
any lethal effects occurring at high dosage levels, including mode of 
death (e.g., cardiac arrest/respiratory arrest), and time of death 
should be submitted in conjunction with acute toxicity laboratory 
reports. Reports of gross necropsies performed upon surviving animals 
should be submitted, as well as results of necropsies performed upon 
animals succumbing to the test substance, provided that such animals are 
examined prior to the onset of autolysis. Results of microscopic 
examinations, when indicated by the nature or results of an acute 
toxicity study, shall also be submitted.
    (b) Additional data criteria for petitions involving substances 
normally used in or on the human or animal body. (1) Petitioners 
submitting exemption requests for substances normally used on or taken 
into the human body or animal body shall, in addition to the 
requirements of paragraph (a) of this section submit the following data, 
where reasonably available:
    (i) Summary laboratory reports of data obtained in subacute and 
chronic animal studies where the data pertain to the absorption, 
distribution, metabolism and excretion of substances in question;
    (ii) A median lethal dosage (LD50) determination conducted in one 
additional species. Of the two LD50 determinations required for persons 
submitting exemption requests under this part, one should be conducted 
in a nonrodent species;
    (iii) Summary reports of data obtained in human studies designed to 
measure the absorption, distribution, metabolism, and excretion of 
substances in question; and
    (iv) Data indicating, insofar as is known, the mechanism of action 
of the substance in question and the mechanism by which expected 
toxicological effects occur. If these mechanisms are

[[Page 755]]

unknown, the petition should state this.
    (2) Petitioners submitting exemption requests for substances 
normally used on or taken into the human or animal body shall, in 
addition to the requirements of paragraphs (a) and (b)(1) of this 
section, submit an evaluation of the pharmacology and toxicology of the 
substance in question based on reasonably available medical and 
scientific literature. The evaluation should be a comprehensive one, and 
should include proper literature citations. To the extent possible, 
information submitted by the petitioner justifying an exemption based on 
the medical and scientific literature will be evaluated under the 
criteria specified in Sec.  1702.9(a) for evaluating experimental data. 
In certain cases where the experimental data specified by Sec.  1702.9 
(a) and (b) are unavailable, the medical and scientific literature may 
justify granting an exemption, particularly where the pharmacology and 
toxicology of the substance is well documented in the literature.
    (c) Optional data criteria for petitions involving substances not 
used in or on the human or animal body. The following types of data, 
although often not generated for household substances not normally used 
in or on the human or animal body, may be available to a petitioner and 
should, where reasonably available, be submitted.
    (1) Summary laboratory reports of data obtained in subacute and 
chronic animal studies where such data pertain to the absorption, 
distribution, metabolism, and excretion of the substance in question;
    (2) Results of median lethal dosage (LD50) studies conducted in 
additional species of animals; and
    (3) Any additional experimental studies relevant to the exemption 
request which would provide the Commission with additional means of 
assessing the hazards to children of the product for which exemption is 
sought.