[Federal Register Volume 62, Number 247 (Wednesday, December 24, 1997)]
[Notices]
[Pages 67377-67388]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-33639]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0148]
International Conference on Harmonisation; Guidance on
Impurities: Residual Solvents
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guidance entitled ``Q3C Impurities:
[[Page 67378]]
Residual Solvents.'' The guidance was prepared under the auspices of
the International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH). The guidance
recommends acceptable amounts of residual solvents in pharmaceuticals
for the safety of the patient, and recommends the use of less toxic
solvents in the manufacture of drug substances and dosage forms.
DATES: Effective December 24, 1997. Submit written comments at any
time.
ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guidance are
available from the Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-4573.
FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: John J. Gibbs, Center for Drug Evaluation
and Research (HFD-820), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-6430.
Regarding ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research (CDER) and Biologics Evaluation and Research
(CBER), FDA, and the Pharmaceutical Research and Manufacturers of
America. The ICH Secretariat, which coordinates the preparation of
documentation, is provided by the International Federation of
Pharmaceutical Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
In the Federal Register of May 2, 1997 (62 FR 24302), FDA published
a draft tripartite guideline entitled ``Impurities: Residual Solvents''
(Q3C). The notice gave interested persons an opportunity to submit
comments by June 16, 1997.
After consideration of the comments received and revisions to the
guidance, a final draft of the guidance was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies on July 17, 1997.
In accordance with FDA's Good Guidance Practices (62 FR 8961,
February 27, 1997), this document has been designated a guidance,
rather than a guideline.
Residual solvents in pharmaceuticals are organic volatile chemicals
that are used or produced in the synthesis of drug substances or
excipients, or in the preparation of drug products. They are not
completely removed by practical manufacturing techniques. The guidance
recommends acceptable amounts of residual solvents in pharmaceuticals
for the safety of the patient. The guidance recommends the use of less
toxic solvents and describes levels considered to be toxicologically
acceptable for some residual solvents. The guidance applies to residual
solvents in drug substances, excipients, and drug products, and to all
dosage forms and routes of administration. The guidance does not apply
to potential new drug substances, excipients, or drug products used
during the clinical research stages of development, nor does it apply
to existing marketed drug products.
This guidance represents the agency's current thinking on
acceptable amounts of residual solvents in pharmaceuticals. It does not
create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statute,
regulations, or both.
As with all of FDA's guidances, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guidance. The comments in the docket will be periodically
reviewed, and, where appropriate, the guidance will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guidance to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The guidance and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guidance is
available on the Internet (http://www.fda.gov/cder/guidance.htm).
The text of the guidance follows:
Q3C Impurities: Residual Solvents \1\
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\1\ This guidance represents the agency's current thinking on
acceptable amounts of residual solvents in pharmaceuticals. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. An alternative approach may be
used if such approach satisfies the requirements of the applicable
statute, regulations, or both.
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1. Introduction
The objective of this guidance is to recommend acceptable
amounts for residual solvents in pharmaceuticals for the safety of
the patient. The guidance recommends use of less toxic solvents and
describes levels considered to be toxicologically acceptable for
some residual solvents.
Residual solvents in pharmaceuticals are defined here as organic
volatile chemicals that are used or produced in the manufacture of
drug substances or excipients, or in the preparation of drug
products. The solvents are not completely removed by practical
manufacturing techniques. Appropriate selection of the solvent for
the synthesis of drug substance may enhance the yield, or determine
characteristics such as crystal form, purity, and solubility.
Therefore, the solvent may sometimes be a critical parameter in the
synthetic process. This guidance does not address solvents
deliberately used as excipients nor does it address solvates.
However, the content of solvents in such products should be
evaluated and justified.
Since there is no therapeutic benefit from residual solvents,
all residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or other
quality-based requirements. Drug products should contain
[[Page 67379]]
no higher levels of residual solvents than can be supported by
safety data. Some solvents that are known to cause unacceptable
toxicities (Class 1, Table 1) should be avoided in the production of
drug substances, excipients, or drug products unless their use can
be strongly justified in a risk-benefit assessment. Some solvents
associated with less severe toxicity (Class 2, Table 2) should be
limited in order to protect patients from potential adverse effects.
Ideally, less toxic solvents (Class 3, Table 3) should be used where
practical. The complete list of solvents included in this guidance
is given in Appendix 1.
The lists are not exhaustive and other solvents can be used and
later added to the lists. Recommended limits of Class 1 and 2
solvents or classification of solvents may change as new safety data
becomes available. Supporting safety data in a marketing application
for a new drug product containing a new solvent may be based on
concepts in this guidance or the concept of qualification of
impurities as expressed in the guidance for drug substance (Q3A,
Impurities in New Drug Substances) or drug product (Q3B, Impurities
in New Drug Products), or all three guidances.
2. Scope of the Guidance
Residual solvents in drug substances, excipients, and drug
products are within the scope of this guidance. Therefore, testing
should be performed for residual solvents when production or
purification processes are known to result in the presence of such
solvents. It is only considered necessary to test for solvents that
are used or produced in the manufacture or purification of drug
substances, excipients, or drug products. Although manufacturers may
choose to test the drug product, a cumulative method may be used to
calculate the residual solvent levels in the drug product from the
levels in the ingredients used to produce the drug product. If the
calculation results in a level equal to or below that recommended in
this guidance, no testing of the drug product for residual solvents
need be considered. If, however, the calculated level is above the
recommended level, the drug product should be tested to ascertain
whether the formulation process has reduced the relevant solvent
level to within the acceptable amount. Drug product should also be
tested if a solvent is used during its manufacture.
This guidance does not apply to potential new drug substances,
excipients, or drug products used during the clinical research
stages of development, nor does it apply to existing marketed drug
products.
The guidance applies to all dosage forms and routes of
administration. Higher levels of residual solvents may be acceptable
in certain cases such as short-term (30 days or less) or topical
application. Justification for these levels should be made on a
case-by-case basis.
See Appendix 2 of this document for additional background
information related to residual solvents.
3. General Principles
3.1 Classification of Residual Solvents by Risk Assessment
The term ``tolerable daily intake'' (TDI) is used by the
International Program on Chemical Safety (IPCS) to describe exposure
limits of toxic chemicals and the term ``acceptable daily intake''
(ADI) is used by the World Health Organization (WHO) and other
national and international health authorities and institutes. The
new term ``permitted daily exposure'' (PDE) is defined in the
present guidance as a pharmaceutically acceptable intake of residual
solvents to avoid confusion of differing values for ADI's of the
same substance.
Residual solvents assessed in this guidance are listed in
Appendix 1 by common names and structures. They were evaluated for
their possible risk to human health and placed into one of three
classes as follows:
Class 1 solvents: Solvents to be avoided--
Known human carcinogens, strongly suspected human carcinogens,
and environmental hazards.
Class 2 solvents: Solvents to be limited--
Nongenotoxic animal carcinogens or possible causative agents of
other irreversible toxicity such as neurotoxicity or teratogenicity.
Solvents suspected of other significant but reversible
toxicities.
Class 3 solvents: Solvents with low toxic potential--
Solvents with low toxic potential to man; no health-based
exposure limit is needed. Class 3 solvents have PDE's of 50
milligrams (mg) or more per day.
3.2 Methods for Establishing Exposure Limits
The method used to establish permitted daily exposures for
residual solvents is presented in Appendix 3. Summaries of the
toxicity data that were used to establish limits are published in
Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.
3.3 Options for Describing Limits of Class 2 Solvents
Two options are available when setting limits for Class 2
solvents.
Option 1: The concentration limits in parts per million (ppm)
stated in Table 2 can be used. They were calculated using equation (1)
below by assuming a product mass of 10 grams (g) administered daily.
[GRAPHIC] [TIFF OMITTED] TN24DE97.015
Here, PDE is given in terms of mg/day and dose is given in g/day.
These limits are considered acceptable for all substances,
excipients, or products. Therefore, this option may be applied if
the daily dose is not known or fixed. If all excipients and drug
substances in a formulation meet the limits given in Option 1, then
these components may be used in any proportion. No further
calculation is necessary provided the daily dose does not exceed 10
g. Products that are administered in doses greater than 10 g per day
should be considered under Option 2.
Option 2: It is not considered necessary for each component of
the drug product to comply with the limits given in Option 1. The
PDE in terms of mg/day as stated in Table 2 can be used with the
known maximum daily dose and equation (1), as shown in Option 1 in
the previous paragraph, to determine the concentration of residual
solvent allowed in drug product. Such limits are considered
acceptable provided that it has been demonstrated that the residual
solvent has been reduced to the practical minimum. The limits should
be realistic in relation to analytical precision, manufacturing
capability, and reasonable variation in the manufacturing process
and the limits should reflect contemporary manufacturing standards.
Option 2 may be applied by adding the amounts of a residual
solvent present in each of the components of the drug product. The
sum of the amounts of solvent per day should be less than that given
by the PDE.
Consider an example of the use of Option 1 and Option 2 applied
to acetonitrile in a drug product. The permitted daily exposure to
acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm.
The maximum administered daily mass of a drug product is 5.0 g, and
the drug product contains two excipients. The composition of the
drug product and the calculated maximum content of residual
acetonitrile are given in the following table.
------------------------------------------------------------------------
Amount in Acetonitrile
Component formulation content Daily exposure
------------------------------------------------------------------------
Drug substance 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 400 ppm 0.36 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug product 5.0 g 728 ppm 3.64 mg
------------------------------------------------------------------------
Excipient 1 meets the Option 1 limit, but the drug substance,
excipient 2, and drug product do not meet the Option 1 limit.
Nevertheless, the product meets the Option 2 limit of 4.1 mg per day
and thus conforms to the recommendations in this guidance.
[[Page 67380]]
Consider another example using acetonitrile as residual solvent.
The maximum administered daily mass of a drug product is 5.0 g, and
the drug product contains two excipients. The composition of the
drug product and the calculated maximum content of residual
acetonitrile are given in the following table.
------------------------------------------------------------------------
Amount in Acetonitrile
Component formulation content Daily exposure
------------------------------------------------------------------------
Drug substance 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 2,000 ppm 1.80 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug product 5.0 g 1,016 ppm 5.08 mg
------------------------------------------------------------------------
In this example, the product meets neither the Option 1 nor the
Option 2 limit according to this summation. The manufacturer could
test the drug product to determine if the formulation process
reduced the level of acetonitrile. If the level of acetonitrile was
not reduced during formulation to the allowed limit, then the
manufacturer of the drug product should take other steps to reduce
the amount of acetonitrile in the drug product. If all of these
steps fail to reduce the level of residual solvent, in exceptional
cases the manufacturer could provide a summary of efforts made to
reduce the solvent level to meet the guidance value, and provide a
risk-benefit analysis to support allowing the product to be utilized
with residual solvent at a higher level.
3.4 Analytical Procedures
Residual solvents are typically determined using chromatographic
techniques such as gas chromatography. Any harmonized procedures for
determining levels of residual solvents as described in the
pharmacopoeias should be used, if feasible. Otherwise, manufacturers
would be free to select the most appropriate validated analytical
procedure for a particular application. If only Class 3 solvents are
present, a nonspecific method such as loss on drying may be used.
Validation of methods for residual solvents should conform to
ICH guidances ``Q2A Text on Validation of Analytical Procedures''
and ``Q2B Validation of Analytical Procedures: Methodology.''
3.5 Reporting Levels of Residual Solvents
Manufacturers of pharmaceutical products need certain
information about the content of residual solvents in excipients or
drug substances in order to meet the criteria of this guidance. The
following statements are given as acceptable examples of the
information that could be provided from a supplier of excipients or
drug substances to a pharmaceutical manufacturer. The supplier might
choose one of the following as appropriate:
Only Class 3 solvents are likely to be present. Loss on
drying is less than 0.5 percent.
Only Class 2 solvents X, Y, * * * are likely to be
present. All are below the Option 1 limit. (Here the supplier would
name the Class 2 solvents represented by X, Y, * * * .)
Only Class 2 solvents X, Y, * * * and Class 3 solvents are
likely to be present. Residual Class 2 solvents are below the Option
1 limit and residual Class 3 solvents are below 0.5 percent.
If Class 1 solvents are likely to be present, they should be
identified and quantified.
``Likely to be present'' refers to the solvent used in the final
manufacturing step and to solvents that are used in earlier
manufacturing steps and not removed consistently by a validated
process.
If solvents of Class 2 or Class 3 are present at greater than
their Option 1 limits or 0.5 percent, respectively, they should be
identified and quantified.
4. Limits of Residual Solvents
4.1 Solvents to Be Avoided
Solvents in Class 1 should not be employed in the manufacture of
drug substances, excipients, and drug products because of their
unacceptable toxicity or their deleterious environmental effect.
However, if their use is unavoidable in order to produce a drug
product with a significant therapeutic advance, then their levels
should be restricted as shown in Table 1, unless otherwise
justified. The solvent 1,1,1-Trichloroethane is included in Table 1
because it is an environmental hazard. The stated limit of 1,500 ppm
is based on a review of the safety data.
Table 1.--Class 1 Solvents in Pharmaceutical Products
(Solvents That Should Be Avoided)
------------------------------------------------------------------------
Concentration
Solvent limit (ppm) Concern
------------------------------------------------------------------------
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmental
hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1,500 Environmental hazard
------------------------------------------------------------------------
4.2 Solvents to Be Limited
Solvents in Table 2 should be limited in pharmaceutical products
because of their inherent toxicity. PDE's are given to the nearest 0.1
mg/day, and concentrations are given to the nearest 10 ppm. The stated
values do not reflect the necessary analytical precision of
determination. Precision should be determined as part of the validation
of the method.
Table 2.--Class 2 Solvents in Pharmaceutical Products
------------------------------------------------------------------------
Concentration
Solvent PDE (mg/day) limit (ppm)
------------------------------------------------------------------------
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3,880
1,2-Dichloroethene 18.7 1,870
[[Page 67381]]
Dichloromethane 6.0 600
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1,090
N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethyleneglycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3,000
2-Methoxyethanol 0.5 50
Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1,180
N-Methylpyrrolidone 48.4 4,840
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetralin 1.0 100
Toluene 8.9 890
1,1,2-Trichloroethene 0.8 80
Xylene\1\ 21.7 2,170
------------------------------------------------------------------------
\1\ Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl
benzene.
4.3 Solvents with Low Toxic Potential
Solvents in Class 3 (shown in Table 3) may be regarded as less
toxic and of lower risk to human health. Class 3 includes no solvent
known as a human health hazard at levels normally accepted in
pharmaceuticals. However, there are no long-term toxicity or
carcinogenicity studies for many of the solvents in Class 3. Available
data indicate that they are less toxic in acute or short-term studies
and negative in genotoxicity studies. It is considered that amounts of
these residual solvents of 50 mg per day or less (corresponding to
5,000 ppm or 0.5 percent under Option 1) would be acceptable without
justification. Higher amounts may also be acceptable provided they are
realistic in relation to manufacturing capability and good
manufacturing practice (GMP).
Table 3.--Class 3 Solvents Which Should Be Limited by GMP or Other
Quality-Based Requirements
------------------------------------------------------------------------
Acetic acid Heptane
Acetone Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethyl ketone
tert-Butylmethyl ether Methylisobutyl ketone
Cumene 2-Methyl-1-propanol
Dimethyl sulfoxide Pentane
Ethanol 1-Pentanol
Ethyl acetate 1-Propanol
Ethyl ether 2-Propanol
Ethyl formate Propyl acetate
Formic acid Tetrahydrofuran
------------------------------------------------------------------------
4.4 Solvents for Which No Adequate Toxicological Data Were Found
The following solvents (Table 4) may also be of interest to
manufacturers of excipients, drug substances, or drug products.
However, no adequate toxicological data on which to base a PDE were
found. Manufacturers should supply justification for residual levels
of these solvents in pharmaceutical products.
Table 4.--Solvents for Which No Adequate Toxicological Data Were Found
------------------------------------------------------------------------
1,1-Diethoxypropane Methylisopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid
------------------------------------------------------------------------
[[Page 67382]]
Glossary
Genotoxic carcinogens: Carcinogens that produce cancer by
affecting genes or chromosomes.
LOEL: Abbreviation for lowest-observed effect level.
Lowest-observed effect level: The lowest dose of substance in a
study or group of studies that produces biologically significant
increases in frequency or severity of any effects in the exposed
humans or animals.
Modifying factor: A factor determined by professional judgment
of a toxicologist and applied to bioassay data to relate that data
safely to humans.
Neurotoxicity: The ability of a substance to cause adverse
effects on the nervous system.
NOEL: Abbreviation for no-observed-effect level.
No-observed-effect level: The highest dose of substance at which
there are no biologically significant increases in frequency or
severity of any effects in the exposed humans or animals.
PDE: Abbreviation for permitted daily exposure.
Permitted daily exposure: The maximum acceptable intake per day
of residual solvent in pharmaceutical products.
Reversible toxicity: The occurrence of harmful effects that are
caused by a substance and which disappear after exposure to the
substance ends.
Strongly suspected human carcinogen: A substance for which there
is no epidemiological evidence of carcinogenesis but there are
positive genotoxicity data and clear evidence of carcinogenesis in
rodents.
Teratogenicity: The occurrence of structural malformations in a
developing fetus when a substance is administered during pregnancy.
BILLING CODE 4160-01-F
[[Page 67383]]
Appendix 1. List of Solvents Included in the Guidance
[GRAPHIC] [TIFF OMITTED] TN24DE97.007
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[GRAPHIC] [TIFF OMITTED] TN24DE97.008
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[GRAPHIC] [TIFF OMITTED] TN24DE97.009
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[GRAPHIC] [TIFF OMITTED] TN24DE97.010
BILLING CODE 4160-01-F
[[Page 67387]]
Appendix 2. Additional Background
A2.1 Environmental Regulation of Organic Volatile Solvents
Several of the residual solvents frequently used in the
production of pharmaceuticals are listed as toxic chemicals in
Environmental Health Criteria (EHC) monographs and the Integrated
Risk Information System (IRIS). The objectives of such groups as the
IPCS, the U.S. Environmental Protection Agency (EPA), and FDA
include the determination of acceptable exposure levels. The goal is
protection of human health and maintenance of environmental
integrity against the possible deleterious effects of chemicals
resulting from long-term environmental exposure. The methods
involved in the estimation of maximum safe exposure limits are
usually based on long-term studies. When long-term study data are
unavailable, shorter term study data can be used with modification
of the approach such as use of larger safety factors. The approach
described therein relates primarily to long-term or lifetime
exposure of the general population in the ambient environment, i.e.,
ambient air, food, drinking water, and other media.
A2.2 Residual Solvents in Pharmaceuticals
Exposure limits in this guidance are established by referring to
methodologies and toxicity data described in EHC and IRIS
monographs. However, some specific assumptions about residual
solvents to be used in the synthesis and formulation of
pharmaceutical products should be taken into account in establishing
exposure limits. They are as follows:
(1) Patients (not the general population) use pharmaceuticals to
treat their diseases or for prophylaxis to prevent infection or
disease.
(2) The assumption of lifetime patient exposure is not necessary
for most pharmaceutical products but may be appropriate as a working
hypothesis to reduce risk to human health.
(3) Residual solvents are unavoidable components in
pharmaceutical production and will often be a part of drug products.
(4) Residual solvents should not exceed recommended levels
except in exceptional circumstances.
(5) Data from toxicological studies that are used to determine
acceptable levels for residual solvents should have been generated
using appropriate protocols such as those described, for example, by
the Organization for Cooperation and Development, EPA, and the FDA
Red Book.
Appendix 3. Methods for Establishing Exposure Limits
The Gaylor-Kodell method of risk assessment (Gaylor, D. W., and
R. L. Kodell, ``Linear Interpolation Algorithm for Low Dose
Assessment of Toxic Substance,'' Journal of Environmental Pathology
and Toxicology, 4:305, 1980) is appropriate for Class 1 carcinogenic
solvents. Only in cases where reliable carcinogenicity data are
available should extrapolation by the use of mathematical models be
applied to setting exposure limits. Exposure limits for Class 1
solvents could be determined with the use of a large safety factor
(i.e., 10,000 to 100,000) with respect to the NOEL. Detection and
quantitation of these solvents should be by state-of-the-art
analytical techniques.
Acceptable exposure levels in this guidance for Class 2 solvents
were established by calculation of PDE values according to the
procedures for setting exposure limits in pharmaceuticals
(Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by IPCS
for Assessing Human Health Risk of Chemicals (EHC 170, WHO, 1994).
These methods are similar to those used by the U.S. EPA (IRIS) and
the U.S. FDA (Red Book) and others. The method is outlined here to
give a better understanding of the origin of the PDE values. It is
not necessary to perform these calculations in order to use the PDE
values tabulated in Section 4 of this document.
PDE is derived from the NOEL or the LOEL in the most relevant
animal study as follows:
[GRAPHIC] [TIFF OMITTED] TN24DE97.011
The PDE is derived preferably from a NOEL. If no NOEL is obtained,
the LOEL may be used. Modifying factors proposed here, for relating
the data to humans, are the same kind of ``uncertainty factors''
used in EHC (EHC 170, WHO, Geneva, 1994), and ``modifying factors''
or ``safety factors'' in Pharmacopeial Forum. The assumption of 100
percent systemic exposure is used in all calculations regardless of
route of administration.
The modifying factors are as follows:
F1 = A factor to account for extrapolation between species.
F1 = 5 for extrapolation from rats to humans.
F1 = 12 for extrapolation from mice to humans.
F1 = 2 for extrapolation from dogs to humans.
F1 = 2.5 for extrapolation from rabbits to humans.
F1 = 3 for extrapolation from monkeys to humans.
F1 = 10 for extrapolation from other animals to humans.
F1 takes into account the comparative surface area:body weight
ratios for the species concerned and for man. Surface area (S) is
calculated as:
[GRAPHIC] [TIFF OMITTED] TN24DE97.012
in which M = body mass, and the constant k has been taken to be 10.
The body weights used in the equation are those shown below in Table
A3.1.
F2 = A factor of 10 to account for variability between individuals.
A factor of 10 is generally given for all organic solvents, and
10 is used consistently in this guidance.
F3 = A variable factor to account for toxicity studies of short-term
exposure.
F3 = 1 for studies that last at least one half-lifetime (1 year
for rodents or rabbits; 7 years for cats, dogs and monkeys).
F3 = 1 for reproductive studies in which the whole period of
organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in
nonrodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in
nonrodents.
F3 = 10 for studies of a shorter duration.
In all cases, the higher factor has been used for study durations
between the time points, e.g., a factor of 2 for a 9-month rodent
study.
F4 = A factor that may be applied in cases of severe toxicity, e.g.,
nongenotoxic carcinogenicity, neurotoxicity or teratogenicity. In
studies of reproductive toxicity, the following factors are used:
F4 = 1 for fetal toxicity associated with maternal toxicity.
F4 = 5 for fetal toxicity without maternal toxicity.
F4 = 5 for a teratogenic effect with maternal toxicity.
F4 = 10 for a teratogenic effect without maternal toxicity.
F5 = A variable factor that may be applied if the no effect level
was not established.
When only an LOEL is available, a factor of up to 10 could be
used depending on the severity of the toxicity.
The weight adjustment assumes an arbitrary adult human body
weight for either sex of 50 kilograms (kg). This relatively low
weight provides an additional safety factor against the standard
weights of 60 kg or 70 kg that are often used in this type of
calculation. It is recognized that some adult patients weigh less
than 50 kg; these patients are considered to be accommodated by the
built-in safety factors used to determine a PDE. If the solvent was
present in a formulation specifically intended for pediatric use, an
adjustment for a lower body weight would be appropriate.
As an example of the application of this equation, consider a
toxicity study of acetonitrile in mice that is summarized in
Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The
NOEL is calculated to be 50.7 mg kg-1 day-1.
The PDE for acetonitrile in this study is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TN24DE97.013
In this example,
F1 = 12 to account for the extrapolation from mice to humans.
F2 = 10 to account for differences between individual humans.
[[Page 67388]]
F3 = 5 because the duration of the study was only 13 weeks.
F4 = 1 because no severe toxicity was encountered.
F5 = 1 because the no effect level was determined.
Table A3.1--Values Used in the Calculations in This Document
Rat body 425 g Mouse 43 liter (L)/day
weight respirat
ory
volume
Pregnant 330 g Rabbit 1,440 L/day
rat body respirat
weight ory
volume
Mouse 28 g Guinea 430 L/day
body pig
weight respirat
ory
volume
Pregnant 30 g Human 28,800 L/day
mouse respirat
body ory
weight volume
Guinea 500 g Dog 9,000 L/day
pig body respirat
weight ory
volume
Rhesus 2.5 kg Monkey 1,150 L/day
monkey respirat
body ory
weight volume
Rabbit 4 kg Mouse 5 milliliter (mL)/day
body water
weight consumpt
(pregnan ion
t or
not)
Beagle 11.5 kg Rat water 30 mL/day
dog body consumpt
weight ion
Rat 290 L/day Rat food 30 g/day
respirat consumpt
ory ion
volume
The equation for an ideal gas, PV = nRT, is used to convert
concentrations of gases used in inhalation studies from units of ppm
to units of mg/L or mg/cubic meter (m3). Consider as an
example the rat reproductive toxicity study by inhalation of carbon
tetrachloride (molecular weight 153.84) summarized in Pharmeuropa,
Vol. 9, No. 1, Supplement, April 1997, page S9.
[GRAPHIC] [TIFF OMITTED] TN24DE97.014
The relationship 1000 L = 1 m3 is used to convert to mg/
m3.
Dated: December 16, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-33639 Filed 12-23-97; 8:45 am]
BILLING CODE 4160-01-F
