#100 
Impurities:  Residual Solvents in New Veterinary 
Medicinal Products, Active Substances and 
Excipients (Revision 2) 
VICH GL18(R2) 
Guidance for Industry 
Draft Guidance 
This guidance document is being distributed for comment purposes only. 
This version of the guidance replaces the version made available November 2011.  This revision 
updates the listings and classification of solvents. 
Submit comments on this draft guidance by the dated provided in the Federal Register notice 
announcing the availability of the draft guidance.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with docket number FDA-1999-D-2955. 
For further information regarding this document, contact Mai Huynh, Center for Veterinary 
Medicine (HFV-142), Food and Drug Administration, 7500 Standish Place, Rockville MD 
20855, 240-402-0669, email: Mai.huynh@fda.hhs.gov. 
Additional copies of this draft guidance document may be requested from the Policy and 
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 
7500 Standish Place, Rockville MD 20855, and may be viewed on the Internet at 
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or http://www.regulations.gov. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
July 2022 VICH GL18(R2) (QUALITY)  IMPURITIES 
December 2021 
Revision at Step 9 
For consultation at Step 4 
I : R S
MPURITIES   ESIDUAL  OLVENTS IN 
NEW VETERINARY MEDICINAL 
,
PRODUCTS  ACTIVE SUBSTANCES 
AND EXCIPIENTS 
(REVISION 2) 
 
Revision at Step 9 
Recommended for Consultation at Step 4 of the VICH Process 
 in October 2019 
by the VICH Steering Committee 
This Guideline has been developed by the appropriate VICH Expert Working Group will be subject to 
consultation by the parties, in accordance with the VICH Process.  At Step 7 of the Process the final draft 
is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Table of Contents 
1. Introduction .......................................................................................................................... 1 
2. Scope of the Guidance ......................................................................................................... 2 
3. General Principles ................................................................................................................ 3 
3.1  Classification of Residual Solvents by Risk Assessment ........................................ 3 
3.2  Methods for Establishing Exposure Limits ............................................................. 3 
3.3  Options for Describing Limits of Class 2 Solvents ................................................. 3 
3.4  Analytical Procedures ............................................................................................... 5 
3.5  Reporting Levels of Residual Solvents .................................................................... 6 
4. Limits of Residual Solvents ................................................................................................. 6 
4.1  Solvents that should be Avoided .............................................................................. 6 
4.2  Solvents that should be Limited ............................................................................... 7 
4.3  Solvents with Low Toxic Potential ........................................................................... 8 
4.4  Solvents for Which No Adequate Toxicological Data Was Found ....................... 9 
GLOSSARY................................................................................................................................. 10 
Appendix 1:  List of Solvents Included in the Guidance ......................................................... 11 
Appendix 2:  Additional Background ....................................................................................... 15 
A2.1  Environmental Regulation of Organic Volatile Solvents ..................................... 15 
A2.2  Residual Solvents in Pharmaceuticals ................................................................... 15 
Appendix 3:  Methods for Establishing Exposure Limits ....................................................... 16 
i  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Impurities:  Residual Solvents in New Veterinary Medicinal 
Products, Active Substances and Excipients (Revision 2) 
Draft Guidance for Industry 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
1. Introduction
The objective of this guidance is to recommend acceptable amounts for residual solvents in 
pharmaceuticals for the safety of the target animal as well as for the safety of residues in 
products derived from treated food producing animals.  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 active substances or excipients, or in the preparation of 
veterinary medicinal products.  The solvents are not completely removed by practical 
manufacturing techniques.  Appropriate selection of the solvent for the synthesis of active 
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.  Veterinary medicinal products should contain 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 active 
substances, excipients, or veterinary medicinal 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 target animals and human consumers 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. List of Solvents
Included in the Guidance.
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 
veterinary medicinal product containing a new solvent may be based on concepts in this 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
guidance or the concept of qualification of impurities as expressed in the guidance for active 
substance (Guidance for Industry (GFI) #92 (VICH GL10(R)), Impurities in New Veterinary 
Drug Substances1) or veterinary medicinal product (GFI #93 (VICH GL11(R)), Impurities in 
New Veterinary Medicinal Products2), or all three guidances. 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDAs guidance documents should be viewed only as recommendations, unless specific 
regulatory or statutory requirements are cited.  The use of the word should in Agency guidances 
means that something is suggested or recommended, but not required. 
2. Scope of the Guidance
Residual solvents in active substances, excipients, and in veterinary medicinal 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 necessary to test for solvents that are used or produced in the manufacture or 
purification of medicinal substances, excipients, or veterinary medicinal products.  Although 
manufacturers may choose to test the veterinary medicinal product, a cumulative method may be 
used to calculate the residual solvent levels in the product from the levels in the ingredients used 
to produce the product.  If the calculation results in a level equal to or below that recommended 
in this guidance, no testing of the veterinary medicinal product for residual solvents need be 
considered.  If, however, the calculated level is above the recommended level, the veterinary 
medicinal product should be tested to ascertain whether the formulation process has reduced the 
relevant solvent level to within the acceptable amount.  The veterinary medicinal product should 
also be tested if a solvent is used during its manufacture. 
This guidance does not apply to potential new active substances, excipients, or veterinary 
medicinal products used during the clinical research stages of development, nor does it apply to 
existing marketed veterinary medicinal products. 
The guidance applies to all dosage forms and routes of administration.  Higher levels of residual 
solvents may be acceptable in certain cases or topical application. Justification for these levels 
should be made on a case-by-case basis. 
See Appendix 2. Additional Background for additional background information related to 
residual solvents. 
1 https://www.fda.gov/media/70365/download 
2 https://www.fda.gov/media/70368/download 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
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 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 ADIs of the same substance. 
 
Residual solvents assessed in this guidance are listed in Appendix 1. List of Solvents Included in 
the Guidance 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 
 
Non-genotoxic 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 PDEs of 50 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. Methods for Establishing Exposure Limits.  Summaries of the toxicity data that 
were used to establish limits are published in Pharmeuropa, Vol. 9, No. 1, Supplement, April 
1997 and in Parts II to IV of the ICH Guideline on Impurities: Guideline for Residual Solvents 
(Q3C(R8). 
 
3.3  Options for Describing Limits of Class 2 Solvents 
Three options are available when setting limits for Class 2 solvents. 
 
Option 1:  The concentration limits in ppm stated in Table 2 can be used. They were calculated 
using equation (1) below by assuming a product mass of 10 g administered daily. 
 
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(1)     
 
 
Here, PDE is given in terms of mg/day and dose is given in g/day. 
 
These limits are considered acceptable for residual solvents in all substances, excipients, or 
products.  Therefore, this option may be applied if the daily dose is not known or fixed.  If the 
residual solvents in all excipients and active 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 residual solvents in each component of the 
veterinary medicinal 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) 
above to determine the concentration of residual solvent allowed in the veterinary medicinal 
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, 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 veterinary medicinal 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 veterinary 
medicinal 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 veterinary medicinal 
product is 5.0 g, and the veterinary medicinal product contains two excipients.  The composition 
of the veterinary medicinal product and the calculated maximum content of residual acetonitrile 
are given in the following table. 
 
Amount in  Acetonitrile  
Component  Daily exposure 
formulation  content 
Active 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 
Veterinary medicinal 
5.0 g  728 ppm  3.64 mg 
product 
 
Excipient 1 meets the Option 1 limit, but the active substance, excipient 2, and the veterinary 
medicinal 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. 
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Consider another example using acetonitrile as residual solvent.  The maximum administered 
daily mass of a veterinary medicinal product is 5.0 g, and the veterinary medicinal product 
contains two excipients.  The composition of the veterinary medicinal product and the calculated 
maximum content of residual acetonitrile is given in the following table. 
 
Amount in   Acetonitrile  
Component  Daily exposure 
formulation  content 
Active substance  0.3 g  800 ppm  0.24 mg 
Excipient 1  0.9 g  2000 ppm  1.80 mg 
Excipient 2  3.8 g  800 ppm  3.04 mg 
Veterinary medicinal 
5.0 g  1016 ppm  5.08 mg 
product 
 
In this example, the product meets neither the Option 1 nor the Option 2 limit.  The manufacturer 
could test the 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 product should take other steps to reduce the amount of acetonitrile in the 
product or option 3 should be considered. 
 
Option 3:  Applicants may justify higher levels for the PDE and concentration limit based upon 
the actual daily dose, actual target species, and relevant toxicological data and considering 
consumer safety aspects.  Use of Option 3 will be handled on a case-by-case basis by the 
regulatory authorities.  This option may be applied as: 
 
3a  The applicant may provide an appropriate body weight for the actual target species and/or 
the actual dose and recalculate the PDE and/or concentration limit using the ICH equations and 
ICH supporting toxicological data. 
 
3b  The applicant may provide new toxicological data (with or without actual target animal and 
dose information) and recalculate the PDE and concentration limit using the equation provided 
by ICH. 
 
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 non-specific method such as loss on drying may be used. 
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Validation of methods for residual solvents should conform to the VICH guidances GFI #63 
(VICH GL1), Validation of Analytical Procedures: Definition and Terminology,3 and GFI #64 
(VICH GL2), Validation of Analytical Procedures: Methodology.4 
 
3.5  Reporting Levels of Residual Solvents 
Manufacturers of pharmaceutical products need certain information about the content of residual 
solvents in excipients or active 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 active 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%. 
 
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%. 
 
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%, 
respectively, they should be identified and quantified. 
 
4.  Limits of Residual Solvents 
4.1  Solvents that should be Avoided 
Solvents in Class 1 should not be employed in the manufacture of active substances, excipients, 
and veterinary medicinal products because of their unacceptable toxicity or their deleterious 
environmental effect.  However, if their use is unavoidable in order to produce a veterinary 
medicinal product with a significant therapeutic advance, then their levels should be restricted as 
shown in Table 1, unless otherwise justified.  1,1,1-Trichloroethane is included in Table 1 
because it is an environmental hazard.  The stated limit of 1500 ppm is based on a review of the 
safety data. 
 
 
 
3 https://www.fda.gov/media/70168/download 
4 https://www.fda.gov/media/70189/download 
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Table 1. Class 1 Solvents in Pharmaceutical Products (solvents that should be avoided) 
Concentration Limit 
Solvent  Concern 
(ppm) 
Benzene  2  Carcinogen 
Carbon tetrachloride  4  Toxic and environmental hazard 
1,2-Dichloroethane  5  Toxic 
1,1-Dichloroethene  8  Toxic 
1,1,1-Trichloroethane  1500  Environmental hazard 
 
4.2  Solvents that should be Limited 
Solvents in Table 2 should be limited in pharmaceutical products because of their inherent 
toxicity.  PDEs 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 
PDE   Concentration Limit 
Solvent 
(mg/day)  (ppm) 
Acetonitrile  4.1  410 
Chlorobenzene  3.6  360 
Chloroform  0.6  60 
Cumene  0.7  70 
Cyclohexane  38.8  3880 
Cyclopentyl methyl ether  15.0  1500 
1,2-Dichloroethene  18.7  1870 
Dichloromethane  6.0  600 
1,2-Dimethoxyethane  1.0  100 
N,N-Dimethylacetamide  10.9  1090 
N,N-Dimethylformamide  8.8  880 
1,4-Dioxane  3.8  380 
2-Ethoxyethanol  1.6  160 
Ethylene glycol  6.2  620 
Formamide  2.2  220 
Hexane  2.9  290 
Methanol  30.0  3000 
2-Methoxyethanol  0.5  50 
Methylbutylketone  0.5  50 
Methylcyclohexane  11.8  1180 
Methylisobutylketone  45  4500 
N-Methylpyrrolidone  5.3  530 
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PDE   Concentration Limit 
Solvent 
(mg/day)  (ppm) 
Nitromethane  0.5  50 
Pyridine  2.0  200 
Sulfolane  1.6  160 
Tertiary-butyl alcohol  35  3500 
Tetrahydrofuran  7.2  720 
Tetralin  1.0  100 
Toluene  8.9  890 
1,1,2-Trichloroethene  0.8  80 
Xylene*  21.7  2170 
* 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 target 
animal and human consumer 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 5000 ppm or 
0.5% 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. 
 
Table 3. Class 3 Solvents Which Should be Limited by GMP or Other Quality-based 
Requirements 
Acetic acid  Isobutyl acetate 
Acetone  Isopropyl acetate 
Anisole  Methyl acetate 
1-Butanol  3-Methyl-1-butanol 
2-Butanol  Methylethyl ketone 
Butyl acetate  2-Methyl-1-propanol 
tert-Butylmethyl ether  2-Methyltetrahydrofuran 
Dimethylsulfoxide  Pentane 
Ethanol  1-Pentanol 
Ethyl acetate  1-Propanol 
Ethyl ether  2-Propanol 
Ethyl formate  Propyl acetate 
Formic acid  Triethylamine 
Heptane   
 
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4.4  Solvents for Which No Adequate Toxicological Data Was Found 
The following solvents (Table 4) may also be of interest to manufacturers of excipients, active 
substances, or veterinary medicinal products.  However, no adequate toxicological data on which 
to base a PDE was found.  Manufacturers should supply justification for residual levels of these 
and other solvents for which a PDE has not been established for use in pharmaceutical products. 
 
Table 4. Solvents for which no adequate Toxicological Data was 
found 
1,1-Diethoxypropane  Methylisopropyl ketone 
1,1-Dimethoxymethane  Methyltetrahydrofuran 
2,2-Dimethoxypropane  Petroleum ether 
Isooctane  Trichloroacetic acid 
Isopropyl ether  Trifluoroacetic acid 
 
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GLOSSARY 
Genotoxic carcinogens: Carcinogens which 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 judgement 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 in humans of carcinogenesis but there are positive genotoxicity data and clear evidence 
of carcinogenesis in rodents (or other animal species). 
 
Teratogenicity: The occurrence of structural malformations in a developing fetus when a 
substance is administered during pregnancy. 
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Appendix 1:  List of Solvents Included in the Guidance 
Solvent  Other Names  Structure  Class 
Acetic acid  Ethanoic acid  CH COOH  Class 3 
3
2-Propanone 
Acetone  CH COCH   Class 3 
3 3
Propan-2-one 
Acetonitrile    CH CN  Class 2 
3
Anisole  Methoxybenzene  OCH3 Class 3 
 
Benzene  Benzol  Class 1 
 
n-Butyl alcohol 
1-Butanol  CH (CH ) OH  Class 3 
3 2 3
Butan-1-ol 
sec-Butyl alcohol 
2-Butanol  CH CH CH(OH)CH   Class 3 
3 2 3
Butan-2-ol 
Butyl acetate  Acetic acid butyl ester  CH COO(CH ) CH   Class 3 
3 2 3 3
2-Methoxy-2-methyl-
tert-Butylmethyl ether  (CH ) COCH   Class 3 
3 3 3
propane 
t-Butyl alcohol 
Tertiary-butyl alcohol  (CH ) COH  Class 2 
3 3
tert-butanol 
Carbon tetrachloride  Tetrachloromethane  CCl   Class 1 
4
Chlorobenzene    Cl  Class 2 
 
Chloroform  Trichloromethane  CHCl   Class 2 
3
Isopropylbenzene 
Cumene  (1-Methyl)ethylbenzene  CH(CH 3 ) 2  Class 2 
 
Cyclohexane  Hexamethylene  Class 2 
 
Cyclopentyl methyl ether  CPME  Class 2 
   
sym-Dichloroethane 
1,2-Dichloroethane  Ethylene dichloride  CH ClCH Cl  Class 1 
2 2
Ethylene chloride 
1,1-Dichloroethylene 
1,1-Dichloroethene    Class 1 
Vinylidene chloride 
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Solvent  Other Names  Structure  Class 
1,2-Dichloroethylene 
1,2-Dichloroethene    Class 2 
Acetylene dichloride 
Dichloromethane  Methylene chloride  CH Cl   Class 2 
2 2
Ethyleneglycol dimethyl 
Ether 
1,2-Dimethoxyethane  H COCH CH OCH   Class 2 
3 2 2 3
Monoglyme 
Dimethyl Cellosolve 
N,N-Dimethylacetamide  DMA  CH CON(CH )   Class 2 
3 3 2
N,N-Dimethylformamide  DMF  HCON(CH )   Class 2 
3 2
Methylsulfinylmethane 
Dimethyl sulfoxide  Methyl sulfoxide  (CH ) SO  Class 3 
3 2
DMSO 
p-Dioxane 
1,4-Dioxane  O  O  Class 2 
[1,4]Dioxane 
 
Ethanol  Ethyl alcohol  CH CH OH  Class 3 
3 2
2-Ethoxyethanol  Cellosolve  CH CH OCH CH OH  Class 2 
3 2 2 2
Ethyl acetate  Acetic acid ethyl ester  CH COOCH CH   Class 3 
3 2 3
1,2-Dihydroxyethane 
Ethyleneglycol  HOCH CH OH  Class 2 
2 2
1,2-Ethanediol 
Diethyl ether 
Ethyl ether  Ethoxyethane  CH CH OCH CH   Class 3 
3 2 2 3
1,1-Oxybisethane 
Ethyl formate  Formic acid ethyl ester  HCOOCH CH   Class 3 
2 3
Formamide  Methanamide  HCONH   Class 2 
2
Formic acid    HCOOH  Class 3 
Heptane  n-Heptane  CH (CH ) CH   Class 3 
3 2 5 3
Hexane  n-Hexane  CH (CH ) CH   Class 2 
3 2 4 3
Isobutyl acetate  Acetic acid isobutyl ester  CH COOCH CH(CH )   Class 3 
3 2 3 2
Isopropyl acetate  Acetic acid isopropyl ester  CH COOCH(CH )   Class 3 
3 3 2
Methanol  Methyl alcohol  CH OH  Class 2 
3
2-Methoxyethanol  Methyl Cellosolve  CH OCH CH OH  Class 2 
3 2 2
Methyl acetate  Acetic acid methyl ester  CH COOCH   Class 3 
3 3
Isoamyl alcohol 
3-Methyl-1-butanol  Isopentyl alcohol  (CH ) CHCH CH OH  Class 3 
3 2 2 2
3-Methylbutan-1-ol 
2-Hexanone 
Methylbutyl ketone  CH (CH ) COCH   Class 2 
3 2 3 3
Hexan-2-one 
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Solvent  Other Names  Structure  Class 
Cyclohexylmethane 
Methylcyclohexane    CH3 Class 2 
 
2-Butanone 
Methylethyl ketone  MEK  CH CH COCH   Class 3 
3 2 3
Butan-2-one 
4-Methylpentan-2-one 
Methylisobutyl ketone  4-Methyl-2-pentanone  CH COCH CH(CH )   Class 2 
3 2 3 2
MIBK 
Isobutyl alcohol 
2-Methyl-1-propanol  (CH ) CHCH OH  Class 3 
3 2 2
2-Methylpropan-1-ol 
1-Methylpyrrolidin-2-one 
N-Methylpyrrolidone      Class 2 
1-Methyl-2-pyrrolidinone  N O
CH 3   
2-methyloxolane 
2-Methyltetrahydrofuran  Class 3 
tetrahydrosylvan 
 
Nitromethane    CH NO   Class 2 
3 2
Pentane  n-Pentane  CH (CH ) CH   Class 3 
3 2 3 3
Amyl alcohol 
1-Pentanol  Pentan-1-ol  CH (CH ) CH OH  Class 3 
3 2 3 2
Pentyl alcohol 
Propan-1-ol 
1-Propanol  CH CH CH OH  Class 3 
3 2 2
Propyl alcohol 
Propan-2-ol 
2-Propanol  (CH ) CHOH  Class 3 
3 2
Isopropyl alcohol 
Propyl acetate  Acetic acid propyl ester  CH COOCH CH CH   Class 3 
3 2 2 3
Pyridine    N  Class 2 
 
Tetrahydrothiophene 1,1-
Sulfonane  Class 2 
dioxide   
S
   
O O  
Tetramethylene oxide 
Tetrahydrofuran  Class 2 
Oxacyclopentane 
O   
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Solvent  Other Names  Structure  Class 
1,2,3,4-Tetrahydro-
Tetralin  Class 2 
naphthalene 
 
Toluene  Methylbenzene  CH 3  Class 2 
 
1,1,1-Trichloroethane  Methylchlororoform  CH CCl   Class 1 
3 3
1,1,2-Trichloroethene  Trichloroethene  HClC=CCl   Class 2 
2
Triethylamine  N,N,-Diethylethanamine  N(CH CH )   Class 3 
2 3 3
Xylene*  Dimethybenzene  CH 3  CH 3  Class 2 
Xylol 
 
* usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene   
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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 International Programme on 
Chemical Safety (IPCS), the United States Environmental Protection Agency (USEPA), and the 
United States Food and Drug Administration (USFDA) 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 life-time 
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: 
 
Veterinary patients (rather than the general animal population) receive pharmaceuticals to treat 
their diseases or for prophylaxis to prevent infection or disease. However, there are some 
veterinary medicinal products which are used as aids in agricultural production which are 
unrelated to the presence of infection or disease in the animal population. 
 
The assumption of life-time exposure of the veterinary patient is not necessary for most 
pharmaceutical products but may be appropriate as a working hypothesis to reduce risk to human 
health as a life-time exposure of the human consumer to the edible tissues of food animals 
treated with the veterinary medicinal product. 
 
Residual solvents are unavoidable components in pharmaceutical production and will often be a 
part of veterinary medicinal products. 
 
Residual solvents should not exceed recommended levels except in exceptional circumstances, 
and then should be justified. 
 
Data from toxicological studies that are used to determine acceptable levels for residual solvents 
should have been generated using appropriate protocols including, but not necessarily limited to 
those described by OECD, EPA, and the FDA Red Book. 
 
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Appendix 3:  Methods for Establishing Exposure Limits 
The Gaylor-Kodell method of risk assessment (Gaylor, D. W. and Kodell, R. L.: Linear 
Interpolation algorithm for low dose assessment of toxic substance. J Environ. Pathology, 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 no-observed-effect 
level (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 (Environmental Health Criteria 170, WHO, 1994). These methods are 
similar to those used by the USEPA (IRIS) and the USFDA (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 no-observed-effect level (NOEL), or the lowest-observed effect level 
(LOEL) in the most relevant animal study as follows: 
 
 
NNNNPPNN xx WWWWWWWWhtt AAAAAAAAAAttAAWWAAtt  
PPPPPP = 
The PDE is derived preferably from a NOFFE1L xx.   FFIf2  nxxo FF N3 Oxx EFFL4  xxis  FFo5btained, the LOEL may be used. 
Modifying factors proposed here, for relating the data to humans, are the same kind of 
uncertainty factors used in Environmental Health Criteria (Environmental Health Criteria 170, 
World Health Organization, Geneva, 1994), and modifying factors or safety factors in 
Pharmacopeial Forum.  The assumption of 100% 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: 
 
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S = kM0.67   
 
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 non-rodents. 
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents. 
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., non-genotoxic 
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 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 recognised 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.  
 
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-l. The PDE for acetonitrile in this study is calculated 
as follows: 
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50.7 mg kg -1day-1 x 50 kg
PDE =  = 4.22 mg.day -1 
   12 x 10 x 5 x 1 x 1
 
In this example, 
 
F1 = 12 to account for the extrapolation from mice to humans 
F2 = 10 to account for differences between individual humans 
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 A.3.1. Values used in the calculations in this document 
rat body weight  425g    mouse respiratory volume  43 L/day 
pregnant rat body weight  330g    rabbit respiratory volume  1440 L/day 
  guinea pig respiratory 
mouse body weight  28g  430 L/day 
volume  
pregnant mouse body   
30g  human respiratory volume  28,800L/day 
weight 
guinea pig body weight  500g    dog respiratory volume  9,000 L/day 
Rhesus monkey body   
2.5kg  monkey respiratory volume  1,150 L/day 
weight 
rabbit body weight   4kg    mouse water consumption  5 mL 
beagle dog body weight  11.5 kg    rat water consumption  30 mL/day 
rat respiratory volume  290 L/day    rat food consumption  30 g/day 
 
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/m3.  Consider as an example the rat 
reproductive toxicity study by inhalation of carbon tetrachloride (molecular weight 153.84) is 
summarized in Pharmeuropa, Vol, 9, No. 1, Supplement, April 1997, page S9. 
 
n P 300 x 10-6atm x 153840 mg mol-1 46.15 mg
= = = = 1.89 mg/L  
  V RT 0.082 L atm K-1 mol-1 x 298 K 24.45L
 
The relationship 1000 L = 1 m3 is used to convert to mg/ m3. 
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