100 

Guidance for Industry 

Impurities: Residual Solvents in New 

Veterinary Medicinal Products, Active 

Substances and Excipients (Revision) 

VICH GL18(R) 

Submit comments on this guidance at any time. Submit written comments to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 

1061, Rockville, MD 20852. Submit electronic comments on the guidance at 

http://www.regulations.gov. All written comments should be identified with the Docket No.

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, 240-276-8273, Mai.huynh@fda.hhs.gov. 

Additional copies of this guidance document may be requested from the Communications 

Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 

Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either 

http://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

November 2, 2011 

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Contains Nonbinding Recommendations 

VICH GL18(R) (IMPURITIES SOLVENTS) 

June 2011 

Revision at Step 9 

For Implementation at Step 7 

IMPURITIES: RESIDUAL SOLVENTS IN 

NEW VETERINARY MEDICINAL 

PRODUCTS, ACTIVE SUBSTANCES 

AND EXCIPIENTS 

(REVISION) 

Adopted at Step 7 of the VICH Process 

by the VICH Steering Committee 

in June 2011 

for implementation in June 2012 

This Guidance has been developed by the appropriate VICH Expert Working Group and is 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. 

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Contains Nonbinding Recommendations 

IMPURITIES: RESIDUAL SOLVENTS IN

NEW VETERINARY MEDICINAL PRODUCTS, 

ACTIVE SUBSTANCES AND EXCIPIENTS (REVISION) 

1. INTRODUCTION................................................................................................ 4

2. SCOPE OF THE GUIDANCE ............................................................................ 4

3. GENERAL PRINCIPLES ................................................................................... 5

3.1 Classification of Residual Solvents by Risk Assessment.......................... 5

3.2 Methods for Establishing Exposure Limits ................................................ 5

3.3 Options for Describing Limits of Class 2 Solvents .................................... 5

3.4 Analytical Procedures ............................................................................... 7

3.5 Reporting Levels of Residual Solvents ..................................................... 7

4. LIMITS OF RESIDUAL SOLVENTS.................................................................. 7

4.1 Solvents that should be Avoided............................................................... 7

4.2 Solvents that should be Limited................................................................ 8

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 1: LIST OF SOLVENTS INCLUDED IN THE GUIDANCE................... 11

APPENDIX 2: ADDITIONAL BACKGROUND........................................................ 14

APPENDIX 2: ADDITIONAL BACKGROUND........................................................ 14

A2.1 Environmental Regulation of Organic Volatile Solvents....................... 14

A2.2 Residual Solvents in Pharmaceuticals................................................. 14

APPENDIX 3: METHODS FOR ESTABLISHING EXPOSURE LIMITS ................. 15

APPENDIX 3: METHODS FOR ESTABLISHING EXPOSURE LIMITS ................. 15

Table A.3.1: Values used in the calculations in this document ....................... 17

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IMPURITIES: RESIDUAL SOLVENTS IN NEW VETERINARY

MEDICINAL PRODUCTS, ACTIVE SUBSTANCES AND EXCIPIENTS

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. 

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 guidance or the concept 

of qualification of impurities as expressed in the guidance for active substance (VICH GL 10(R), 

Impurities in New Veterinary Drug Substances) or veterinary medicinal product (VICH GL 11(R), 

Impurities in New Veterinary Medicinal Products), or all three guidances. 

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. 

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Contains Nonbinding Recommendations 

See Appendix 2 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 "acceptable daily intake" (ADI) is used by the World 

Health Organisation (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 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. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 

9, No. 1, Supplement, April 1997 and in Part II and Part III of the ICH Guideline on Impurities: 

Guideline for Residual Solvents (Q3C(R4). 

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. 

dose

PDE x 1000 Concentrat (1) = (ppm)ion 

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 

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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. 

Component Amount in 

formulation 

Acetonitrile 

content 

Daily exposure 

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 

product 

5.0 g 728 ppm 3.64 mg 

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. 

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. 

Component Amount in 

formulation 

Acetonitrile 

content 

Daily exposure 

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 

product 

5.0 g 1016 ppm 5.08 mg 

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 

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Contains Nonbinding Recommendations 

provide a risk-benefit analysis to support allowing the product to be utilised with residual solvent at a 

higher level. 

3.4 Analytical Procedures 

Residual solvents are typically determined using chromatographic techniques such as gas 

chromatography. Any harmonised 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. 

Validation of methods for residual solvents should conform to the VICH guidances "Validation of 

analytical procedures: definition and terminology" and "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 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. 

Table 1: Class 1 Solvents in pharmaceutical products (solvents that should be avoided) 

Solvent Concentration 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 1500 Environmental hazard 

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Contains Nonbinding Recommendations 

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 

Solvent PDE 

(mg/day) 

Concentration Limit 

(ppm) 

Acetonitrile 4.1 410 

Chlorobenzene 3.6 360 

Chloroform 0.6 60 

Cyclohexane 38.8 3880 

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 

N-Methylpyrrolidone 5.3 530 

Nitromethane 0.5 50 

Pyridine 2.0 200 

Sulfolane 1.6 160 

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 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 

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Cumene 2-Methyl-1-propanol 

Dimethylsulfoxide Pentane 

Ethanol 1-Pentanol 

Ethyl acetate 1-Propanol 

Ethyl ether 2-Propanol 

Ethyl formate Propyl acetate 

Formic acid 

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 CH3COOH 3 

Acetone 2-Propanone 

Propan-2-one 

CH3COCH3 3 

Acetonitrile CH3CN 2 

Anisole Methoxybenzene C6H5OCH3 3 

Benzene Benzol C6H6 1 

1-Butanol n-Butyl alcohol 

Butan-1-ol 

CH3(CH2)3OH 3 

2-Butanol sec-Butyl alcohol 

Butan-2-ol 

CH3CH2CH(OH)CH3 3 

Butyl acetate Acetic acid butyl ester CH3COO(CH2)3CH3 3 

tert-Butylmethyl 

ether 

2-Methoxy-2-methylpropane 

(CH3)3COCH3 3 

Carbon 

tetrachloride 

Tetrachloromethane CCl4 1 

Chlorobenzene 

Cl

C6H5Cl 2 

Chloroform Trichloromethane CHCl3 2 

Cumene Isopropylbenzene 

(1-

Methyl)ethylbenzene 

CH(CH3)2

C6H5CH(CH3)2 3 

Cyclohexane Hexamethylene C6H12 2 

1,2-Dichloroethane sym-Dichloroethane 

Ethylene dichloride 

Ethylene chloride 

CH2ClCH2Cl 1 

1,1-Dichloroethene 1,1-Dichloroethylene 

Vinylidene chloride 

H2C=CCl2 1 

1,2-Dichloroethene 1,2-Dichloroethylene 

Acetylene dichloride 

ClHC=CHCl 2 

Dichloromethane Methylene chloride CH2Cl2 2 

1,2-

Dimethoxyethane 

Ethyleneglycol 

dimethyl ether 

Monoglyme 

Dimethyl cellosolve 

H3COCH2CH2OCH3 2 

N,NDimethylacetamide DMA CH3CON(CH3)2 2 

N,NDimethylformamide DMF HCON(CH3)2 2 

OCH 3

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Dimethyl sulfoxide Methylsulfinylmethane

Methyl sulfoxide 

DMSO 

CH3)2SO 3 

1,4-Dioxane p-Dioxane 

[1,4]Dioxane 

O1CH2CH2OCH2C1H2 2 

Ethanol Ethyl alcohol CH3CH2OH 3 

2-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH 2 

Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 3 

Ethyleneglycol 1,2-Dihydroxyethane 

1,2-Ethanediol 

HOCH2CH2OH 2 

Ethyl ether Diethyl ether 

Ethoxyethane 

1,1’-Oxybisethane 

CH3CH2OCH2CH3 3 

Ethyl formate Formic acid ethyl ester HCOOCH2CH3 3 

Formamide Methanamide HCONH2 2 

Formic acid HCOOH 3 

Heptane n-Heptane CH3(CH2)5CH3 3 

Hexane n-Hexane CH3(CH2)4CH3 2 

Isobutyl acetate Acetic acid isobutyl 

ester 

CH3COOCH2CH(CH3)2 3 

Isopropyl acetate Acetic acid isopropyl 

ester 

CH3COOCH(CH3)2 3 

Methanol Methyl alcohol CH3OH 2 

2-Methoxyethanol Methyl cellosolve CH3OCH2CH2OH 2 

Methyl acetate Acetic acid methyl 

ester 

CH3COOCH3 3 

3-Methyl-1-butanol Isoamyl alcohol 

Isopentyl alcohol 

3-Methylbutan-1-ol 

(CH3)2CHCH2CH2OH 3 

Methylbutyl ketone 2-Hexanone 

Hexan-2-one 

CH3(CH2)3COCH3 2 

Methylcyclohexane Cyclohexylmethane C6H11CH3 2 

Methylethyl ketone 2-Butanone 

MEK 

Butan-2-one 

CH3CH2COCH3 3 

Methylisobutyl 

ketone 

4-Methylpentan-2-one 

4-Methyl-2-pentanone 

MIBK 

CH3COCH2CH(CH3)2 3 

2-Methyl-1-

propanol 

Isobutyl alcohol 

2-Methylpropan-1-ol 

(CH3)2CHCH2OH 3 

NMethylpyrrolidone 1-Methylpyrrolidin-2-

one 

1-Methyl-2-

pyrrolidinone 

N O

CH3

CH3N1CH2CH2CH2C1=O 2 

Nitromethane CH3NO2 2 

CH3

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Pentane n-Pentane CH3(CH2)3CH3 3 

1-Pentanol Amyl alcohol 

Pentan-1-ol 

Pentyl alcohol 

CH3(CH2)3CH2OH 3 

1-Propanol Propan-1-ol 

Propyl alcohol 

CH3CH2CH2OH 3 

2-Propanol Propan-2-ol 

Isopropyl alcohol 

(CH3)2CHOH 3 

Propyl acetate Acetic acid propyl 

ester 

CH3COOCH2CH2CH3 3 

Pyridine C6H5N 2 

Sulfonane Tetrahydrothiophene 

1,1-dioxide 

O=S1

(CH2CH2CH2C1H2)=O 2 

Tetrahydrofuran Tetramethylene oxide 

Oxacyclopentane 

O1CH2CH2CH2C1H2 2 

Tetralin 1,2,3,4-Tetrahydronaphthalene C10H12

(Empirical formula) 

2 

Toluene Methylbenzene 

CH3

C6H5CH3 2 

1,1,1-

Trichloroethane 

Methylchloroform CH3CCl3 1 

1,1,2-

Trichloroethene 

Trichloroethylene HClC=CCl2 2 

Xylene* Dimethybenzene 

Xylol 

CH3

CH3

C6H4(CH3)2 2 

* usually 60 % m-xylene, 14 % p-xylene, 9 % o-xylene with 17 % ethyl benzene 

N

O

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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: 

 

PDE = 

NOEL x Weight Adjustment

F1 x F2 x F3 x F4 x F5

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 Environmental Health Criteria (Environmental Health Criteria 170, World Health 

Organisation, 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: 

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. 

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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 

summarised 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: 

 

PDE = 50.7 mg kg -1day -1 x 50 kg

12 x 10 x 5x 1 x 1 = 4.22 mg.day -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 

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Page 17 of 18 

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 

mouse body weight 28g guinea pig respiratory 430 L/day 

 volume 

pregnant mouse body weight 30g human respiratory volume 28,800L/day 

guinea pig body weight 500g dog respiratory volume 9,000 L/day 

Rhesus monkey body weight 2.5kg monkey respiratory volume 1,150 L/day 

Rabbit body weight 4kg mouse water consumption 5 mL 

(pregnant or not) 

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 summarised in 

Pharmeuropa, Vol, 9, No. 1, Supplement, April 1997, page S9. 

 

n

V = P

RT = 300 x 10-6 atm x 153840 mg mol-1

0.082 L atm K-1 mol-1 x 298 K = 46.15 mg

24.45L = 1.89 mg/L

The relationship 1000 L = 1 m3

 is used to convert to mg/ m3.