**100**

**Guidance for Industry**

**[Impurities: Residual Solvents In]{.smallcaps}**

**[New Veterinary Medicinal Products,]{.smallcaps}**

**[Active Substances and Excipients]{.smallcaps}**

**[VICH GL18]{.smallcaps}**

**FINAL GUIDANCE**

####  {#section .ZUT}

####  {#section-1 .ZUT}

#### This final guidance recommends acceptable amounts for residual solvents in new animal drugs (referred to as pharmaceuticals or veterinary medicinal products in the guidance) for the safety of target animals as well as for the safety of human consumers of products derived from treated food producing animals. It is intended to assist in developing new animal drug applications (referred to as marketing applications in the guidance) submitted to the European Union, Japan and the United States. {#this-final-guidance-recommends-acceptable-amounts-for-residual-solvents-in-new-animal-drugs-referred-to-as-pharmaceuticals-or-veterinary-medicinal-products-in-the-guidance-for-the-safety-of-target-animals-as-well-as-for-the-safety-of-human-consumers-of-products-derived-from-treated-food-producing-animals.-it-is-intended-to-assist-in-developing-new-animal-drug-applications-referred-to-as-marketing-applications-in-the-guidance-submitted-to-the-european-union-japan-and-the-united-states. .ZUT}

####  {#section-2 .ZUT}

#### Comments and suggestions regarding this document should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, Email: <fdadockets@oc.fda.gov>. Please refer to Docket No.99D-4071 when commenting on this document. {#comments-and-suggestions-regarding-this-document-should-be-submitted-to-the-dockets-management-branch-hfa-305-food-and-drug-administration-5630-fishers-lane-rm.-1061-rockville-md-20852-email-fdadocketsoc.fda.gov.-please-refer-to-docket-no.99d-4071-when-commenting-on-this-document. .ZUT}

####  {#section-3 .ZUT}

#### For questions regarding this final document contact Kevin J. Greenlees, Center for Veterinary Medicine, (HFV-153), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6977, e-mail: <kgreenle@cvm.fda.gov>. {#for-questions-regarding-this-final-document-contact-kevin-j.-greenlees-center-for-veterinary-medicine-hfv-153-food-and-drug-administration-7500-standish-place-rockville-md-20855-301-827-6977-e-mail-kgreenlecvm.fda.gov. .ZUT}

####  {#section-4 .ZUT}

####  {#section-5 .ZUT}

####  {#section-6 .ZUT}

######### **U.S. Department of Health and Human Services**

######### **Food and Drug Administration**

**Center for Veterinary Medicine**

**May 15, 2001**

**VICH GL18 [(Impurities Solvents)]{.smallcaps}**

**June 2000**

**For implementation at Step 7**

Impurities: Residual Solvents in

new veterinary medicinal

products, active substances

and excipients

Recommended for Implementation

at Step 7 of the VICH Process

on 15 June 2000

by the VICH Steering Committee

[This Guidance has been developed by the appropriate VICH Expert Working
Group on the basis of the ICH guidances on the same subject and was
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]{.smallcaps} USA.

**[IMPURITIES: RESIDUAL SOLVENTS IN]{.smallcaps}**

**[NEW VETERINARY MEDICINAL PRODUCTS,]{.smallcaps}**

**[ACTIVE SUBSTANCES AND EXCIPIENTS]{.smallcaps}**

**1. INTRODUCTION [4](#introduction)**

2\. SCOPE OF THE GUIDANCE [5](#scope-of-the-guidance)

3\. GENERAL PRINCIPLES [5](#general-principles)

3.1 Classification of Residual Solvents by Risk Assessment
[5](#classification-of-residual-solvents-by-risk-assessment)

3.2 Methods for Establishing Exposure Limits
[6](#methods-for-establishing-exposure-limits)

3.3 Options for Describing Limits of Class 2 Solvents
[6](#options-for-describing-limits-of-class-2-solvents)

3.4 Analytical Procedures [7](#analytical-procedures)

3.5 Reporting Levels of Residual Solvents
[8](#reporting-levels-of-residual-solvents)

4\. LIMITS OF RESIDUAL SOLVENTS [8](#limits-of-residual-solvents)

4.1 Solvents that should be Avoided
[8](#solvents-that-should-be-avoided)

4.2 Solvents that should be Limited
[9](#solvents-that-should-be-limited)

4.3 Solvents with Low Toxic Potential
[9](#solvents-with-low-toxic-potential)

4.4 Solvents For Which No Adequate Toxicological Data Was Found
[10](#solvents-for-which-no-adequate-toxicological-data-was-found)

GLOSSARY [11](#glossary)

APPENDIX 1: LIST OF SOLVENTS INCLUDED IN THE GUIDANCE
[12](#appendix-1-list-of-solvents-included-in-the-guidance)

APPENDIX 2: ADDITIONAL BACKGROUND
[17](#appendix-2-additional-background)

A2.1 Environmental Regulation of Organic Volatile Solvents
[17](#a2.1-environmental-regulation-of-organic-volatile-solvents)

A2.2 Residual Solvents in Pharmaceuticals
[17](#a2.2-residual-solvents-in-pharmaceuticals)

APPENDIX 3: METHODS FOR ESTABLISHING EXPOSURE LIMITS
[18](#appendix-3-methods-for-establishing-exposure-limits)

Table A.3.1: Values used in the calculations in this document
[20](#table-a.3.1-values-used-in-the-calculations-in-this-document)

**IMPURITIES: RESIDUAL SOLVENTS IN NEW VETERINARY MEDICINAL PRODUCTS,
ACTIVE SUBSTANCES AND EXCIPIENTS**

####  {#section-7 .ZUT}

####  {#section-8 .ZUT}

#### *This final guidance represents the agency\'s current thinking and does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative method may be used as long as it satisfies the requirements of applicable statutes and regulations*.  {#this-final-guidance-represents-the-agencys-current-thinking-and-does-not-create-or-confer-any-rights-for-or-on-any-person-and-does-not-operate-to-bind-fda-or-the-public.-an-alternative-method-may-be-used-as-long-as-it-satisfies-the-requirements-of-applicable-statutes-and-regulations. .ZUT}

# 

# 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, page 9) 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, page 9)
should be limited in order to protect target animals and human consumers
from potential adverse effects. Ideally, less toxic solvents (Class 3,
Table 3, page 10) should be used where practical. The complete list of
solvents included in this guidance is given in Appendix 1.

The list of solvents is 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, Impurities in New Veterinary Drug Substances) [^1]or veterinary
medicinal product (VICH GL 11, Impurities in New Veterinary Medicinal
Products)[^2], 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. Manufacturers should 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 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 that should be avoided

Known human carcinogens, strongly suspected human carcinogens, and
environmental hazards.

**Class 2 solvents:** Solvents that should 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.

## 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 should be
used. They were calculated using equation (1) below by assuming a
product mass of 10 g administered daily.

$$(1)\text{  Concentration }(\text{ppm})\text{ = }\frac{\text{1000 x PDE}}{\text{dose}}$$

Here, PDE is given in terms of mg/day and dose is given in g/day.

These limits are considered recommended 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
should 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.

  ----------------- ----------------- ----------------- -----------------
  **Component**     **Amount in\      **Acetonitrile\   **Daily
                    formulation**     content**         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        5.0 g             728 ppm           3.64 mg
  medicinal 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.

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 are given in the following
table.

  ----------------- ----------------- ----------------- -----------------
  **Component**     **Amount in\      **Acetonitrile\   **Daily
                    formulation**     content**         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        5.0 g             1016 ppm          5.08 mg
  medicinal 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 should 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 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]

## 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 recommended 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    **Concern**
                          Limit\             
                          (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**

  ----------------------- ----------------------- -----------------------
  **Solvent**             **PDE\                  **Concentration Limit\
                          (mg/day)**              (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     48.4                    4840

  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\*                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

  Cumene                              2-Methyl-1-propanol

  Dimethylsulfoxide                   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 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
  ----------------------------------- -----------------------------------

# 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.

#  

# APPENDIX 1: LIST OF SOLVENTS INCLUDED IN THE GUIDANCE

**Solvent Other Names Structure Class\
**

Acetic acid Ethanoic acid CH3COOH Class 3

Acetone 2-Propanone CH3COCH3 Class 3\
Propan-2-one

Acetonitrile CH3CN Class 2

Anisole Methoxybenzene
![](media/image1.wmf){width="0.9513888888888888in"
height="0.4673611111111111in"} Class 3

Benzene Benzol ![](media/image2.wmf){width="0.59375in"
height="0.5020833333333333in"} Class 1

1-Butanol *n*-Butyl alcohol CH3(CH2)3OH Class 3\
Butan-1-ol

2-Butanol *sec*-Butyl alcohol CH3CH2CH(OH)CH3 Class 3\
Butan-2-ol

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

*tert*-Butylmethyl ether 2-Methoxy-2-methyl-propane (CH3)3COCH3 Class 3

Carbon tetrachloride Tetrachloromethane CCl4 Class 1

Chlorobenzene ![](media/image3.wmf){width="0.96875in" height="0.575in"}
Class 2

Chloroform Trichloromethane CHCl3 Class 2

Cumene Isopropylbenzene
![](media/image4.wmf){width="1.2631944444444445in" height="0.575in"}
Class 3\
(1-Methyl)ethylbenzene

Cyclohexane Hexamethylene
![](media/image5.wmf){width="0.6895833333333333in"
height="0.6104166666666667in"} Class 2

1,2-Dichloroethane *sym*-Dichloroethane CH2ClCH2Cl Class 1\
Ethylene dichloride\
Ethylene chloride

1,1-Dichloroethene 1,1-Dichloroethylene H2C=CCl2 Class 1\
Vinylidene chloride

1,2-Dichloroethene 1,2-Dichloroethylene ClHC=CHCl Class 2\
Acetylene dichloride

Dichloromethane Methylene chloride CH2Cl2 Class 2

1,2-Dimethoxyethane Ethyleneglycol dimethyl ether H3COCH2CH2OCH3 Class
2\
Monoglyme\
Dimethyl Cellosolve

N,N-Dimethylacetamide DMA CH3CON(CH3)2 Class 2

N,N-Dimethylformamide DMF HCON(CH3)2 Class 2

Dimethyl sulfoxide Methylsulfinylmethane (CH3)2SO Class 3\
Methyl sulfoxide\
DMSO

1,4-Dioxane p-Dioxane ![](media/image6.wmf){width="0.5083333333333333in"
height="0.4625in"} Class 2\
\[1,4\]Dioxane

Ethanol Ethyl alcohol CH3CH2OH Class 3

2-Ethoxyethanol Cellosolve CH3CH2OCH2CH2OH Class 2

Ethyl acetate Acetic acid ethyl ester CH3COOCH2CH3 Class 3

Ethyleneglycol 1,2-Dihydroxyethane HOCH2CH2OH Class 2\
1,2-Ethanediol

Ethyl ether Diethyl ether CH3CH2OCH2CH3 Class 3\
Ethoxyethane\
1,1'-Oxybisethane

Ethyl formate Formic acid ethyl ester HCOOCH2CH3 Class 3

Formamide Methanamide HCONH2 Class 2

Formic acid HCOOH Class 3

Heptane n-Heptane CH3(CH2)5CH3 Class 3

Hexane n-Hexane CH3(CH2)4CH3 Class 2

Isobutyl acetate Acetic acid isobutyl ester CH3COOCH2CH(CH3)2 Class 3

Isopropyl acetate Acetic acid isopropyl ester CH3COOCH(CH3)2 Class 3

Methanol Methyl alcohol CH3OH Class 2

2-Methoxyethanol Methyl Cellosolve CH3OCH2CH2OH Class 2

Methyl acetate Acetic acid methyl ester CH3COOCH3 Class 3

3-Methyl-1-butanol Isoamyl alcohol (CH3)2CHCH2CH2OH Class 3\
Isopentyl alcohol\
3-Methylbutan-1-ol

Methylbutyl ketone 2-Hexanone CH3(CH2)3COCH3 Class 2\
Hexan-2-one

Methylcyclohexane Cyclohexylmethane
![](media/image7.wmf){width="1.0069444444444444in"
height="0.5840277777777778in"} Class 2

Methylethyl ketone 2-Butanone CH3CH2COCH3 Class 3\
MEK\
Butan-2-one

Methylisobutyl ketone 4-Methylpentan-2-one CH3COCH2CH(CH3)2 Class 3\
4-Methyl-2-pentanone\
MIBK

2-Methyl-1-propanol Isobutyl alcohol (CH3)2CHCH2OH Class 3\
2-Methylpropan-1-ol

N-Methylpyrrolidone 1-Methylpyrrolidin-2-one
![](media/image8.wmf){width="0.7916666666666666in" height="0.85in"}
Class 2\
1-Methyl-2-pyrrolidinone

Nitromethane CH3NO2 Class 2

Pentane *n*-Pentane CH3(CH2)3CH3 Class 3

1-Pentanol Amyl alcohol CH3(CH2)3CH2OH Class 3\
Pentan-1-ol\
Pentyl alcohol

1-Propanol Propan-1-ol CH3CH2CH2OH Class 3\
Propyl alcohol

2-Propanol Propan-2-ol (CH3)2CHOH Class 3\
Isopropyl alcohol

Propyl acetate Acetic acid propyl ester CH3COOCH2CH2CH3 Class 3

Pyridine ![](media/image9.wmf){width="0.7680555555555556in"
height="0.6895833333333333in"} Class 2

Sulfonane Tetrahydrothiophene 1,1-dioxide
![](media/image10.wmf){width="0.6798611111111111in" height="0.7625in"}
Class 2

Tetrahydrofuran Tetramethylene oxide
![](media/image11.wmf){width="0.6361111111111111in"
height="0.6527777777777778in"} Class 3\
Oxacyclopentane

Tetralin 1,2,3,4-Tetrahydro-naphthalene
![](media/image12.wmf){width="1.1694444444444445in"
height="0.7354166666666667in"} Class 2

Toluene Methylbenzene
![](media/image13.wmf){width="1.1444444444444444in"
height="0.6590277777777778in"} Class 2

1,1,1-Trichloroethane Methylchlororoform CH3CCl3 Class 1

1,1,2-Trichloroethene Trichloroethene HClC=CCl2 Class 2

Xylene\* Dimethybenzene
![](media/image14.wmf){width="1.2354166666666666in"
height="0.6381944444444444in"} Class 2\
Xylol

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

#  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 should 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.

#  

# 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:

![](media/image15.wmf)

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 = kM^0.67^

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 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:

![](media/image16.wmf)

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

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/m^3^. 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.

![](media/image17.wmf)

The relationship 1000 L = 1 m^3^ is used to convert to mg/ m^3^.

[^1]: In the U.S., VICH GL 10 guidance can be found on the CVM home page
    ([www.fda.gov/cvm](http://www.fda.gov/cvm)) as guidance number 92.

[^2]: In the U.S., VICH GL 11 guidance can be found on the CVM home page
    ([www.fda.gov/cvm](http://www.fda.gov/cvm)) as guidance number 93.

[^3]: In the U.S., these guidances can be found on the CVM home page
    ([www.fda.gov/cvm](http://www.fda.gov/cvm)) as guidance numbers 63
    and 64.