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U.S.EFA
DfE Screen for Fragrances
Human Health Criteria
1 Introduction
The DfE Screen for Fragrances was developed by the Environmental Protection Agency's Design for
Environment (DfE) Program and a group of stakeholders that included the fragrance industry, cleaning
product formulators, environmental non-governmental organizations, and others. This screen is designed
to identify safer aroma chemicals and fragrance formulations for use in cleaning products. The contents
of this screen, including definitions and toxicological preferences, were developed to facilitate use of safer
chemistry under the DfE Program.
The DfE Screen for Fragrances applies to fragrances used in the following types of cleaning products: all
purpose cleaners, carpet care products, machine warewash detergents, dishwash detergents, floor care
products, manual dishwash detergents, hard surface cleaners, washroom cleaners, hand soaps (non-
FDA regulated) and laundry detergents. Product categories that are outside the scope of this screen
include air fresheners, hand soaps (those regulated by FDA), and personal care products such as lotions.
Fragrances are complex mixtures of fragrance raw materials used for the primary purpose of imparting a
scent and/or masking base odor. For the purpose of this screen, a fragrance raw material is any
substance, obtained by chemical synthesis or derived from a natural source.
Evaluation under the screen considers all components of a fragrance formulation. All non-aroma
fragrance raw materials must meet the DfE Screen for their ingredient class (i.e. solvents must meet the
DfE Screen for Safer Solvents).
More than 2,000 chemical substances with diverse chemical structures, and therefore diverse human and
environmental health profiles, are used in formulation by the fragrance industry. To identify safer
chemicals for this diverse set of raw materials, a range of human health endpoints serve as the basis for
screening out fragrance raw materials of high concern. A fragrance must meet all the criteria for each
human health endpoint in order to pass the screen.
The screening criteria for the human health endpoints in the screen apply to all chemicals present in the
fragrance at or above 0.01 percent by weight. DfE's 0.01 % threshold reflects a stakeholder-agreed and
conservative approach to screening fragrances.
EPA may choose to perform an in-depth review of a fragrance chemical or compound under certain
conditions. For example, in cases involving conflicting data, EPA would rely on GHS criteria. An example
of another situation that may trigger an in-depth review includes chemicals that are detected via
biomonitoring studies.
For any fragrance raw material (chemical component) that is subject to EPA or OECD formal chemical
evaluation efforts and for which a screening-level hazard characterization has been developed, that
hazard characterization will serve as the primary basis for evaluation under the fragrance screen. Details
on how EPA develops screening-level hazard characterizations can be found at:
http://www.epa.gov/champ/. Data not previously located for EPA or OECD formal chemical evaluation
efforts may also be evaluated.
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The DfE Screen for Fragrances is a pragmatic, customized approach that uses hazard-based lists,
combined with literature review, modeling, and expert judgment. It is appropriately different from methods
typically used by EPA to evaluate chemicals in regulatory programs conducted under the Toxic
Substances Control Act (TSCA). Two factors make the DfE approach appropriate for screening fragrance
materials. First, the screen will be used to evaluate fragrances that typically contain large numbers of raw
materials in such small quantities that they are not reviewed under ecolabeling programs. Second, the
intent in developing the fragrances screen is to provide a practical, cost-effective tool for moving the
chemical components of fragrances towards safer substitutes. While the approach is streamlined, where
concern exists for chemicals the intent is to understand and account for that concern. EPA will consider
all sources of developing information, including enhancements to estimation models such as EPI Suite™
that occur overtime, the Nanomaterials Stewardship Program, and the EPA Endocrine Disrupter
Screening Program.1
Reviews under this screen will be conducted by qualified third-parties. Reviewers will consult relevant
sources and supporting documents that describe the derivation and scope of the classification criteria for
the different endpoints to ensure consistent use of the information. Third-party reviewers will use credible
data, and use the supporting documents referenced in the DfE Screen for Fragrances: Human Health
Criteria to conduct reviews under this screen. Every subsection in Section 5 of this screen includes
references for data interpretation. The third-party reviewer will proceed with the screening process as
described below and as is illustrated in Diagram 1 below:
1. If the ingredient has been evaluated under EPA or OECD formal evaluation efforts, the resulting
characterization(s) shall be the primary source of information for screening. Data not previously located
for EPA or OECD chemical evaluation efforts may also be evaluated; and
2. If an EPA or OECD assessment is not available, the third-party reviewer will proceed with the
chemical screening as described in this document.
1 "The Agency does not consider endocrine disruption to be an adverse endpoint per se, but as a step
that could lead to toxic outcomes, such as cancer or adverse reproductive effects...."[1. USEPA,
Special Report on Environmental Endocrine Disruption: An Effects Assessment and Analysis. , in Risk
Assessment Forum. 1997: Washington DC.
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Diagram 1: Data Evaluation Process
Has the fragrance raw material been
evaluated under EPA's formal
chemical evaluation process or by
OECD?
yes
Use the EPA formal chemical evaluation
process and OECD HPV Chemical
Program reports as the primary sources
of data for the fragrance raw material
screening. Data not previously located
for EPA or OECD chemical evaluation
efforts may also be evaluated.
no
Review public literature for
additional data on the fragrance
raw material
Review hazard lists maintained by
authoritative bodies to determine
if concerns exist.
Use GHS criteria as defined in the
screen to review fragrance raw
material as needed using a weight
of evidence approach.
Use estimation models when data
are unavailable.
Screen each fragrance raw
material - if any fail the criterion
for any one endpoint, the
fragrance does not pass the
screen.
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General Requirements
2.1 The manufacturer shall fully disclose the fragrance formulation, including all raw materials (either
individual chemicals or essential oils) intentionally added or present at a level of 0.01 percent by
weight or higher.
2.2 The reviewer shall use the European Flavour and Fragrance Association (EFFA) Code of
Practice/Labeling Manual to identify components of essential oils that are potential concerns and
therefore must be screened (http://www.effa.be/cop 2008.htm).
2.3 Fragrances must meet the International Fragrance Association (IFRA) Standards. The cleaning
product manufacturer shall demonstrate compliance by supplying a written letter from all
suppliers.
3 Terms
3.1 Acute aquatic toxicity is the intrinsic property of a substance to be injurious to an organism in a
short-term exposure to that substance. (GHS)
3.2 Acute mammalian toxicity refers to those adverse effects occurring following oral or dermal
administration of a single dose of a substance, or multiple doses given within 24 hours, or an
inhalation exposure of 4 hours. (GHS)
3.3 Attribute: The general property of the fragrance or raw material that is being evaluated (i.e.
acute mammalian toxicity, biodegradability).
3.4 Auxiliary fragrance raw material: Any ingredient in the fragrance whose primary function is
something other than to impart a scent. For the purposes of this screen, this may include
solvents, surfactants, chelating agents, and anti-oxidants.
3.5 Bioaccumulation is a process in which a chemical substance is absorbed in an organism by all
routes of exposure as occurs in the natural environment, i.e., dietary and ambient environment
sources. Bioaccumulation is the net result of competing processes of chemical uptake into the
organism at the respiratory surface and from the diet and chemical elimination from the organism
including respiratory exchange, fecal egestion, metabolic biotransformation of the parent
compound and growth dilution. [2]
3.6 Biodegradation is a process in which the destruction of the chemical is accomplished by the
action of a living organism. (Handbook of Property Estimation Methods for Chemicals, 2000)
3.7 Carcinogen denotes a chemical substance or mixture of chemical substances which induces
cancer or increases its incidence. (GHS)
3.8 Chronic aquatic toxicity is the potential or actual properties of a substance to cause adverse
effects to aquatic organisms during exposures which are determined in relation to the life cycle of
the organism. (GHS)
3.9 A component of an essential oil is defined as a chemical constituent of the essential oil present
in the fragrance at greater than 0.01 weight %.
3.10 Criteria: Endpoints and cutoffs for attribute information. Example: oral acute mammalian toxicity
LD50 must be > 50 mg/kg. Data quality requirements (including acceptable test methods and
information sources) are developed for all criteria.
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3.11 Degradation products of concern are chemicals formed from degradation of fragrance
chemicals with high acute aquatic toxicity (L/E/IC50 < 10ppm) and which mineralize <60% in 28
days.
3.12 Dermal sensitizer: A substance that will induce an allergic response following skin contact
(GHS)
3.13 Developmental toxicity: Adverse effects in the developing organism that may result from
exposure prior to conception (either parent), during prenatal development, or postnatally to the
time of sexual maturation. Adverse developmental effects may be detected at any point in the
lifespan of the organism. The major manifestations of developmental toxicity include: (1) death of
the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional
deficiency. (EPA Risk Assessment Guidelines)
3.14 Fragrance (or fragrance finished product): A complex mixture of fragrance raw materials for
use in a cleaning product for the primary purpose of imparting a scent and/or masking base odor.
3.15 Fragrance compound: A blend of fragrance ingredients, representing a specific fragrance
formula. (IFRA Code of Practice)
3.16 Fragrance raw material: Any substance, obtained by chemical synthesis or derived from a
natural source, intentionally added or present in a fragrance at greater than 0.01 percent by
weight whose primary purpose is to impart scent. In the context of this screen, fragrance raw
materials include aroma chemicals, fragrant extracts (essential oils), and components of essential
oils.
3.17 Genotoxicity: The more general terms genotoxic and genotoxicity apply to agents or processes
which alter the structure, information content, or segregation of DMA, including those which cause
DMA damage by interfering with normal replication processes, or which in a non-physiological
manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators
for mutagenic effects. (GHS)
3.18 Mutagen: The term mutagenic and mutagen will be used for agents giving rise to an increased
occurrence of mutations in populations of cells and/or organisms. (GHS)
3.19 Neurotoxicity: An adverse change in the structure or function of the central and/or peripheral
nervous system following exposure to a chemical, physical, or biological agent. (US EPA Risk
Assessment Guidelines)
3.20 Persistence: A chemical's persistence refers to the length of time the chemical can exist in the
environment before being destroyed (i.e., transformed) by natural processes. (EPA PBT Final
Rule)
3.21 Photo sensitizer: A substance that will lead to an allergic response following skin contact under
the influence of light exposure.
3.22 Reproductive toxicity: The occurrence of biologically adverse effects on the reproductive
systems of females or males that may result from exposure to environmental agents. The toxicity
may be expressed as alterations to the female or male reproductive organs, the related endocrine
system, or pregnancy outcomes. The manifestation of such toxicity may include, but not be
limited to, adverse effects on onset of puberty, gamete production and transport, reproductive
cycle normality, sexual behavior, fertility, gestation, parturition, lactation, developmental toxicity,
premature reproductive senescence, or modifications in other functions that are dependent on the
integrity of the reproductive systems. (US EPA Risk Assessment Guidelines)
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3.23 Respiratory sensitizer: A substance that will induce hypersensitivity of the airways following
inhalation of the substance. (GHS)
3.24 System toxicity/organ effects repeated exposure: Substances that produce specific target
organ/systemic toxicity arising from a repeated exposure. All significant health effects that can
impair function, both reversible and irreversible, immediate and/or delayed are included. (GHS)
4 Preferences
4.1 When data are developed specifically for review under this screen, data collected from dermal
and inhalation exposure routes are preferred over oral exposure data because the former are
more likely routes of exposure for cleaning products. When data are developed for repeated
dose toxicity, EPA requests that a functional observational battery be added to the test method to
provide neurotoxicity information.
4.2 The GHS criteria and data evaluation approach and EPA risk assessment guidance will inform
professional judgment in the review of both NOAEL and LOAEL values. NOAEL and LOAEL
values are preferred to no observed effect levels and lowest observed effect levels. In reviews
that include conflicting data, a weight of evidence approach will determine a pass or fail.
4.3 Measured data and analogs will be preferred over estimation models. Acceptable analogs will be
based on a chemically (e.g., based on chemical structure) or biologically (e.g., based on
metabolic breakdown, or likely mechanistic/mode of action considerations) similar chemical.
Estimation models may supplement data evaluation as part of weight of evidence.
4.4 Use of existing data should follow the EPA HPV Challenge Program and OECD HPV Programme
data adequacy guidelines: http://www.epa.qov/HPV/pubs/qeneral/datadfin.htm.
4.5 The links and references in this document are current as of the publication date of this screen.
The reviewer must use the most recent version of each authoritative list, all data interpretation
guidance, and each test protocol when reviewing fragrances against this screen. In the case
where a link or reference in this document is superseded by a more recent version, the more
recent version must be used.
5 Attributes of Concern for all Fragrances
All fragrance raw materials present at 100 ppm (or 0.01 percent by weight) or greater in the fragrance will
be screened using the criteria described below.
5.1 ACUTE MAMMALIAN TOXICITY
5.1.1 Criteria and Data Evaluation
To be acceptable under the screen, fragrances must have a median lethal dose or concentration greater
than those values listed in Table 1. Fragrances shall be evaluated for acute mammalian toxicity based on
test data or weight of evidence from literature review, analogs, models and professional judgment. Acute
mammalian toxicity will be evaluated for all routes of exposure where data is available. Data must be
available on at least one route of exposure for each fragrance raw material. Failure to pass this endpoint
by any route of exposure results in failure to pass the screen.
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Table 1 -Acute Mammalian Toxicity
Route of Exposure
Oral LD50 (mg/kg bw)
Dermal LD50 (mg/kg bw)
Inhalation, gas LC50 (ppmV)
Inhalation, vapor LC50 (mg/L)
Inhalation, dust/mist/fumes LC50 (mg/L)
Median Lethal
Dose/Concentration
>50
>200
>500
>2.0
>0.5
5.1.2 Supporting Information
The following EU Risk Phrases [3] can be used to streamline the evaluation of fragrance raw materials for
acute mammalian toxicity:
- R20 "Harmful by inhalation";
- R21 "Harmful in contact with skin";
- R22 "Harmful if swallowed";
- R23 "Toxic by inhalation";
- R24 "Toxic in contact with skin";
- R25 "Toxic if swallowed";
- R26 "Very toxic by inhalation";
- R27 "Very toxic in contact with skin";
- R28 "Very toxic if swallowed"; and
- All combinations of risk phrases containing one of more of the above.
5.1.3 Test Methods for GHS Review
- OPPTS Harmonized Guideline 870.1100: Acute oral toxicity [4];
- OPPTS Harmonized Guideline 870.1200: Acute dermal toxicity [5];
- OPPTS Harmonized Guideline 870.1300: Acute inhalation toxicity [6];
- OECD Test Guideline 420: Acute Oral Toxicity-Fixed Dose Method [7];
- OECD Test Guideline 423: Acute Oral Toxicity - Acute Toxic Class Method [8];
- OECD Test Guideline 425: Acute Oral Toxicity - Up-and-Down Procedure [9];
- OECD Test Guideline 402: Acute Dermal Toxicity [10]; and
- OECD Test Guideline 403: Acute Inhalation Toxicity [11].
5.1.4 Data Interpretation
For additional information, see GHS Ch 3.1 Acute Toxicity [12].
5.2 CARCINOGENICITY
5.2.1 Criteria and Data Evaluation
Fragrance raw materials considered carcinogens by one of the authoritative bodies in Table 2 do not pass
the screen.
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Table 2 - Carcinogens
Authoritative Body
National Toxicology Program
(NTP)
U.S. Environmental Protection
Agency (EPA)
International Agency for
Research on Cancer (IARC)
EU CMR List [3]
EU Risk Phrases3 [3]
Criteria that will not pass the DfE Screen
Known to be Human Carcinogen
Reasonably Anticipated to be Human Carcinogen
(2005/1999) "Carcinogenic to humans", "Likely to be carcinogenic to
humans", or "Suggestive evidence of carcinogenic potential"
(1996) "Known/Likely"
(1 986) "Group A - Human Carcinogen", "Group B - Probable human
carcinogen," or "Group C - Possible human carcinogen"
Group 1 - carcinogenic to humans
Group 2A - probably carcinogenic to humans
Group 2B - possibly carcinogenic to humans
Category 1 - Known
Category 2 - Should be considered carcinogenic to humans
Category 3 - Possible carcinogenic effects
R45: "May cause cancer"
R49: "May cause cancer by inhalation"
R40: "Limited evidence of a carcinogenic effect"
a Any combination containing one or more of the risk phrases above shall also not pass the screen.
5.2.2 Supplemental Criteria: GHS Review
In the case where carcinogenicity data have not been reviewed by IARC, NTP, EPA, or by the EU in the
context of the CMR list and R-phrases, a supplemental assessment may be performed. When a
supplemental assessment is performed, GHS criteria will be used to review all available data.
Additionally, if a fragrance raw material appears on the list of substances prioritized for testing for
endocrine disruption by the European Commission [13, 14], the raw material will be screened against
GHS criteria using test data or weight of evidence. Components not on the established lists in Table 2,
but that are considered known or presumed human carcinogens (Category 1), or suspected human
carcinogens (Category 2) under GHS [15], will not pass the screen.
5.2.3 Test Methods for GHS Review
- OECD Test Guideline 451: Carcinogenicity Studies [16];
- OECD Test Guideline 453: Combined Chronic Toxicity/Carcinogenicity Studies [17];
- OPPTS Harmonized Guidelines 870.4200: Carcinogenicity [18];
- OPPTS Harmonized Guidelines 870.4300: Combined chronic toxicity/carcinogenicity [19] and
- NTP 2 Year Study Protocol: "Specifications for the conduct of studies to evaluate the toxic
and carcinogenic potential of chemical, biological and physical agents in laboratory
animals for the National Toxicology Program" [20].
5.2.4 Data Interpretation
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING",
then "DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then
either of the files listed as: "Annex I of Directive 67548EEC". [21];
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24];
- GHS Ch 3.6 Carcinogenicity [15];
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- Section 2, Hazard Assessment in Guidelines for Carcinogen Risk Assessment (Risk
Assessment Forum) (EPA 2005),
http://oaspub.epa.gov/eims/eimscomm.getfile7p download id=439797 [25] and
- The following link can be used to identify substances prioritized for testing for endocrine
disruption by the European Commission:
http://ec.europa.eu/environment/endocrine/strategy/substances en.htm#priority list. To
download the list of substances, see the zipped file under the heading "Priority List" [13].
- The following report describes the process used to develop the endocrine disrupters priority
list: http://ec.europa.eu/environment/endocrine/documents/final report 2007.pdf [14].
5.3 GENETIC TOXICITY
5.3.1 Criteria and Data Evaluation
Fragrance raw materials considered mutagens or genetic toxicants by authoritative bodies in Table 4 do
not pass the screen. Additional requirements may also apply, based on test data and weight of evidence.
Table 3 - Mutagenicity and Genetic Toxicity
Authoritative Body
EU CMR List [3]
EU Risk Phrases [3]
Criteria that will not pass the DfE Screen
Category 1 - "Substances known to be mutagenicto man"
Category 2 - "Substances which should be regarded as if they
are mutagenicto man"
Category 3 - "Substances which cause concern for man owing
to possible mutagenic effects"
R46: "May cause heritable genetic damage"3
R68: "Possible risk of irreversible effects"
a Any combination containing R46 shall also not pass the screen.
5.3.2 Supplemental Criteria: GHS Review
In the case where mutagenicity or genetic toxicity data have not been reviewed by the EU in the context
of the CMR list or R-phrases, a supplemental assessment may be performed. When a supplemental
assessment is performed, GHS criteria will be used to review all available data. Components not on the
established lists in Table 3, but that are known to induce heritable mutations in germ cells (Category 1 A),
or should be regarded as if they induce heritable mutations in germ cells (Category 1B) or may induce
heritable mutations in germ cells (Category 2) under GHS [15], will not pass the screen.
5.3.3 Test Methods for GHS Review
- OECD Test Guideline 478: Genetic Toxicology: Rodent Dominant Lethal Test [26];
- OECD Test Guideline 485: Genetic Toxicology, Mouse Heritable Translocation Assay [27];
- OECD Test Guideline 475: Mammalian Bone Marrow Chromosome Aberration Test [28];
- OECD Test Guideline 484: Genetic Toxicology: Mouse Spot Test [29];
- OECD Test Guideline 474: Mammalian Erythrocyte Micronucleus Test [30];
- OECD Test Guideline 483: Mammalian Spermatogonial Chromosome Aberration Test [31];
- OECD Test Guideline 486: Unscheduled DMA Synthesis (UDS) Test with Mammalian Liver
Cells in vivo [32];
- OECD Test Guideline 473: In vitro Mammalian Chromosome Aberration Test [33];
- OECD Test Guideline 476: In vitro Mammalian Cell Gene Mutation Test [34]; and
- OECD Test Guideline 471: Bacterial Reverse Mutation Test [35].
- OECD Test Guideline 479: Genetic Toxicology: In Vitro Sister Chromatid Exchange Assay in
Mammalian Cells [36]
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- OPPTS Harmonized Guideline 870.5100: Bacterial reverse mutation test [37]
- OPPTS Harmonized Guideline 870.5375: In vitro mammalian chromosome aberration test
[38]
- OPPTS Harmonized Guideline 870.5300: In vitro mammalian cell gene mutation test [39]
- OPPTS Harmonized Guideline 870.5395: Mammalian erythrocyte micronucleus test [40]
- OPPTS Harmonized Guideline 870.5385: Mammalian bone marrow chromosomal aberration
test [41]
- OPPTS Harmonized Guideline 870.5380: Mammalian spermatogonial chromosomal
aberration test [42]
5.3.4. Data Interpretation
The following sources should be consulted for additional information:
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING",
then "DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then
either of the files listed as: "Annex I of Directive 67548EEC". [21]
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24]; and
- GHS Ch 3.5 Germ Cell Mutagenicity [43].
5.4 REPEATED DOSE AND NEUROTOXICITY
5.4.1 Criteria
If a fragrance contains one or more fragrance raw materials that are considered systemic or
neurotoxicants per GHS, then the compound must be evaluated using the GHS criteria for mixtures [44,
45]. To pass the screen, the fragrance must not be considered a specific target organ toxicant by any
route of exposure (i.e., no GHS Category 1 or Category 2 fragrances).
5.4.2 Data Evaluation: Review of Fragrance Raw Materials
Each fragrance raw material that is evaluated using GHS must be screened for general systemic
toxicity/organ effects and neurotoxicity effects. If a fragrance raw material meets any of the conditions
below, it must be reviewed based on GHS criteria, using test data or weight of evidence:
- Requiring at least one of the specified EU Risk Phrases [3]
R33 "Danger of cumulative effects" (repeated exposure)
R39 "Danger of very serious irreversible effects" (single exposure)
R48 "Danger of serious damage to health by prolonged exposure" (repeated
exposure)
R68 "Possible risk of irreversible effects" (single exposure), or
- Having new data not yet incorporated into the EU Risk Phrases, or
- Appears on the list of substances prioritized for testing for endocrine disruption by the
European Commission. [13, 14].
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Table 5a - GHS Category 1 - Specific Target Organ Toxicity - Repeated Exposure
Route of Exposure
Oral (mg/kg-bw/day)
Dermal (mg/kg-bw/day)
Inhalation (gas) (ppm/6h/day)
Inhalation (vapor) (mg/L/6h/day)
Inhalation (dust/mist/fume) (mg/L/6h/day)
Guidance values1
<10
<20
<50
<0.2
<0.02
' The doses provided are for 90-day studies. Guidance values are tripled for chemicals evaluated
in 28-day studies and similarly modified for studies of longer durations.
Table 5b - GHS Category 2 - Specific Target Organ Toxicity - Repeated Exposure
Route of Exposure
Oral (mg/kg-bw/day)
Dermal (mg/kg-bw/day)
Inhalation (gas) (ppm/6h/day)
Inhalation (vapor) (mg/L/6h/day)
Inhalation (dust/mist/fume) (mg/L/6h/day)
Guidance values1
10-100
20 - 200
50 - 250
0.2-1.0
0.02-0.2
' The doses provided are for 90-day studies. Guidance values are tripled for chemicals evaluated
in 28-day studies and similarly modified for studies of longer durations.
If one or more fragrance raw materials meet GHS criteria for Category 1 or Category 2 Specific Target
Organ Toxicity - Repeated Exposure, then the fragrance must be evaluated per GHS mixture rules (see
section 5.4.3).
5.4.3 Data Evaluation: Review of Fragrances
Fragrance raw materials that meet GHS criteria for Category 1 or Category 2 Specific Target Organ
Toxicity - Repeated Exposure will be limited based on percentage as described by the GHS mixture
rules. The GHS mixture rules (GHS section 3.9.3.4 - Classification of mixtures when data are available
for all components or only for some components of the mixture [45]) will be applied. To pass the screen,
the fragrance must not be considered a specific target organ toxicant by any route of exposure (i.e., no
GHS Category 1 or Category 2 fragrances).
5.4.4 Test Methods for GHS Review, Preferred
- OECD Test Guideline 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents [46];
- OECD Test Guideline 409: Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents [47];
- OECD Test Guideline 411: Subchronic Dermal Toxicity: 90-day Study [48];
- OECD Test Guideline 413: Subchronic Inhalation Toxicity: 90-day Study [49];
- OPPTS Harmonized Guideline 870.3100: 90-Day oral toxicity in rodents [50];
- OPPTS Harmonized Guideline 870.3150: 90-Day oral toxicity in nonrodents [51];
- OPPTS Harmonized Guideline 870.3250: 90-Day dermal toxicity [52]; and
- OPPTS Harmonized Guideline 870.3465: 90-Day inhalation toxicity [53].
5.4.5 Test Methods for GHS Review, Acceptable
- OECD Test Guideline 412: Repeated Dose Inhalation Toxicity: 28-day [54];
- OECD Test Guideline 410: Repeated Dose Dermal Toxicity: 28-day Study [55];
- OECD Test Guideline 407: Repeated Dose 28-day Oral Toxicity Study in Rodents [56];
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- OECD Test Guideline 422: Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test [57];
- OPPTS Harmonized Guideline 870.3050: Repeated dose 28-day oral toxicity study in rodents
[58]; and
- OPPTS Harmonized Guideline 870.3200: 28-Day dermal toxicity [59];
5.4.6 Data Interpretation
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING", then
"DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then either of
the files listed as: "Annex I of Directive 67548EEC". [21]
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24]
- GHS Ch 3.9 Specific Target Organ Toxicity Repeated Exposure [45],
- The following link can be used to identify substances prioritized for testing for endocrine
disruption by the European Commission:
http://ec.europa.eu/environment/endocrine/strategy/substances en.htm#priority list. To
download the list of substances, see the zipped file under the heading "Priority List". [13]
[13]
- The following report describes the process used to develop the endocrine disrupters priority
list: http://ec.europa.eu/environment/endocrine/documents/final report 20Q7.pdf[141.
5.5 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
5.5.1 Criteria and Data Evaluation
Fragrance raw materials considered reproductive or developmental toxicants by one of the authoritative
bodies in Table 6a do not pass the screen.
Table 6a - Reproductive/Developmental Toxicity
Authoritative Body
EU CMR List [3]
EU Risk Phrases3 [3]
Criteria that will not pass the DfE Screen
Category 1 : "known" to impair fertility in humans or cause
developmental toxicity in humans"
Category 2: "should be regarded as if they impair fertility to
humans or cause developmental toxicity to humans"
Category 3 "cause concern for human fertility or to possible
developmental toxic effects"
R60: "May impair fertility"
R61 : "May cause harm to the unborn child"
R62: "Possible risk of impaired fertility"
R63: "Possible risk of harm to the unborn child"
R64: "May cause harm to breastfed babies"
a Any combination containing one or more of the risk phrases above shall also not pass the screen.
5.5.2 Supplemental Criteria: GHS Review
In the case where reproductive or developmental toxicity data have not been reviewed by the EU in the
context of the CMR list or R-phrases, a supplemental assessment may be performed. When a
supplemental assessment is performed, GHS criteria and the guidance values in Table 6b will be used to
review all available data. Additionally, if a fragrance raw material appears on the list of substances
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prioritized for testing for endocrine disruption by the European Commission [13, 14], the raw material will
be screened against GHS criteria using test data or weight of evidence.
Table 6b - Reproductive/Developmental Toxicity
Route of Exposure
Oral (mg/kg-bw/day)
Dermal (mg/kg-bw/day)
Inhalation (gas)
(ppm/6h/day)
Inhalation (vapor)
(mg/L/6h/day)
Inhalation (dust/mist)
(mg/L/6h/day)
Guidance Values
>250
>200
>250
>1.0
>0.2
5.5.3 Test Methods for GHS Review
5.5.3.1 Fertility test methods, preferred
- OECD Test Guideline 415: One-Generation Reproduction Toxicity Study [60] and
- OECD Test Guideline 416: Two-Generation Reproduction Toxicity Study [61].
5.5.3.2 Fertility test methods, acceptable
The following test methods may be used to identify reproductive toxicity, per GHS [62]:
- OPPTS Harmonized Guideline 870.3800: Reproduction and fertility effects [63];
- OECD Test Guideline 421: Reproduction/Developmental Toxicity Screening Test [64];
- OECD Test Guideline 422: Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test [57];
- OPPTS Harmonized Guideline 870.3550: Reproduction/developmental toxicity screening test
[65]
- OPPTS Harmonized Guideline 870.3650: Combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test [66].
5.5.3.3 Developmental toxicity test methods, preferred
- OECD Test Guideline 414: Prenatal Developmental Toxicity Study [67]
5.5.3.4 Developmental toxicity test methods, acceptable
The following test methods may be used to identify developmental toxicity, per GHS [62]:
- OPPTS Harmonized Guideline 870.3800: Reproduction and fertility effects [63];
- OECD Test Guideline 421: Reproduction/Developmental Toxicity Screening Test [64];
- OECD Test Guideline 422: Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test [57];
- OPPTS Harmonized Guideline 870.3550: Reproduction/developmental toxicity screening test
[65]; and
- OPPTS Harmonized Guideline 870.3650: Combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test [66].
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5.5.4 Data Interpretation
The following sources should be consulted for additional information:
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING",
then "DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then
either of the files listed as: "Annex I of Directive 67548EEC". [21];
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24];
- GHS Ch 3.7 Reproductive Toxicity [62]
- Part A, Section 3, Hazard Characterization in Guidelines for Reproductive Toxicity Risk
Assessment (EPA 1998), http://www.epa.gov/ncea/raf/pdfs/repro51.pdf [68].
- Part A, Section 3, Hazard Characterization in Guidelines for Developmental Toxicity Risk
Assessment (EPA 1991), http://www.epa.gov/NCEA/raf/pdfs/devtox.pdf [69].
- The following link can be used to identify substances prioritized for testing for endocrine
disruption by the European Commission:
http://ec.europa.eu/environment/endocrine/strategy/substances en.htm#priority list. To
download the list of substances, see the zipped file under the heading "Priority List". [13]
- The following report describes the process used to develop the endocrine disrupters priority
list: http://ec.europa.eu/environment/endocrine/documents/final report 2007.pdf [14].
5.6 PHOTO SENSITIZATION
No fragrance raw material considered a photo sensitizer according to the International Flavor &
Fragrance Association Standards and Code of Practice (IFRA CoP, current amendment) [70] will pass the
screen.
5.7 RESPIRATORY SENSITIZATION
5.7.1 Criteria and Data Evaluation
Although recognized animal models for the testing of respiratory hypersensitivity are not available at
present, the following will be applied when models are available. Fragrance raw materials that carry the
EU Risk Phrase R42: "May cause sensitization by inhalation" [3] do not pass the screen.
5.7.2 Supplemental Criteria: GHS Review
In the case where respiratory sensitization data have not been reviewed by the EU in the context of R-
phrases, a supplemental assessment may be performed. When a supplemental assessment is
performed, GHS criteria will be used to review all available data. Materials considered Category 1:
"Respiratory Sensitizer" under GHS [71] do not pass the screen.
5.7.3 Data Interpretation
The following sources should be consulted for additional information:
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING",
then "DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then
either of the files listed as: "Annex I of Directive 67548EEC". [21];
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24]; and
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- GHS Ch 3.4 Respiratory and Skin Sensitization [71].
5.8 SKIN SENSITIZATION
5.8.1 Criteria
Each fragrance raw material that is considered a dermal sensitizer under GHS may be present in the
cleaning product formulation at a level no greater than 0.01 percent by weight. A fragrance raw material
shall be considered a dermal sensitizer if it falls in one of the categories below. (When evaluating dermal
sensitization, percutaneous dermal absorption is assumed to be 100%.)
- EU Risk Phrase R43: "May cause sensitization by skin contact" [3];
- EU 26 Allergens List, found at
http://ec.europa.eu/enterprise/chemicals/legislation/detergents/legislation/allergenic subs
t.pdf:
International Flavor & Fragrance Association Standards and Code of Practice (IFRA CoP)
[70]: Fragrance raw material is listed as a dermal sensitizer; or
- GHS Category 1: "Dermal Sensitizer" [71 ].
5.8.1.1 Supplemental Criteria - Quantitative Risk Assessment (QRA) Thresholds
From the Research Institute of Fragrance Materials Standards and Code of Practice, "no fragrance raw
materials shall be present in the cleaning product above the QRA threshold specified for the fragrance
raw material for the intended category of use [70]."
5.8.1.2 Supplemental Criteria- d-Limonene
When cf-Limonene is used at a level above the threshold for sensitizers (0.01 percent by weight), it may
be present because of its solvent properties. Where this is the case, the DfE screening approach treats
cf-Limonene as a solvent, and no longer considers this chemical under the DfE Screen for Fragrances.
The oxidation products of cf-Limonene have tested positive for dermal sensitization but may be used in a
DfE-recognized product in concentrations at which the potential oxidation products may be present at 20
millimoles per liter (mmol/L) or less (corresponding to a cf-Limonene concentration of 1.36 % or less, as a
percent by weight) in an overall formulation. Because of their high potential toxicity to aquatic organisms,
cf-Limonene should not be used in products that will be directly released to the environment. Also,
products that contain cf-Limonene should not also contain oxidizers, like hydrogen peroxide, which may
accelerate the formation of cf-Limonene oxidation products and harm product integrity.
5.8.2 Test Methods for GHS Review
- OPPTS Harmonized Guideline 870.2600: Skin Sensitization [72];
- OECD Test Guideline 406: Skin Sensitisation [73]; and
- OECD Test Guideline 429: Skin Sensitisation: Local Lymph Node Assay [74].
5.8.3 Data Interpretation
- EU Dangerous Substances Directive, http://ecb.irc.ec.europa.eu/documentation/. To access
the list of substances carrying Risk Phrases, click on "CLASSIFICATION-LABELLING", then
"DIRECTIVE 67-548-EEC", then "ANNEX I OF DIRECTIVE 67-548-EEC", and then either of
the files listed as: "Annex I of Directive 67548EEC". [21];
- EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent
updates/amendments) [22-24];
- GHS Ch 3.4 Respiratory or Skin Sensitization [71 ];
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EU Cosmetics Directive 7th Amendment (76/768/EEC and subsequent updates/amendments)
[75]; and
Internatio
amendment) [70].
International Flavor and Fragrance Association Standards and Code of Practice (43rd
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