# Design for the Environment Program Master Criteria for Safer Ingredients

(formerly the General Screen for Safer Ingredients)

Version 2.0

July 2010

Office of Pollution Prevention & Toxics U.S. Environmental Protection AgencyU.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### Table of Contents

1 Introduction

................................................................................................................... ....................... 2

2 General Re quirements

......................................................................................................... ............... 3

3 Terms

.................................................................................................................................................. 4

4 Preferences

.................................................................................................................... ..................... 6

5 Attributes of Concer n for All C hemicals

.............................................................................................. 7

5.1 Acute Mammali an Toxicity

..................................................................................................... 7

5.2 Carcinogenicity

................................................................................................................ ....... 8

5.3 Genetic To xicity

............................................................................................................... ..... 10

5.4 Neurotox icity

.................................................................................................................. ....... 12

5.5 Repeated Dose Toxicity

....................................................................................................... 13

5.6 Reproductive and Develo pmental To xicity

........................................................................... 15

5.7 Respiratory S ensitization

...................................................................................................... 17

5.8 Skin Sensitization

............................................................................................................. .... 18

5.9 Environmental Toxi city and Fate

.......................................................................................... 19

5.10 Eutrophica tion

................................................................................................................. ..... 20

6 Test Methods

................................................................................................................... .................. 22

6.1 Acute Mammali an Toxicity

................................................................................................... 22

6.2 Carcinogenicity

................................................................................................................ ..... 22

6.3 Genetic To xicity

............................................................................................................... ..... 22

6.4 Neurotox icity

.................................................................................................................. ....... 22

6.5 Repeated Dose Toxicity

....................................................................................................... 23

6.6 Reproductive and Develo pmental To xicity

........................................................................... 23

6.7 Skin Sensitization

............................................................................................................. .... 24

6.8 Environmental Toxi city and Fate

.......................................................................................... 24

6.8.1 Acute Aquatic Toxicity

............................................................................................. 24

6.8.2 Persistence (measured as biodegra dation)

............................................................ 25

6.8.3 Bioaccumula tion

...................................................................................................... 25

References

..................................................................................................................... ............................. 26

1

### 1 U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### Introduction

Purpose

The Design for the Environment (DfE) Master Crit eria for Safer Ingredients (Master Criteria) are comprehensive, science-based criteria designed to ensur e that the safest possible ingredients are used in DfE-labeled products. DfE evaluates every ingredient in a formulation within its functional class context and based on its key, distinguishing human health an d environmental characteristics. In this way, potential product ingredients can be viewed as part of a continuum of improved or safer ingredient choices. These criteria also enhance the transparency of the DfE Program.

The Master Criteria make it possible to draw a lin e demarcating the greener or “low-concern” end of the continuum of chemical safety. To define low concern, DfE uses toxicological thresholds established by highly respected health and environmental protection authorities, including the United Nation’s Globally Harmonized System (GHS) for the Classification and Labeling of Ha zard Substances and the U.S. EPA’s New Chemicals Program. For functional classes wh ere no low-concern ingredien ts currently exist, DfE works with its stakeholders to carefully modify the Master Criteria in a way that allows for ingredient choices while ensuring the safest possible ingredients in that functional class. These criteria were designed for use in distinguishing safer chemicals for the DfE Program.

DfE product review is chem istry and toxicology intensive, calling on the extensive expertise of the EPA’s Office of Pollution Prevention and Toxics. The Office ’s depth of expertise helps ensure that chemicals are fully and accurately characterized based on the best available information. Information for the review is drawn from peer-reviewed literature, primary so urce materials, hazardous chemical lists, Agency databases, and predictive tools which estimate potential human health and environmental concerns based on a chemical’s struct ural and/or biological similarity to known chemicals of concern. EPA will consider all sources of developing information, such as the Endocrine Disruptor Screening Program or enhancements to estimation models such as EPI Suite TM that occur over time.

Development

The Master Criteria were developed by the Envi ronmental Protection Agency’s DfE Program. The contents of these criteria, including definitions and toxicological prefer ences, were devel oped to facilitate use of safer chemistry under the DfE Program.

Scope

In DfE’s Safer Product Labeling Program, the Master Cr iteria serves as the primary tool to advance Green Chemistry in product formulation and to implement Informed Substitution, the reasoned transition from a chemical of particular concern to safer chemicals or non-chemical alternatives. DfE will use the Master Criteria to review all product ingredients (and t heir chemical components). Where DfE has developed more customized criteria for specific functional classe s of chemicals, e.g., surfactants, solvents, etc., those criteria will apply. All chemicals in products designed for direct release to the environment (e.g. graffiti removers and marine cleaners) must also pass the DfE Criteria for Environmental Toxicity and Fate for Chemicals in Direct Release Products.

2U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### 2 General Requirements

2.1 Data for all relevant routes of exposure will be evaluated.

2.2 The GHS criteria and data evaluation approach and EPA risk assessment guidance will inform professional judgment in the review of both no observed adverse effect levels/concentrations (NOAEL/NOAEC) and lowest observed adverse effe ct levels/concentrations (LOAEL/LOAEC). NOAEL/NOAEC and LOAEL/LOAEC values ar e preferred over no observed effect levels/concentrations (NOEL/NOEC) and lowe st observed effect levels/concentrations (LOEL/LOEC). In reviews that include conflic ting data, a weight of evidence approach will determine a pass or fail.

2.3 Use of existing data should follow the EPA HPV Challenge Program and OECD HPV Programme data adequacy guidelines: http://www.epa.gov/HPV/pubs/general/datadfin.htm

.

2.4 EPA will perform an additional in-depth review of a c hemical under certain c onditions. Conflicting data on a chemical, detection in bio- or envi ronmental monitoring studies, or presence on a flagging list will trigger such a review. The additional review will apply GHS criteria and other criteria explained in this document.

3U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### 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 chemical that is being evaluated (i.e. acute mammalian toxicity, biodegradability).

3.4 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. [1]

3.5 Biodegradation is a process in which the destruction of the chemical is accomplished by the action of a living organism. (Handbook of Pr operty Estimation Methods for Chemicals, 2000)

3.6 Carcinogen denotes a chemical substance or mixture of chemical substances which induces cancer or increases its incidence. (GHS)

3.7 A chemical is identified by its Chemical Abstract Service (CAS) number.

3.8 Chronic aquatic toxicity is the potential or actual properti es of a substance to cause adverse effects to aquatic organisms during exposures whic h are determined in relation to the life cycle of the organism. (GHS)

3.9 Criteria : Endpoints and cutoffs for attribute information. Example: oral acute mammalian toxicity LD50 must be > 50 mg/kg. Data quality requi rements (including acceptable test methods and information sources) are developed for all criteria.

3.10 Dermal sensitizer: A substance that will induce an allergic response following skin contact (GHS)

3.11 Developmental toxicity : Adverse effects in the developing organism that may result from exposure prior to conception (either parent), durin g prenatal development, or postnatally to the time of sexual maturation. Adverse development al effects may be detected at any point in the lifespan of the organism



### . The major manifestations of developmen tal toxicity include: (1) death of the developing organism, (2) structural abnorma lity, (3) altered growth, and (4) functional deficiency. (EPA Risk Assessment Guidelines [2])

3.12 An endocrine disruptor is an external agent that interferes in some way with the role of natural hormones in the body. An agent might disrupt t he endocrine system by affecting any of the various stages of hormone production and activi ty, such as by preventing the synthesis of hormones, by directly binding to hormone receptors, or by interfering with the natural breakdown of hormones. (EPA) [3]

3.13 Flagging list: A publicly available list of chemicals that may have potential hazard concerns as identified by the authors of that list.

4U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

3.14 Genotoxicity : The more general terms genotoxic and genotoxicity apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replicati on processes, or which in a non-physiological manner (temporarily) alter its replicat ion. Genotoxicity test results are usually taken as indicators for mutagenic effects. (GHS)

3.15 An ingredient may be one chemical or a blend of multiple chemicals that are intentionally added.

3.16 Inorganic phosphate : This category includes all inorganic soluble forms of phosphates, such as, phosphoric acid [PO 4 H 3 or OP(=O)(O)O] and its salts or phosphate salts, pyrophosphates, polyphosphates, and organic and inorganic forms of phosphorous that can be oxidized to phosphates rapidly. Inorganic forms of phosphonic acid (H 2 PO 3 or OP(=O)O) are not included in this category because monopotassium phosphoni c acid [13977-65-6] has been shown not to be an algal nutrient, not to be a replacement for phosphate in algal growth medium, and not to cause exponential growth of green algae. (US EPA New Chemicals) [Note: Inorganic forms of phosphonic acid are not typically used in cleaning products.]

3.17 LOAEL : Lowest Observed Adverse Effect Level

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 f unction of the central and/or peripheral nervous system following exposure to a chemic al, physical, or biological agent. (US EPA Risk Assessment Guidelines)

3.20 NOAEL: No Observed Adverse Effect Level

3.21 Persistence: The length of time the chemical c an exist in the environment before being destroyed (i.e., transformed) by natural processes. (EPA PBT Final Rule [4])

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, gam ete production and transport, reproductive cycle normality, sexual behavior, fertility, gestation, parturition, la ctation, 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 [5])

3.23 Respiratory sensitizer: A substance that will induce hyperse nsitivity of the airways following inhalation of the substance. (GHS)

3.24 Suitable analog: Suitable analogs will be based on a chemically (e.g., based on chemical structure) or biologically (e.g., based on metabol ic breakdown, or likely mechanistic/mode of action considerations) similar chemical. Guidance for identifying a suitable analog can be found in OECD Series on Testing and Assessment No. 80 Guidance on Grouping of Chemicals [6]. The analog used must be appropriate for the attribute being evaluated.

3.25 Weight-of-evidence : For the purposes of this document, weight-of-evidence refers to the process of considering the strengths and weaknesses of various pieces of information in reaching and supporting a conclusion concerning a pr operty of the substance. (ECHA [7])

5U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### 4 Preferences

4.1 When data are developed to meet the requirements fo r Repeated Dose Toxicity, EPA requests that a functional observational battery, such as OPPTS 870.6200: Neurotoxicity Screening Battery [8], be added to the test method to provide neurotoxicity information.

4.2 Data for the evaluation of chemicals under these cr iteria are preferred in the following order: 1) measured data on the specific chemical, 2) meas ured data from a suitable analog, 3) estimated data from appropriate models. Data requirem ents specific to each attribute are outlined in Section 4. The majority of measured data are expected to be from laboratory experiments. However, any available human dat a will be considered, e.g. Human Repeat Insult Patch Tests. Human data may require appropriate review for ethical treatment of the subjects.

4.3 The links and references in this document are current as of the publication date of these Criteria. The reviewer must use the most recent versi on of each authoritative list, EPA data interpretation guidance, and test protocol when reviewing a chem ical against these criteria. In the case where a GHS reference in this document is superseded by a more recent version, EPA may choose to update these Criteria to incorporate that newer version. EPA will cons ider all sources of developing information, such as the EPA Endocrine Disruptor Screening Program 1 [9] or enhancements to estimation models such as EPI Suite TM [10] that occur over time.

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....”[3. USEPA, Special Report on Environmental Endocrine Disruption: An Effects Assessment and Analysis. , in Risk Assessment Forum . 1997: Washington DC.

6U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### 5 Attributes of Concern for All Chemicals

Each attribute listed below applies to all chemicals not covered by specific functional class criteria.

5.1 ACUTE MAMMALIAN TOXICITY

Criteria

Applying GHS criteria [11], a chemical does not pa ss the Criteria if the median lethal dose or concentration is less than or equal to those values listed in Table 1a. For inhalation studies, exposure duration should be at least four hours; the thresholds for inhalation are the sa me for exposures greater than four hours. Exposures of less than four hours will be evaluated on a case-by-case basis.

Table 1a – GHS Thresholds

Route (units) Median Lethal Dose/Concentration Oral LD50 (mg/kg bw) 2,000 Dermal LD50 (mg/kg bw) 2,000 Inhalation, gas LC50 (ppmV) 20,000 Inhalation, vapor LC50 (mg/L) 20 Inhalation, dust/mist/fumes LC50 (mg/L) 5

Additionally, a chemical does not pass the Criteria if it carries one of the following EU Risk Phrases, which align with the GHS thresholds in Table 1a:

Table 1b – Acute Toxicity Risk Phrases

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 combination risk phrases containing one or more of the above.

Data Requirements All available data, measured and/or es timated, for the chemical and/or a suitable analog will be reviewed against the criteria using a we ight-of-evidence approach.

Sources for Data Interpretation

– GHS Ch 3.1 Acute Toxicity [11].

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-LABELLING”, then

7U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

“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”. [12]; and

8U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.2 CARCINOGENICITY

Criteria

Chemicals considered carcinogens according to the aut horitative lists in Table 2 do not pass the Criteria. Chemicals not on those authoritative lists, but that are known or presumed human carcinogens (Category 1), or suspected human carcinogens (Category 2) under GHS [13], do not pass the Criteria.

Table 2 – Authoritative Lists and GHS Criteria

Authoritative Body Does not pass DfE Criteria
National Toxicology Program (NTP) Known to be Human Carcinogen Reasonably Anticipated to be Human Carcinogen

U.S. Environmental Protection Agency (EPA) (2005/1999) Carcinogenic to humans, Likely to be carcinogenic to humans, or Suggestive eviden ce of carcinogenic potential 2 (1996) Known/Likely (1986) Group A – Human Carcinogen, Group B – Probable human

carcinogen, or Group C – Possible human carcinogen 2
International Agency for Research on Cancer (IARC) Group 1 – Carcinogenic to humans Group 2A – Probably carcinogenic to humans Group 2B – Possibly carcinogenic to humans 2

EU CMR List [14] Category 1 – Known to be carcinogenic to humans Category 2 – Should be regarded as if carcinogenic to humans Category 3 – Cause for concern for humans owing to possible

carcinogenic effects

EU Risk Phrases [14] R45: May cause cancer R49: May cause cancer by inhalation R40: Limited evidence of a carcinogenic effect And all combination risk phrases cont aining one or more of the above. Globally Harmonized System (GHS) [13] Category 1A – Known to have carcinogenic potential for humans Category 1B – Presumed to have carcinogenic potential for humans Category 2 – Suspected human carcinogens

Data Requirements

All available data will be evaluated. Measured and/or estimated data, for the ch emical and/or a suitable analog will be reviewed against GHS criteria using a weight-of-evidence approach.

Flagging Lists

All relevant data and information used to place a chemical on the following flagging lists will be considered when reviewing a listed chemical against the carcinogenicity criteria. 1. Substances prioritized for testing for endo crine disruption by the European Commission as Category 1 or 2 [15, 16], 2. Substances prioritized for testing for endocrine disruption by the US EPA Endocrine Disruptor Screening Program [9],

2 Chemicals listed as “possibly carcinogenic to humans” are evaluated largely on animal studies. DfE will consider appropriate data that show cancer concerns are not relev ant to humans, e.g., because of an animal specific tissue effect or mode of action. If the data de monstrate that cancer conc erns are not relevant to humans, that chemical can be considered under the DfE Criteria.

9U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

3. Substances listed on the State of Californi a Environmental Protection Agency, Office of Environmental Health Hazard Assessment (O EHHA) California Proposition 65 (Safe Drinking Water and Toxic Enforcement Act Of 1986) as Known to the State to Cause Cancer [17].

Sources for Data Interpretation

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-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”. [12];

– EU Dangerous Preparations Directive Ar ticle 6 and Annex II (1999/45/EC and subsequent updates/amendments) [18-20];

– GHS Ch 3.6 Carcinogenicity [13];

– Section 2, Hazard Assessment in Guide lines for Carcinogen Risk Assessment (Risk Assessment Forum) (EPA 2005), http://oaspub.epa.gov/eims/eimsco mm.getfile?p_download_id=439797 [21] and

– The following link can be used to identify substances prioritized for testing for endocrine disruption by the European Commission: http://ec.europa.eu/environmen t/endocrine/strategy/substanc es_en.htm#priority_list . To download the list of substances, see the zipped file under the heading “Priority List” [15].

– The following report describes the process us ed to develop the endocrine disrupters priority list: http://ec.europa.eu/environment/endocri ne/documents/final_report_2007.pdf [16].

– EPA Endocrine Disruptors Screening Program, available at: http:// www.epa.gov/endo/ [9].

– Supplemental Guidance for Assessing Su sceptibility from Early-Life Exposure to Carcinogens, available at: http://cfpub.epa.gov/ncea/CFM/re cordisplay.cfm?deid=160003 [22].

10U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.3 GENETIC TOXICITY

Criteria

Chemicals considered mutagens or genetic toxicants ac cording to the authoritative lists in Table 3 do not pass the Criteria. Chemicals not on those authoritative lists, but which are classifiable as to their potential to cause genetic toxicity according to GHS [23] do not pass the Criteria. Effects to be considered include heritable germ cell mutagenicity (including gene mutation and chromosome mutation), germ cell genetic toxicity, and somatic cell mutagenicity or genetic toxicity.

Table 3 – Authoritative Lists and GHS Criteria

Authoritative Body Does not pass DfE Criteria

EU CMR List [14] Category 1 – Substances known to be mutagenic to humans Category 2 – Substances which should be regarded as if they

are mutagenic to humans Category 3 – Substances which cause concern for human owing

to possible mutagenic effects 3

EU Risk Phrases [14] R46: May cause heritable genetic damage R68: Possible risk of irreversible effects And all combination risk phrases cont aining one or more of the above.

Globally Harmonized System (GHS) [23] Category 1A – Chemicals known to induce heritable mutations in germ cells of humans Category 1B – Chemicals which should be regarded as if they

induce heritable mutations in the germ cells of humans Category 2 – Chemicals which cause concern for humans owing

to the possibility that they may induce heritable mutations in the germ cells of humans

Data Requirements

All available data, including in vivo

, in vitro , and epidemiological studies, will be evaluated. Measured and/or estimated data, for the chemical and/or a suitable analog will be reviewed against GHS criteria using a weight-of-evidence approach.

Sources for Data Interpretation

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-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”; [12]

– EU Dangerous Preparations Directive Ar ticle 6 and Annex II (1999/45/EC and subsequent updates/amendments) [18-20]; and

– GHS Ch 3.5 Germ Cell Mutagenicity [23].

3 Per EU guidance, chemicals classified as Category 3 su bstances may be placed in th at category based on positive results in assays showing (a) mutagenic effects or (b) other cellular interaction relevant to mutagenicity. If a chemical is classified in Category 3(b) only and that classificati on appears overly conservative, then the submitter may request EPA expert review. In such as case, if EPA determines the data do not support a concern for possible mutagenic effects, then the chemical will pass the criteria.

11U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.4 NEUROTOXICITY

Criteria

Chemicals that are considered neurotoxicants under GH S [24] (see GHS guidance values in Table 4) do not pass the screen. Neurotoxicit y is evaluated using the GHS chapter called Specific Target Organ Toxicity Repeated Exposure.

Table 4 – GHS Guidance Values

Route of Administration (units) Guidance Value* Oral (mg/kg-bw/day) 100 Dermal (mg/kg-bw/day) 200 Inhalation (gas) (ppm/6h/day) 250 Inhalation (vapor) (m g/L/6h/day) 1.0 Inhalation (dust/mist) (mg/L/6h/day) 0.2 *The doses provided are for 90-day studi es. Guidance values are tripled for chemicals evaluated in 28-day studies.

Data Requirements

All available data, measured and/or es timated, for the chemical and/or a suitable analog will be reviewed against the criteria using a we ight-of-evidence approach.

Sources for Data Interpretation

– Section 3, Hazard Characterization in Guidelines for Neurotox icity Risk Assessmen t [25]; and

– GHS Ch. 3.9 Specific Target Orga n Toxicity Repeated Exposure [24].

12U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.5 REPEATED DOSE TOXICITY

Criteria

Chemicals that are considered repeated dose (syste mic) toxicants under GHS [24] (see GHS guidance values in Table 5a) do not pass the Criteria. Repeat ed dose toxicity is evaluated using the GHS chapter called Specific Target Organ Toxicity Repeated Exposure.

Table 5a – GHS Guidance Values

Route of Administration (units) Guidance Value* Oral (mg/kg-bw/day) 100 Dermal (mg/kg-bw/day) 200 Inhalation (gas) (ppm/6h/day) 250 Inhalation (vapor) (m g/L/6h/day) 1.0 Inhalation (dust/mist/fume) (mg/L/6h/day) 0.2 *The doses provided are for 90-day studies. Gui dance values are tripled for chemicals evaluated in 28-day studies and similarly modifi ed for studies of longer durations.

Additionally, a chemical does not pass the Criteria if it carries one of the following EU Risk Phrases:

Table 5b – Repeated Dose Toxicity Authoritative Lists

Authoritative Body Does not pass DfE Criteria

EU Risk Phrases [14] 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) And all combination risk phrases cont aining one or more of the above.

Data Requirements

All available data, measured and/or es timated, for the chemical and/or a suitable analog will be reviewed against the criteria using a weig ht-of-evidence approach.

Flagging Lists

All relevant data and information used to place a chemical on the following flagging lists will be considered when reviewing a listed chemical against the repeated dose toxicity criteria. 1. Substances prioritized for testing for endo crine disruption by the European Commission as Category 1 or 2 [15, 16], 2. Substances prioritized for testing for endocrine disruption by the US EPA Endocrine Disruptor Screening Program [9],

Sources for Data Interpretation

– GHS Ch 3.9 Specific Target Organ Toxicity Repeated Exposure [24],

– The following link can be used to identify substances prioritized for testing for endocrine disruption by the European Commission:

13U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

http://ec.europa.eu/environmen t/endocrine/strategy/substanc es_en.htm#priority_list . To download the list of substances, see the zipped file under the heading “Priority List”. [15]

– The following report describes the process us ed to develop the endocrine disrupters priority list: http://ec.europa.eu/environment/endocri ne/documents/final_report_2007.pdf [16].

– EPA Endocrine Disruptors Screening Program, available at: http://www.epa.gov/endo/ [9].

14U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.6 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Criteria

Chemicals that are considered reproductive or dev elopmental toxicants under GHS criteria [26] and demonstrate adverse effects at doses at or below the values in Table 6a do not pass the Criteria.

Table 6a – TSCA 8(e) Guidance Values [27]

Route of Administration (units) Guidance Value
Oral (mg/kg-bw/day) 250 Dermal (mg/kg-bw/day) 500 Inhalation (gas) (ppm/6h/day) 250

Inhalation (vapor) (mg/L/6h/day) 2.5

Inhalation (dust/mist) (mg/L/6h/day) 0.5

Additionally, a chemical does not pass the Criteria if it carries one of the following EU Risk Phrases:

Table 6b – Reproductive and Developmental Toxicity Authoritative Lists

Authoritative Body Does not pass DfE Criteria

EU CMR List [14] 4 Category 1 – Known to impair fertility in humans or known to cause developmental toxicity in humans Category 2 – Should be regarded as if they impair fertility in

humans or cause developmental toxicity to humans Category 3 – Cause concern for human fertility or possible

developmental toxic effects

EU Risk Phrases [14] 4 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 And all combination risk phrases cont aining one or more of the above.

Data Requirements

All available data, measured and/or es timated, for the chemical and/or a suitable analog will be reviewed against the criteria using a weight-of-evidence appr oach. Following the approach in the SIDS Dossier [28], both fertility and developmental effects should be considered.

4 The EU classification criteria do not currently consider a limit dose above which an adverse effect would not trigger classification. EPA will consider evidence demonstrati ng that a chemical carrying a reproductive/developmental toxicity risk phrase or listed as toxic to reproduction (in Table 5a) did not cause an adverse effect below the TSCA 8(e) Guidance Values listed in Table 5b. Such a chemical may be det ermined, upon EPA review, to pass the DfE criteria for reproductive/developmental toxicity.

15U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

Flagging Lists

All relevant data and information used to place a chemical on the following flagging lists will be considered when reviewing a listed chemical against the reproductive and developmental toxicity criteria. 1. Substances prioritized for testing for endo crine disruption by the European Commission as Category 1 or 2 [15, 16] 2. Substances prioritized for testing for endocrine disruption by the US EPA Endocrine Disruptor Screening Program [9] 3. Substances listed on the State of Californi a Environmental Protection Agency, Office of Environmental Health Hazard Assessment (O EHHA) California Proposition 65 (Safe Drinking Water and Toxic Enforcement Act Of 1986) as Known to the State to Cause Reproductive Toxicity [17].

Sources for Data Interpretation

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-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” [12];

– EU Dangerous Preparations Directive Ar ticle 6 and Annex II (1999/45/EC and subsequent updates/amendments) [18-20];

– GHS Ch 3.7 Reproductive Toxicity [26]

– Part A, Section 3, Hazard Characterization in Guidelines for Reproductive Toxicity Risk Assessmen t (EPA 1998), http://www.epa.gov/ncea/raf/pdfs/repro51.pdf [5].

– Part A, Section 3, Hazard Characterization in Guidelines for Developmental Toxicity Risk Assessmen t (EPA 1991), http://www.epa.gov/NCEA/raf/pdfs/devtox.pdf [2].

– The following link can be used to identify substances prioritized for testing for endocrine disruption by the European Commission: http://ec.europa.eu/environmen t/endocrine/strategy/substanc es_en.htm#priority_list . To download the list of substances, see the zipped file under the heading “Priority List”. [15]

– The following report describes the process us ed to develop the endocrine disrupters priority list: http://ec.europa.eu/environment/endocri ne/documents/final_report_2007.pdf [16]

– EPA Endocrine Disruptors Screening Program, available at: http://www.epa.gov/endo/ [9].

16U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.7 RESPIRATORY SENSITIZATION

Criteria

Chemicals considered respiratory sensitizers accordin g to the authoritative list in Table 7 do not pass the Criteria. Chemicals not on that authoritative lis t, but that are classified under GHS do not pass the Criteria.

Table 7 – Authoritative Lists and GHS Criteria

Authoritative Body Does not pass DfE Criteria

EU Risk Phrase [14] R42: May cause sensitization by inhalation

Globally Harmonized System (GHS) [29] Category 1A – high frequency of occurrence or sensitization rate in humans Category 1B – low to moderate frequency of occurrence or sensitization rate in humans

Data Requirements

Acknowledging that recognized animal models for the testing of respiratory hypersensitivity are not available at present, data on respiratory sensitiz ation will normally be based on human evidence; all available data will be reviewed. EPA will search public literature and EPA-confident ial data to support the review. Chemicals associated with hypersensitivity after appropriate clinical testing may not pass the criteria. See GHS guidance [29] for further details.

Flagging Lists

Chemicals designated as sensitizer-induced asthmag ens (“Rs” or “Rrs”) on the specified flagging list below require review using all relevant and available data to support GHS classification:

1. Association of Occupational and Environmental Clinics (AOEC) Exposure Code List [30].

Sources for Data Interpretation

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-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”. [12].

– EU Dangerous Preparations Directive Ar ticle 6 and Annex II (1999/45/EC and subsequent updates/amendments) [18-20].

– GHS Ch 3.4 Respiratory and Skin Sensitization [29].

– Association of Occupational and Environmental Clinics Exposure Code List, available from: http://www.aoecdata.org/Default.aspx [30].

17U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.8 SKIN SENSITIZATION

Criteria

Chemicals considered skin sensitizers according to the authoritative list in Table 8 do not pass the Criteria. Chemicals not on that authoritative lis t, but that are classified under GHS do not pass the Criteria.

Table 8 – Authoritative Lists and GHS Criteria

Authoritative Body Does not pass DfE Criteria

EU Risk Phrase [14] R43: May ca use sensitization by skin contact

Globally Harmonized System (GHS) [29] Category 1A – high frequency of occurrence in humans and/or a high potency in animals Category 1B – low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals

Data Requirements

All available data, including in vivo

, in vitro , and epidemiological studies, will be evaluated. Data from estimation models may be considered as part of the weight-of-evidence.

Sources for Data Interpretation

– EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/ . To access the list of substances carry ing Risk Phrases, c lick on “CLASSIFICATI ON-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” [12].

– EU Dangerous Preparations Directive Ar ticle 6 and Annex II (1999/45/EC and subsequent updates/amendments) [18-20].

– GHS Ch 3.4 Respiratory and Skin Sensitization [29].

18U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.9 ENVIRONMENTAL TOXICITY AND FATE (ET&F)

Criteria

If a chemical is an acute aquatic toxicant (i.e., L/ E/IC50 < 100 ppm), then it must biodegrade rapidly and not be bioaccumulative (see Table 12, lines 1-3). If a chemical has low aquatic toxicity (Table 12, line 4), then its half-life must be less than 60 days.

Table 12 – Environmental Toxicity and Fate

Acute Aquatic Toxicity

Value (L/E/IC50) 5,6,7 Persistence (Measured in terms of level of biodegradation) Bioaccumulation Potential

1 If ≤ 1 ppm... ...then may be acceptable if the chemical meets the 10-day window as measured in a ready biodegradation test without degradation products of concern 8

...

...and BCF/BAF <1000. 2 If >1 ppm and ≤ 10 ppm... ...then the chemical must meet the 10-day window as measured in a ready biodegradation test without degradation products of concern 8

... 3 If >10 ppm and <100 ppm... ...then the chemical must reach the pass level within 28 days as measured in a ready

biodegradation test without degradation products of concern 8

... 4 If ≥ 100 ppm... ...then the chemical need not reach the pass level within 28 days as measured in a

ready biodegradation test if there are no degradation products of concern 8 and its half-life < 60 days...

Data Requirements

Acute aquatic toxicity: Measured data are preferred. ECOSAR estimations may be used along with data from a suitable analog(s). Data, whether measur ed or from analogs, are required for each of the following groups of organisms: algae, aquatic invert ebrates and fish (all fresh water). If only estimated data are available, the use of estimated data may be acceptable in combination with EPA expert review. Data for marine species may be added when available.

5 In general, there is a predictable re lationship between acut e aquatic toxicity and chronic aquatic toxicity for organic chemicals, i.e., chemicals that have hi gh acute aquatic toxicity may also have high chronic aquatic toxicity at low concentrations [Rand, G.M., ed. Fundamentals of Aquatic Toxicology . 2 nd ed. 1995, Taylor & Francis: Washington, DC.]. Since acute aquatic toxicity data are more read ily available, t he DfE Screens use these data to screen chemicals that may be toxic to aquatic life. Where measured ch ronic toxicity data is available, it will be assessed with other data and applied in the screen based on the relationship between acute and chronic aquatic toxicity. 6 A case-by-case approach focusing on rate of biodegradation and degradation products of concern will be implemented for chemicals toxic to aquatic organisms at ≤ 1ppm.
7 For determining the aquatic toxicity of substances that are not toxic at thei r solubility limit, see ECOSAR Technical Reference Manual Figure 9, p 17 ( http://www.epa.gov/oppt/newchems/tools/ecosartechfinal.pdf ); When a chemical may have effects at saturation as determined using t he guidance in the ECOSAR m anual, a weight-of-evidence approach in combination with US EPA expert review will be used. EPA may require additional testing including but not limited to solubility testing, chronic aquatic toxicity testing, or acute aquatic toxicity testing of analogs.
8 Degradation products of concern are compounds with high acute aquatic toxicity (L/E/IC50 ≤ 10ppm) which mineralize <60% in 28 days.

19U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

Bioaccumulation potential: Measured data are preferred. Data from a suitable analog is acceptable, and EPI Suite TM estimations (from the most current version) may be used when those data are unavailable. Results from both the BAF and BCF models should be considered. An estimated BAF is preferred to an estimated BCF for compounds where log K ow > 5.

Persistence (measured as level of biodegradation): Measured data are preferred. In t he case where measured data are unavailable, data from estimation models or a suitable analog will be accepted as follows:

(1) If acute aquatic toxicity ≤ 1ppm: Biodegradability must be measured for the chemical or for a suitable analog. Biodegradability predictions from estimation models, such as EPI SuiteTM, will be used only to support weight-of-evidence. (2) If acute aquatic toxicity > 1ppm and ≤ 10ppm: Biodegradability must be measured for the chemical or for a suitable analog. Biodegradability predictions from estimation models, such as EPI SuiteTM, will be used only to support weight-of-evidence. (3) If acute aquatic toxicity > 10ppm and < 100p pm: Biodegradability must be measured for the chemical or for a suitable analog. Biodegradability predictions from estimation models, such as EPI SuiteTM, will be used only to support weight-of-evidence. (4) If acute aquatic toxicity ≥ 100pm: Biodegradability for the chemical or for a suitable analog are preferred. Biodegradability predictions from estimation models, such as EPI Suite TM (the most current version), may be acceptable.

20U.S. EPA Design for the Environment Program Master Criteria Version 2 .0 July 2010

5.10 EUTROPHICATION

Criteria

The total level of phosphorus in the cleaning product w ill be limited to a maximum level of 0.5 weight % in the cleaning product as sold (measured as elemental phosphorus). Inorganic phosphates, as defined by the US EPA New Chemicals Program [31], cannot make up any portion of the 0.5 weight % of phosphorus.

Note: Inorganic phosphates as defined by the US EPA New Chemicals Program [31] will not be allowed in DfE-labeled products. Eutrophication is a priority concern for EPA scientists, and inorganic phosphates can contribute to eutrophication of fresh water and estuar ial ecosystems [31]. Given that the majority of DfE-labeled cleaning products are disposed of down the drain, the likelihood of release to wastewater streams and eventually, water bodies, is high. EPA acknowledges cont ributions to t he phosphorus load from cleaners are relatively small in comparison with other sources 9 and that phosphorus overload may not be an issue in all regions. The EPA policy is consis tent with a commitment to reduce contributions of phosphorus, particularly inorganic phosphates, regardless of concentration.

9 See, for example, 32. Detailed Assessment of Phosphorus Sources in Minnesota Watersheds . 2004, Prepared by Barr Engineering Company for Minnesota Pollution Control Agency. 23 February 2010. http://www.pca.state.mn.us/hot/legislat ure/reports/phosphorus-report.html

.

21U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### 6 Test Methods

The test methods in this section should be used to develop data for conducting chemical reviews based on the criteria in Section 4.

6.1 Acute Mammalian Toxicity – Test Methods for GHS Review

– OPPTS Harmonized Guideline 870.1100: Acute oral toxicity [33];

– OPPTS Harmonized Guideline 870.1200: Acute dermal toxicity [34]

– OPPTS Harmonized Guideline 870.1300: Acute inhalation toxicity [35];

– OECD Test Guideline 420: Acute Oral Toxicity-Fixed Dose Method [36];

– OECD Test Guideline 423: Acute Oral To xicity – Acute Toxic Class Method [37];

– OECD Test Guideline 425: Acute Oral Toxicity – Up-and-Down Procedure [38];

– OECD Test Guideline 402: Acute Dermal Toxicity [39]; and

– OECD Test Guideline 403: Ac ute Inhalation Toxicity [40].

6.2 Carcinogenicity – Test Methods for GHS Review

– OECD Test Guideline 451: Carcinogenicity Studies [41];

– OECD Test Guideline 453: Combined Chroni c Toxicity/Carcinogenicity Studies [42];

– OPPTS Harmonized Guidelines 870.4200: Carcinogenicity [43];

– OPPTS Harmonized Guidelines 870.4300: Comb ined chronic toxicity/carcinogenicity [44] and

– NTP 2 Year Study Protocol: “Specifications for the conduct of studies to evaluate the toxic and carcinogenic potential of chemical, biologica l and physical agents in laboratory animals for the National Toxicology Program” [45].

6.3 Genetic Toxicity – Test Methods for GHS Review

Per GHS [23], results from multiple, acceptable test methods must be used in conjunction for evaluation of genetic toxicity.

– OECD Test Guideline 471 (OPPTS 870.5100): Bacterial Reverse Mutation Test [46, 47];

– OECD Test Guideline 473 (OPPTS 870.5375): In vitro Mammalian Chromosome Aberration Test [48, 49];

– OECD Test Guideline 474 (OPPTS 870.5395): Mammalian Erythrocyte Micronucleus Test [50, 51];

– OECD Test Guideline 475 (OPPTS 870.5385): Mammalian Bone Marrow Chromosome Aberration Test [52, 53];

– OECD Test Guideline 476 (OPPTS 870.5300): In vitro Mammalian Cell Gene Mutation Test [54, 55]; and

– OECD Test Guideline 483 (OPPTS 870.5380): Mammalian Spermatogonial Chromosome Aberration Test [56, 57];

– OECD Test Guideline 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo [58]. This guideline does NOT substitute in the necessary minimum set for either the gene mutation or the chromosome aberration test.

6.4 Neurotoxicity – Preferred Test Methods for GHS Review

– OECD Test Guideline 424: Neurot oxicity Study in Rodents [59] and

– OPPTS Harmonized Guideline 870.6200: Neurotoxicity screening battery [8].

Neurotoxicity – Additional Test Methods for GHS Review

Additional evidence from OECD Test Guideline 42 6: Developmental Neurotoxicity Study [60] and OPPTS Harmonized Guideline: 870.6300 Developmen tal neurotoxicity study [61] can be used to screen chemicals for neurotoxicity.

22U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

6.5 Repeated Dose Toxicity – Preferred Test Methods for GHS Review

– OECD Test Guideline 408: Repeated Dose 90-D ay Oral Toxicity Study in Rodents [62]

– OECD Test Guideline 409: Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents [63]

– OECD Test Guideline 411: Subchronic Dermal Toxicity: 90-day Study [64]

– OECD Test Guideline 413: Subchronic Inhalation Toxicity: 90-day Study [65]

– OPPTS Harmonized Guideline 870.3100: 90-Day oral toxicity in rodents [66]

– OPPTS Harmonized Guideline 870.3150: 90-Day oral toxicity in nonrodents [67]

– OPPTS Harmonized Guideline 870.3250: 90-Day dermal toxicity [68]

– OPPTS Harmonized Guideline 870.3465: 90-Day inhalation toxicity [69]

Repeated Dose Toxicity – Acceptable Test Methods for GHS Review

– OECD Test Guideline 407: Repeated Dose 28- day Oral Toxicity Study in Rodents [70]

– OECD Test Guideline 410: Repeated Dose Dermal Toxicity: 28-day Study [71]

– OECD Test Guideline 412: Repeated Dose Inhalation Toxicity: 28-day Study [72]

– OECD Test Guideline 422: Combined Re peated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test [73]

– OPPTS Harmonized Guideline 870.3050: Repeated do se 28-day oral toxicity study in rodents [74]

– OPPTS Harmonized Guideline 870.3200: 28-Day dermal toxicity [75]

6.6 Reproductive and Developmental Toxicity – Test Methods for GHS Review

Fertility test methods, preferred

– OECD Test Guideline 415: One-Generati on Reproduction Toxicity Study [76] and

– OECD Test Guideline 416: Two-Genera tion Reproduction Toxicity Study [77].

Fertility test methods, acceptable

The following test methods may be used to identify reproductive toxicity, per GHS [26]:

– OPPTS Harmonized Guideline 870.3800: Reproduction and fertility effects [78];

– OECD Test Guideline 421: Reproduction/De velopmental Toxicity Screening Test [79];

– OECD Test Guideline 422: Combined Re peated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test [73];

– OPPTS Harmonized Guideline 870.3550: Repr oduction/developmental toxicity screening test [80]

– OPPTS Harmonized Guideline 870.3650: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [81].

Developmental toxicity test methods, preferred

– OECD Test Guideline 414: Prenatal Developmental Toxicity Study [82]

Developmental toxicity test methods, acceptable

The following test methods may be used to identify developmental toxicity, per GHS [26]:

– OPPTS Harmonized Guideline 870.3800: Reproduction and fertility effects [78];

– OECD Test Guideline 421: Reproduction/De velopmental Toxicity Screening Test [79];

– OECD Test Guideline 422: Combined Re peated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test [73];

– OPPTS Harmonized Guideline 870.3550: Repr oduction/developmental toxicity screening test [80]; and

23U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

– OPPTS Harmonized Guideline 870.3650: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [81].

6.7 Skin Sensitization – Preferred Test Methods for GHS Review

– OECD Test Guideline 406: Skin Sensitization [83]

– OECD Test Guideline 429: Skin Sensit ization: Local Lymph Node Assay [84]

– OPPTS Harmonized Guideline 870.2600: Skin Sensitization [85]

6.8 Environmental Fate and Toxicity

6.8.1 Test Methods, Acute Aquatic Toxicity

A baseline data set is required that includes test data in algae, aquatic invertebrates and fish. Additional aquatic toxicity data in other species or in marine species will also be reviewed if available.

Preferred Test Methods for Fish

– OECD Test Guideline 203: Fish , Acute Toxicity Test [86] and

– OPPTS Harmonized Guideline 850.1075: Fish acute toxicity test, freshwater and marine[87] .

NOTE – EPA may request that the test be carrie d out using semi-static renewal or a flowthrough system with mean measured concentr ation. Any new testing should be done in consultation with EPA.

Preferred Test Methods for Aquatic Invertebrates

– OECD Test Guideline 202, Part 1, D aphnia sp., Acute Immobilisation Test [88];

– OPPTS Harmonized Guideline 850.1010: Aquat ic invertebrate acute toxicity test, freshwater daphnids[89]; and

– OPPTS Harmonized Guideline 850.1035: Mysid acute toxicity test[90].

NOTE – EPA may request that the test be carrie d out using semi-static renewal or a flowthrough system with mean measured concentr ation. Any new testing should be done in consultation with EPA. A 96-hour Mysid shrimp acute toxicity test can be used in place of a daphnid acute toxicity test when the latter is not available.

Preferred Test Methods for Algae

– OECD Test Guideline 201, Alga, Growth Inhibition Test (and biomass) [91] and

– OPPTS Harmonized Guideline 850.5400: Algal toxicity, Tiers I and II (including growth inhibition and biomass) [92].

Alternative Test Methods, Acute Aquatic Toxicity

The following test methods may be considered, when relevant:

– OPPTS Harmonized Guideline 850.1085: Fish acute toxicity mitigated by humic acid [93];

– OPPTS Harmonized Guideline 850.1025: Oyster ac ute toxicity test (shell deposition) [94];

– OPPTS Harmonized Guideline 850.1045: Penaeid acute toxicity test [95];

– OPPTS Harmonized Guideline 850.1055: Bivalve acute toxicity test (embryo larval) [96];

– OPPTS Harmonized Guideline 850.4400: Aquatic plant toxicity test using Lemna spp. Tiers I and II [97].

24U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

6.8.2 Test Methods, Persistence (measured as biodegradation)

Data from experimental methods are generally prefer red over estimations of persistence. For the purposes of screening safer chemicals in Table 12, rows 1-3, ready biodegradation tests are preferred. It is noted that simulation tests are li kely to better describe the biodegradability of a chemical in specific environmental conditions, and these tests can provide information to evaluate the half-life of a chemical t hat is aquatically toxic at ≥ 100 ppm. Simulation tests may also contribute useful information in a weight-of-evid ence evaluation for chemicals aquatically toxic < 100 ppm.

Preferred Test Methods for Persistence

– OECD Test Guideline 301: Ready Biodegradability (sections A-F) [98];

– OECD Test Guideline 310: Ready Biodegr adability – CO2 in sealed vessels [99]; and

– OPPTS Harmonized Guideline 835.3110: Ready biodegradability [100].

– For chemicals where acute aquatic toxicity ≥ 100 ppm (i.e., line 4, Table 12), if the compound degrades by more than 40% in 28 days during one of the Ready Biodegradability tests specified above or by more than 60% in one of the Inherent Biodegradability tests detailed in OECD Test Guidelines 302 (A-C) [16-18] then the halflife of a chemical is likely to be less than 60 days [101].

– Simulation tests may also be used to determine the half-life of a chemical and may be useful in a weight-of-evidence evaluation for chemicals aquatically toxic at < 100ppm.

o OECD Test Guideline 303A (OPPTS 835.3240): Aerobic Sewage Treatment: Activated Sludge Units [102, 103],

o OECD Test Guideline 309 (OPPTS Harmonized Guideline 835.3190): Aerobic Mineralization in Surface Water - Simulation Biodegradation Test [104, 105],

o OECD Test Guideline 314: Simulation Te sts to Assess the Bi odegradability of Chemicals Discharged in Wastewater (Not e: TG 314 uses elements of OECD TG 301, 303A, 309, 310, and 311) [106],

o OPPTS Harmonized Guideline 835.3280–Sim ulation Tests to Assess the Primary and Ultimate Biodegradability of Chemicals Discharged to Wastewater [107],

o OPPTS Harmonized Guideline 835.3170 - Shake Flask Die-Away Test [108], and

o OPPTS Harmonized Guideline 835.3180 - Sediment/Water Microcosm Biodegradation Test [109].

Other Methods of Degradation

On a case-by-case basis, DfE will consider other routes of degradation in the environment, such as hydrolysis or photolysis, and degradation in other relevant media, for example, soil or sediment. In evaluating such degradation studies, DfE will consider the relevance of that degradation pathway to the chemical in questi on as well as the significance of the degradation.

6.8.3 Test Methods, Bioaccumulation

A field-measured BAF (located in the literature) is the most preferred data for indicating bioaccumulation.

Alternative Test Methods for Bioaccumulation

When a field-measured BAF is not availabl e, the following test methods may be used:

– OECD Test Guideline 305: Bioconcentration: Flow-through Fish Test[110];

– OPPTS Harmonized Guideline 850.1710: Oyster BCF[111];

– OPPTS Harmonized Guideline 850.1730: Fish BCF[112]; Modeled data from sources such as EPI Suite TM [10] are acceptable when data are unavailable.

25U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010



### References

1. Arnot, J.A. and F.A. Gobas, A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environmental Reviews, 2006. 14 : p. 257-297. 2. USEPA, Guidelines for Developmental Toxicity Risk Assessment. Federal Register, 1991. 56 (234): p. 63798-63826. 3. USEPA, Special Report on Environmental Endocrine Disruption: An Effects Assessment and Analysis. , in Risk Assessment Forum . 1997: Washington DC. 4. EPA. Persistent Bioaccumulative Toxic (PBT) Chemicals Final Rule 1999 [cited 2010 April 20]; Available from: http://www.epa.gov/fedrgstr/ EPA-WASTE/1999/October/Day

29/f28169.htm

. 5. USEPA, Guidelines for Reproductive Toxicity Risk Assessment. Federal Register, 1996. 61 (212): p. 56274-56322. 6. OECD, OECD Series on Testing and Assessment No 80.: Guidance on Grouping of Chemicals . 2007. 7. ECHA. Practical guide 2: How to report weight of evidence . 2010 [cited 2010 April 21]; Available from: http://echa.europa.eu/doc/publications/practical_guide s/pg_report_weight_of_evidence.p df

. 8. USEPA, Health Effects Test Guidelines: OPPTS 870.6200: Neurotoxicity Screening Battery. 1998. 9. USEPA. Endocrine Disruptor Screening Program . October 21, 2009 [cited 2009 October 22, 2009]; Available from: http://www.epa.gov/endo/

. 10. USEPA. EPI Suite TM . 2008 June 2008]; Available from: http://epa.gov/opptintr/exp osure/pubs/episuite.htm

. 11. GHS, Acute Toxicity . 2009, United Nations. 12. ECB, Directive 67-548-EEC . 2007. 13. GHS, Carcinogenicity . 2009, United Nations. 14. ECB, Annex I of Directive 67-548-EEC . 2007. 15. EuropeanCommission. Endocrine Disrupters Website . June 2009]; Available from: http://ec.europa.eu/environmen t/endocrine/strategy/substanc es_en.htm#priority_list

. 16. Peterson, G., D. Rasmussen, and K. Gustavson. Study on Enhancing the Endocrine Disruptor Priority List with a Focus on Low Production Volume Chemicals . 2007 June 26, 2009; May 2007:[Available from: http://ec.europa.eu/environment/endocrine/docume nts/final_report_2007.pdf

. 17. State of California Environmental Protection Agency. California Proposition 65 (Safe Drinking Water and Toxic Enforcement Act Of 1986) - Chemicals Known to the State to Cause Cancer or Reproductive Toxicity. September 10, 2009 October 22, 2009]. 18. Council Directive 1999/45/EC , E. Commission, Editor. 1999: Official Journal of the European Union. 19. Council Directive 2001/60/EC , E. Commission, Editor. 2001: Official Journal of the European Union. 20. Council Directive 2006/8/EC , E. Commission, Editor. 2006: Official Journal of the European Union. 21. USEPA, Guidelines for Carcinogen Risk Assessment. USEPA Risk Assessment Forum, 2005. 22. 

### Barton, H. , et al. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens 2005 [cited 2009 December 22, 2009]; Available from: http://cfpub.epa.gov/ncea/CFM/re cordisplay.cfm?deid=160003

. 23. GHS, Germ Cell Mutagenicity . 2009, United Nations. 24. GHS, Specific Target Organ System ic Toxicity Repeated Exposure . 2009, United Nations. 25. USEPA, Guidelines for Neurotoxicity Risk Assessment. Federal Register, 1998. 63 (93): p. 26926-26954. 26. GHS, Reproductive Toxicity . 2009, United Nations.

26U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

27. USEPA. Methodology for Risk-Based Prioritization under ChAMP . 2009 [cited 2010 February 4]; Available from: http://www.epa.gov/oppt/existingchemical s/pubs/RBPMethodology_Web_April%202009.p df

. 28. OECD, Manual for the Investigation of HPV Chem icals, Annex 1 Guidance for completing a SIDS Dossier 2007. 29. GHS, Respiratory or Skin Sensitization . 2009, United Nations. 30. Association of Occupationa l and Environmental Clinics. Exposure Code List . 2009 October 22, 2009]; Available from: http://www.aoecdata.org/Default.aspx

. 31. USEPA. U.S. EPA New Chemicals Program C hemical Categories - Inorganic Phosphates . 2002 October 22, 2009]; Available from: http://www.epa.gov/oppt/newchems/pubs/cat02.htm#Phosphates,%20Inorganic

. 32. Detailed Assessment of Phosphorus Sources in Minnesota Watersheds . 2004, Prepared by Barr Engineering Company for Minnesota Pollution Control Agency. 33. USEPA, Health Effects Test Guidelines: OPPTS 870.1100: Acute Oral Toxicity. 1998. 34. USEPA, Health Effects Test Guidelines: OPPTS 870.1200: Acute Dermal Toxicity. 1998. 35. USEPA, Health Effects Test Guidelines: OPPTS 870.1300: Acute Inhalation Toxicity. 1998. 36. OECD, OECD Guidelines for the Testing of Chemic als: Test No. 420: Acute Oral Toxicity

- Fixed Dose Procedure. 2001. 37. OECD, OECD Guidelines for the Testing of Chemic als: Test No. 423: Acute Oral toxicity - Acute Toxic Class Method. 2001. 38. OECD, OECD Guidelines for the Testing of Chemic als: Test No. 425: Acute Oral Toxicity: Up-and-Down Procedure. 2006. 39. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 402: Acute Dermal Toxicity. 1987. 40. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 403: Acute Inhalation Toxicity. 1981. 41. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 451: Carcinogenicity Studies. 1981. 42. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies. 1981. 43. USEPA, Health Effects Test Guidelines: OPPTS 870.4200: Carcinogenicity. 1998. 44. USEPA, Health Effects Test Guidelines: OPPTS 870.4300: Combined Chronic Toxicity/Carcinogenicity. 1998. 45. NTP, Specifications for the conduct of studi es to evaluate the toxic and carcinogenic potential of chemical, biological and physical agents in laboratory animals for the National Toxicology Program . 2006. 46. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 471: Bacterial Reverse Mutation Test. 1997. 47. USEPA, Health Effects Test Guidelines: OPPTS 870.5100: Bacterial Reverse Mutation Test. 1998. 48. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 473: In Vitro Mammalian Chromosome Aberration Test. 1997. 49. USEPA, Health Effects Test Guidelines: OPPTS 870.5375: In Vitro Mammalian Chromosome Aberration Test. 1998. 50. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 474: Mammalian Erythrocyte Micronucleus Test. 1997. 51. USEPA, Health Effects Test Guidelines: OPPTS 870.5395: Mammalian Erythrocyte Micronucleus Test. 1998. 52. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 475: Mammalian Bone Marrow Chromosome Aberration Test. 1997. 53. USEPA, Health Effects Test Guidelines: OPPTS 870.5385: Mammalian Bone Marrow Chromosome Aberration Test. 1998. 54. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 476: In Vitro Mammalian Cell Gene Mutation Test. 1997.

27U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

55. USEPA, Health Effects Test Guidelines: OPPTS 870.5300: In Vitro Mammalian Cell Gene Mutation Test. 1998. 56. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 483: Mammalian Spermatogonial Chromosome Aberration Test. 1997. 57. USEPA, Health Effects Test Guidelines: OPPTS 870.5380: Mammalian Spermatogonial Chromosome Aberration Test. 1998. 58. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In Vivo. 1997. 59. OECD, OECD Guidelines for the Testing of Chem icals: Test No. 424: Neurotoxicity Study in Rodents. 1997. 60. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 426: Developmental Neurotoxicity Study. 2007. 61. USEPA, Health Effects Test Guidelines: OPPTS 870.6300: Developmental Neurotoxicity Study. 1998. 62. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 408: Repeated Dose 90

- Day Oral Toxicity Study in Rodents. 1998. 63. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 409: Repeated Dose 90

- Day Oral Toxicity Study in Non-Rodents. 1998. 64. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 411: Subchronic Dermal Toxicity: 90-day Study. 1981. 65. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 413: Subchronic Inhalation Toxicity: 90-day Study. 1981. 66. USEPA, Health Effects Test Guidelines: OPPTS 870.3100: 90-Day Oral Toxicity in Rodents. 1998. 67. USEPA, Health Effects Test Guidelines: OPPTS 870.3150: 90-Day Oral Toxicity in Nonrodents. 1998. 68. USEPA, Health Effects Test Guidelines: OPPTS 870.3250: 90-Day Dermal Toxicity. 1998. 69. USEPA, Health Effects Test Guidelines: OPPT S 870.3465: 90-Day Inhalation Toxicity. 1998. 70. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 407: Repeated Dose 28

- day Oral Toxicity Study in Rodents. 1995. 71. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 410: Repeated Dose Dermal Toxicity: 21/28-day Study. 1981. 72. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 412: Repeated Dose Inhalation Toxicity: 28-day or 14-day Study. 1981. 73. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. 1996. 74. USEPA, Health Effects Test Guidelines: OPPTS 870.3050: Repeated Dose 28-day Oral Toxicity Study in Rodents. . 2000. 75. USEPA, Health Effects Test Guidelines: OPPTS 870.3200: 28-Day Dermal Toxicity. 1998. 76. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 415: One-Generation Reproduction Toxicity Study. 1983. 77. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 416: Two-Generation Reproduction Toxicity. 2001. 78. USEPA, Health Effects Test Guidelines: O PPTS 870.3800: Reproduction and Fertility Effects. 1998. 79. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 421: Reproduction/Developmental Toxicity Screening Test. 1995. 80. USEPA, Health Effects Test Guidelines: O PPTS 870.3550: Reproduction/Developmental Toxicity Screening Test. 2000. 81. USEPA, Health Effects Test Guidelines: OPPTS 870.3650: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. 2000.

28U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

82. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 414: Prenatal Development Toxicity Study. 2001. 83. OECD, OECD Guidelines for the Testing of Chem icals: Test No. 406: Skin Sensitization. 1992. 84. OECD, OECD Guidelines for the Testing of Chemic als: Test No. 429: Skin Sensitization: Local Lymph Node Assay. 2002. 85. USEPA, Health Effects Test Guidelines: OPPTS 870.2600: Skin Sensitization. 1998. 86. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 203: Fish, Acute Toxicity Test. 1992. 87. USEPA, Ecological Effects Test Guidelines: OPPT S 850.1075: Fish acute toxicity test, freshwater and marine . . 1996. 88. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 202: Daphnia sp. Acute Immobilisation Test. 2004. 89. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1010: Aquatic Invertebrate Acute Toxicity Test, freshwater daphnids. . 1996. 90. USEPA, Ecological Effects Test Guidelines: OPPT S 850.1035: Mysid acute toxicity test.

. 1996. 91. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 201: Alga, Growth Inhibition Test. 2006. 92. USEPA, Ecological Effects Test Guidelines: OPPTS 850.5400: Algal toxicity, Tiers I and II.

. 1996. 93. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1085: Fish Acute Toxicity Mitigated by Humic Acid. . 1996. 94. USEPA, Ecological Effects Test Guidelines: OPPT S 850.1025: Oyster acute toxicity test (shell deposition). . 1996. 95. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1045: Penaeid acute toxicity test. . 1996. 96. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1055: Bivalve Acute Toxicity Test (embryo larval). . 1996. 97. USEPA, Ecological Effects Test Guidelines: OPPT S 850.4400: Aquatic plant toxicity test using Lemna spp. Tiers I and II. . 1996. 98. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 301: Ready Biodegradability. 1992. 99. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 310: Ready Biodegradability - CO2 in sealed vessels (Headspace Test) 2006. 100. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS 835.3110: Ready Biodegradability. 1998. 101. Aronson, D., et al., Estimating biodegradation half-lives for use in chemical screening. Chemosphere, 2006. 63 (11): p. 1953-1960. 102. OECD, OECD Guidelines for the Testing of Chemicals 303A: Aerobic Sewage Treatment: Activated Sludge Units. 2001. 103. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS 835.3240 Simulation Test—Aerobic Sewage Treat ment: A. Activated Sludge Units. 2008. 104. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 309: Aerobic Mineralisation in Surface Water - Simulation Biodegradation Test 2004. 105. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS 835.3190 - Aerobic Mineralization in Surface Water – Simulation Biodegradation Test. 2008. 106. OECD, OECD Guidelines for the Testing of Chemicals: Test No. 314: Simulation Tests to Assess the Biodegradability of Chemicals Discharged in Wastewater

. 2008. 107. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS 835.3280 Simulation Tests to Assess the Primary and Ultimate Biodegradability of Chemicals Discharged to Wastewater. 2008. 108. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS Harmonized Guideline 835.3170 - Shake Flask Die-Away Test 1998.

29U.S. EPA Design for the Environment Program Version 2 .0 Master Criteria July 2010

109. USEPA, Fate, Transport and Transformation Test Guidelines: OPPTS Harmonized Guideline 835.3180 - Sediment/Water Microcosm Biodegradation Test 1998. 110. OECD, OECD Guidelines for the Testing of Chem icals: Test No. 305: Bioconcentration: Flow-through Fish Test. 1996. 111. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1710: Oyster BCF. . 1996. 112. USEPA, Ecological Effects Test Guidelines: OPPTS 850.1730: Fish BCF. . 1996.

30