The following provides a summary of the GHS system as it relates to classification of health hazards. Examples of how this classification system is used in DfE and the GreenScreen® tool are also provided. Although the committee’s discussion primarily focuses on GHS classification schemes, the GreenScreen® tool, and the DfE framework, the committee also describes selected situations when slightly different approaches have been used to inform other alternatives assessment frameworks (e.g., TURI, REACH). This appendix also describes how authoritative lists are used to classify human health hazards and briefly describes approaches used to address end points not included in the GHS classification scheme.
USE OF THE GHS CLASSIFICATION SCHEME TO ASSESS HEALTH HAZARDS
Acute Mammalian Toxicity
The GHS defines acute “toxicity as 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” (UNECE 2013). Chemicals can be classified into five hazard categories based on animal LD50 (oral, dermal) or LC50 (inhalation) values (Table D-1). The criteria consist of hazard levels assigned to the five GHS categories (any exposure route). The hazard levels described by DFE range from Very High Hazard = (Category 1 or 2) to Low (Category 5, or adequate data available and negative studies, no structural alerts, and GHS not classified).
The GHS classification criteria are based on strength of evidence of a chemical posing a carcinogenic hazard. The GHS guidance points out that classification is based on the inherent properties of a chemical and does not provide information on the level of the human cancer risk. The GHS classification criteria (Table D-2) are largely consistent with those of the International Agency for Research on Cancer (IARC) and the National Toxicology Program (NTP).
DfE and GreenScreen® have adopted similar criteria for assessing chemicals for carcinogenicity. According to DfE, their criteria mirror IARC’s classification approach. Although the DfE and GreenScreen® systems incorporate the GHS carcinogen categories, they assign hazard designations differently. The impact, if any, of the differences on the outcomes of alternatives assessments, is unclear.
- GHS Categories 1A and 1B:
- DfE: Very High Hazard/Green Screen: High Hazard
- GHS Category 2:
- DfE: High Hazard/Green Screen: Moderate Hazard
- No GHS Category
- DfE: Moderate Hazard = limited or marginal evidence of carcinogenicity in animals (and inadequate evidence in humans)
- DfE: Low Hazard = negative studies or robust mechanism-based structure-activity-relationships as described in the DfE guidance document (EPA 2011a).
- GreenScreen®: Low Hazard = adequate data available, and negative studies, no structural alerts, and GHS not classified.
DfE and GreenScreen® also assign hazard designations to authorized carcinogen lists. If significant difference in authoritative classification of a chemical occurs, then the GreenScreen® uses the most conservative health classification.
|Exposure Route||Category 1||Category 2||Category 3||Category 4||Category 5|
|Oral (mg/kg bodyweight)||5||50||300||2000||5000|
|Dermal (mg/kg bodyweight)||50||200||1000||2000|
|Dusts and Mists (mg/l)||0.05||0.5||1.0||5|
SOURCE: Adapted from UNECE 2011.
Known or Presumed Carcinogen
Known Human Carcinogen Based on human evidence
Presumed Human Carcinogen Based on demonstrated animal carcinogenicity
|Limited evidence of human or animal carcinogenicity|
The GHS criteria used to assess chemicals for mutagenicity/genotoxicity health end points are adapted from criteria developed for the GHS health hazard “Germ Cell Mutagenicity.” This hazard class is primarily concerned with chemicals that may cause human germ cell mutations. Also considered in classifying substances of this hazard class are mutagenicity/genotoxicity tests in vitro and mammalian somatic cells in vivo (UNECE 2013) (Table D-3).
DfE developed criteria for assessing chemicals as hazards for the mutagenicity /genotoxicity health end point. DfE supplemented the GHS criteria for germ cell mutagenicity with considerations for mutagenicity and genotoxicity in cells other than germ cells:
- GHS Categories 1A and 1B:
- DfE: Very High Hazard for germ cell mutagenicity
- GHS Category 2:
- DfE: High Hazard for germ cell mutagenicity and mutagenicity and genotoxicity in somatic cells. This DfE classification is also applied when there is in vitro evidence of mutagenicity plus in vivo evidence of mutagenicity in somatic cells or germ cells of humans or animals (EPA 2011a).
- No GHS Category
- DfE: Moderate Hazard for germ cell mutagenicity and mutagenicity and genotoxicity in somatic cells = evidence of mutagenicity supported by positive results in in vitro or in vivo somatic cells of humans and animals.
- DfE: Low Hazard for germ cell mutagenicity and mutagenicity and genotoxicity in somatic cells = Negative results for chromosomal aberrations and gene mutations, or no structural alerts.
Many frameworks, including DfE, use authoritative lists to assess chemicals for mutagenicity/genotoxicity end points.
The GHS includes developmental toxicity in the definition of reproductive toxicity, but subdivides reproductive toxicity and developmental toxicity in the classification system. For classification purposes, reproductive toxicity is defined by GHS as adverse effects on sexual function and fertility in adult males and females, including, but not limited to, effects on sexual behavior, fertility, parturition, pregnancy outcomes. Adverse effects on or via lactation are also included in reproductive toxicity. The GHS
|Category 1: Known/Presumed
Known to produce heritable mutations in human germ cells
Positive evidence from epidemiological studies
Positive results in: In vivo heritable germ cell tests in mammals; human germ cell tests; in vivo somatic mutagenicity tests, combined with some evidence of germ cell mutagenicity
May include heritable mutations in human germ cells. Positive evidence from tests in mammals and somatic cell tests. In vivo somatic genotoxicity supported by in vitro mutagenicity data.
SOURCE: Adapted from UNECE 2013.
Known or presumed to cause effects on human reproduction or on development
|Category 1A Known: Based Based on human evidence||Category 1B Presumed: on experimental animals||Human or animal evidence possibly with other information||Effects on or via lactation|
treats lactation effects separately, however, so that a specific hazard warning can be provided to lactating mothers. The GHS criteria for reproductive toxicity consist of placing substances into one of two categories based on the strength of the evidence (Table D-4).
With the exception of DfE, all of the frameworks reviewed by the committee use GHS criteria to establish evidence of reproductive toxicity in chemical hazard assessments (see Table 8.1). GreenScreen® developed the following reproductive toxicity hazard designations based on the GHS criteria:
- High Hazard = GHS Category 1A (Known) and 1B (Presumed)
- Moderate = GHS Category 2 (Suspected) or limited or marginal evidence of reproductive toxicity in animals (see Guidance)
- Low = Adequate data available, and negative, no structural alerts, and GHS not classified.
In contrast to the other frameworks, DfE combines reproductive and developmental toxicity into a single health end point in chemical hazard assessments, and does not use GHS criteria to establish evidence of reproductive toxicity. DfE uses criteria derived from EPA’s Office of Pollution Prevention and Toxics (OPPT) criteria for HPV chemical categorization (EPA 2009) and the EU REACH criteria for Annex IV (EC 2007). The criteria consist of hazard levels assigned to dose/concentration ranges (oral, dermal, and respiratory routes) obtained from experimental animal tests. For inhalation exposure (vapor/gas), for example, the hazard designations in mg/L/day are: High Hazard = < 1; Moderate Hazard = 1-2.5; Low Hazard = > 2.5-20; Very Low Hazard= > 20. Parental (reproductive) and offspring (developmental) exposure to chemicals are evaluated using the criteria and in general, NOAELs and LOAELs as the metric.
DfE-assigned hazard designations from two authoritative lists also provide evidence of reproductive and developmental toxicity. High Hazard = H362 (May cause harm to breast-fed children) and High or Moderate Hazard = CA Proposition 65 List (chemicals known to the state to cause reproductive and developmental toxicity).
The basis or rationale for assigning a higher hazard level to H362 compared to the Prop 65 List is unclear, given the much larger number and broader range of reproductive/developmental toxicants on the Prop 65 List and the transparent and rigorous review and approval process required for listing chemicals. The impact of using different criteria and authoritative lists to identify reproductive and developmental toxicants on the outcome of alternatives assessments is unclear, but should be considered.
Repeated Exposure Human Health End Points
These health end points include neurotoxicity (repeated exposure); repeated dose toxicity; and
systemic toxicity/organ effects (repeated exposure). The frameworks use the GHS criteria for the hazard class “specific target organ toxicity (repeated exposure) to provide evidence of the health end points. The GreenScreen® tool lists GHS criteria for “systemic toxicity/organ effects” as the “information source” for the neurotoxicity end point (Clean Production 2013). However, since “systemic toxicity/organ effects” is not a GHS health hazard class (UNECE 2013), the committee interpreted this as meaning “specific target organ toxicity.”
As described by the GHS, repeated exposures to chemicals in the specific target organ (repeated exposure) hazard class produce significant toxic effects on specific target organs, including effects that impair function, are both reversible and irreversible, and are immediate or delayed. Classifying chemicals as specific target organ toxicants (repeated exposure) based on the GHS criteria requires using expert judgment to conduct weight-of-evidence evaluations of all available evidence. The GHS specifies that all existing data include peer-reviewed published studies and additional data acceptable to regulatory agencies. The information comes either from repeated exposure in humans or animal studies. The GHS states: “it is recognized that human data will be the primary source of evidence for this hazard class” (UNECE 2013).
Chemicals are placed in one of two categories based on the nature and severity of the observed effects. “Category 1: Chemicals that have produced significant toxicity in humans, or that on the basis of evidence from studies in animals can be presumed to have the potential to produce significant toxicity in humans (emphasis in original) following repeated exposure. Placing a chemical in Category 1 is based on: (a) reliable and good quality evidence from human cases or epidemiological studies; or (b) observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Category 2: Chemicals that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health (emphasis in original) following repeated exposure. Placing a chemical in Category 2 is based on observations from animal studies in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations” (UNECE 2013).
GHS guidance values (dose/concentration) for various exposure routes based on standard repeated exposure studies (e.g., 90-day sub-chronic) that provide information on specific target organ toxicity can be used in weight-of-evidence evaluations to assist in classifying chemicals as Category 1 and Category 2. Examples of guidance values (mg/l/6h/d) in a 90-day inhalation (vapor) toxicity study in rats: Category 1 = ≤ 0.2; Category 2 = 0.2 < C ≤ 1.0.
Neurotoxicity (Repeated Exposure)
GreenScreen® does not list the GHS guidance values as an information source for this neurotoxicity. GreenScreen® assigns the following hazard designations to the GHS categories: High Hazard = Category 1; Moderate Hazard = Category 2; Low Hazard = Adequate data available and negative studies, no structural alerts, and GHS not classified. GreenScreen® uses U.S. EPA Risk Assessment Guidance to define applicable neurotoxic effects.
In contrast to the IC2 and BizNGO frameworks, the DfE framework does not classify chemicals as Category 1 and Category 2 neurotoxicants. The DfE framework uses the GHS guidance values independently of conducting weight-of-evidence evaluations of human and animal studies. The GHS guidance values with DfE- assigned hazard designations are used as criteria to provide evidence of neurotoxicity (repeated exposure). For example, in a 90-day rat inhalation (vapor) study, a chemical for which target organ toxicity is observed at a given exposure concentration (mg/L/6h/day) is designated as a hazard according to the following criteria: High Hazard = < 0.2; Moderate Hazard = 0.2—1.0; Low Hazard = > 1.0.
Repeated Dose Toxicity
Repeated dose toxicity is identified as a health end point in the DfE frameworks as shown in Table 8.1. The DfE framework uses the results of repeated dose toxicity studies to evaluate chronic exposure (EPA 2011a). The DfE framework criteria for repeated dose toxicity are the same as the DfE criteria for neurotoxicty (repeated dose). As described above, the criteria consist of GHS guidance values for specific target organ toxicity (repeated exposure) with DfE-assigned hazard designations. DfE points out that the criteria mirror the EPA’s OPPT criteria for HPV chemical categorization (EPA 2009). In addition, the following DfE suggested hazard designations for authoritative lists can be used to supplement the criteria: High Hazard = EU R48 (23/24/25)—Danger of serious damage to health by prolonged exposure (repeated exposure); EU H372—Causes damage to organs.
Moderate Hazard = H373—May cause damage to organs; High or Moderate Hazard = EU R48 (20/21/22)—Danger of serious damage to health by prolonged exposure.
Systemic Toxicity/Organ Effects (Repeated Exposure)
The IC2 and BizNGO frameworks criteria for specific target organ toxicity (repeated exposure) are GHS guidance values with DfE-assigned hazard designations. The criteria are the same as the DfE criteria for the repeated dose toxicity end point discussed earlier. The frameworks use the same authoritative lists with the DfE-suggested hazard designations that are described in the Repeated Dose Toxicity section to supplement the criteria.
Single Exposure Human Health End Points
These end points include: neurotoxicity (single exposure) and systemic toxicity/organ effects (single exposure). The frameworks use GHS criteria for the hazard class, “specific target organ toxicity (single exposure)” to provide evidence for these health end points. A single exposure to chemicals in this hazard class causes specific, non-lethal target organ toxicity (UNECE 2013). This toxicity includes all significant health effects, including both immediate and delayed, reversible and irreversible, that can impair function, but are not covered by other GHS health hazard classes (UNECE 2013). According to the GHS, human data will be the primary source of evidence for this hazard class.
Chemicals are classified using expert judgment based on the weight of all available evidence, including the use of recommended guidance values, and are placed into three categories based on the severity and nature of the observed effect(s). Category 1designation for: chemicals that have produced significant toxicity in humans and chemicals which have the potential to produce significant toxicity in humans following a single exposure, based on animal study evidence (UNECE 2013). Chemicals are placed into the category based on: (a) reliable and good quality evidence from human cases or epidemiological studies, or (b) evidence of significant and/or severe toxic effects in experimental animals that are of relevance to humans and occurred with low exposures. Category 2 describes: chemicals that, based on animal studies, “can be presumed to have the potential to be harmful to human health following single exposure” (UNECE 2013). Chemicals are placed into the category based on observations in studies of experimental animals of significant toxic effects of relevance to human health that are produced at generally moderate exposure concentrations. Category 3: Transient target organ effects for which a chemical may not meet the criteria to be classified in Categories 1 and 2. The effects adversely alter human function for a short duration after exposure and recovery occurs in a reasonable period without significantly altering structure and function. This category only includes narcotic effects and respiratory irritation.
GHS guidance values (dose/concentration) for various exposure routes relevant to humans are used as part of weight of evidence evaluations to assist in classifying chemicals into Categories 1 and 2. Category 3 does not include guidance values because this classification is primarily based on human data (29CFR 1910. 1200). The guidance value ranges are proposed single-dose exposure concentrations that have been shown to produce significant non-lethal toxic effects in experimental animal studies. For example, in a rat inhalation study, guidance value ranges (single exposure) for vapor (mg/L/4h) for Category 1 = C ≤ 10; Category 2 = 20 ≥ C > 10.
Neurotoxicity (Single Exposure)
Some frameworks use hazard designations assigned to neurotoxicant categories as criteria to provide evidence of neurotoxicity (single exposure). GreenScreen® does not list GHS guidance values as a part of the criteria, so it is unclear whether they are used to assist in classifying chemicals into categories. Criteria: Very High Hazard = Category 1; High Hazard = Category 2; Moderate Hazard = Category 3; Low Hazard = adequate data available and negative studies; no structural alerts, and GHS not classified. Screening lists are used in addition to the criteria to provide evidence of the health end point.
Systemic Toxicity/Organ Effects (Single Exposure)
Several frameworks use GHS guidance values to which GreenScreen® has assigned hazard designations as criteria to provide evidence of the systemic toxicity/organ effects health end point. For example, Inhalation-Gas or Vapor (mg/L/4h): Very High Hazard = ≤ 10 (GHS Category 1, Single Exposure, any route); High Hazard = > 10-20 (GHS Category 2, Single Exposure, any route). The frameworks use authoritative lists to supplement the criteria. For example: Very High Hazard = H370
(causes damage to organs); High Hazard = H371 (may cause damage to organs); Moderate Hazard = H335 (may cause respiratory irritation)
GHS criteria provide evidence of the respiratory sensitization health end point. In the context of the GHS, a respiratory sensitizer is a chemical that will lead to hypersensitivity following inhalation exposure. Respiratory hypersensitivity usually means asthma, although other hypersensitivity reactions (rhinitis/conjunctivitis and alveolitis) are considered.
Respiratory sensitizers are classified into GHS Hazard Category 1 if: “(a) there is evidence in humans that the chemical can lead to specific hypersensitivity; and/or (b) if there are positive results from an appropriate animal test” (UNECE 2013). If required, and if there are sufficient data, chemicals can be further categorized in sub-category 1A and sub-category 1B. Category 1A chemicals “show a high frequency of occurrence in humans; or a probability of occurrence of a high sensitization rate in humans based on animal or other tests” (UNECE 2013). Category 1B chemicals “show a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitization rate in humans based on animal or other tests” (UNECE 2013). Reaction severity may also impact classification into Categories 1A and 1B.
Evidence that a chemical can lead to specific hypersensitivity (asthma) is based on human experience. Currently, there are no validated animal models for testing for respiratory hypersensitivity. The human evidence can include: (a) clinical history (medical and occupational) and data from appropriate lung function tests related to exposure to the chemical, confirmed by other supportive evidence (e.g. skin prick test) and (b) data from bronchial challenge tests (29CFR 1910.1200).
The DfE framework and GreenScreen® tool use the GHS criteria differently (and use different assigned hazard designations) to provide evidence of the respiratory sensitization end point. GreenScreen® classifies respiratory sensitizers as: High = GHS category 1A (high frequency of occurrence) and Moderate = GHS category 1B (low to moderate frequency of occurrence). In the DfE framework: High = GHS categories 1A and 1B (occurrence in humans or evidence of sensitization in humans based on animal or other tests) and Moderate = Limited evidence, including the presence of structural alerts.
GreenScreen® and the DfE framework also use the following authoritative lists with assigned hazard designations to supplement the GHS criteria: the EU hazard statement, H334, the Association of Occupational and Environmental Clinics (AOEC) Exposure Code List (asthmagens), and the MAK (Germany occupational exposure limits with “Sa” and “Sah” notations (DFG 2013). It is unclear why the frameworks identify chemicals in the AOEC database that cause reactive air dysfunction syndrome (RADS) as providing evidence of the respiratory sensitization endpoint. RADS results from single, high exposures to irritant chemicals. RADS does not fit the two phase-sensitization mechanism that defines respiratory sensitizers under the GHS. It also is unclear why DfE assigns the same hazard designation to chemicals identified as “generally accepted” asthmagens and “sensitizer-induced” asthmagens in the AOEC database. In contrast to “generally accepted” asthmagens, which are identified based on expert opinion, “sensitizer-induced” asthmagens are identified based on established AOEC criteria (AOEC 2009). The MAK designation does not appear to be consistent with the description in GreenScreen® of “high hazard” as “frequency of occurrence of sensitization.” Sufficient evidence of a MAK respiratory sensitizer requires documentation in only two patients tested at two independent facilities (DFG 2013).
The frameworks do not provide a rationale for listing the MAK and AOEC as authoritative sources for identifying respiratory sensitizers (Quint et al. 2008). As a result, it is not clear why other government agencies (e.g., the UK HSE and NIOSH) and non-government organizations (e.g., ACGIH), which identify occupational respiratory sensitizers that conform to the GHS criteria, are not included as authoritative lists.
The frameworks primarily use GHS criteria to provide evidence of the skin sensitization health end point. A skin sensitizer is defined in the GHS as a chemical that will lead to an allergic response following contact. Sensitization includes an induction phase in which the immune system learns to react. This is followed by an elicitation phase in which clinical symptoms arise upon subsequent exposure to the chemical, usually at a lower concentration.
Skin sensitizers are classified as GHS Category 1. They can be further classified into sub-categories 1A and 1B if required, or if there are sufficient data. A substance is classified as Category 1 if: “(a) there is
evidence in humans that the substance can lead to sensitization by skin contact in a substantial number of persons or (b) there are positive results from an appropriate animal test. Chemicals in sub-category 1A show a high frequency of occurrence in humans and/or a high potency in animals and can be presumed to potentially produce significant sensitization in humans. Sub-category 1B chemicals show a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals and can be presumed to potentially produce significant sensitization in humans” (29CFR 1910.1200). Severity of reaction can be considered in sub-categories 1A and 1B.
“Effects seen in either humans or animals will normally justify classification in a weight of evidence approach” (UNECE 2013). The GHS specifies that evidence should include any or all of six types of data/information, including: (a) positive data from patch testing, usually obtained in more than one dermatology clinic; (b) positive data from appropriate animal studies; (c) well-documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic.
The DfE framework uses a similar hazard designations assigned to the GHS hazard categories to provide evidence of the skin sensitization health endpoint. The DfE framework assigns the following hazard designations: High = GHS Category 1A (high frequency of sensitization in humans and/or high potency in animals); Moderate = GHS Category 1B (low to moderate frequency of sensitization in humans and/or low to moderate potency in animals); Low = adequate data available and not GHS Category 1A or 1B. Sub-category 1A Animal Test Results = High; sub-category 1B Animal Test Results = Moderate.
The frameworks use authoritative lists with assigned hazard designations to establish evidence of skin sensitization in addition to the GHS criteria: H317 (may cause sensitization by skin contact) = High or Moderate Hazard (DfE, IC2, BizNGO). MAK (Germany occupational exposure limits denoted with “Sh” and “Sah”(DFG 2013)x = High (IC2 and BizNGO). The criterion for sufficient evidence of a MAK skin sensitizer, “case reports of clinically relevant sensitization (association of symptoms and exposure) for more than one patient from at least two independent centres” does not appear to meet the “high hazard” description (above) in certain frameworks.
The rationale for identifying the authoritative lists is not provided, so it is not clear why other similar agencies and organization that identify skin sensitizers are not included. The addition of NIOSH and the ACGIH as authoritative lists, for example, would increase the number of identified skin sensitizers that meet the GHS criteria. The TURI framework uses information from the HSDB, Sax (Sax’s Dangerous Properties of Industrial Chemicals textbook), and MSDSs/SDSs. The up-to-date, peer-reviewed animal and human studies on chemicals in the HSDB enable TURI to use weight-of-evidence evaluations to classify skin sensitizers as specified in the GHS criteria. The Sax reference also provides information on animal and human studies. The 2012 Hazard Communication Standard requires health effects information in SDSs to be aligned with GHS criteria. However, compared to ACGIH and NIOSH, these information sources have limitations (see Information Sources Used by Existing Frameworks in Chapter 8).
Skin and Eye Irritation and Corrosion
The GHS addresses effects on the skin and eye as two separate hazard classes—skin corrosion/irritation and serious eye damage/eye irritation. The classification approaches for the hazards, however, are the same. The GHS specifies a “tiered approach with emphasis placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information” (UNECE 2013). All available information related to the health hazards of the skin or eye is considered together in a total weight of evidence approach. The available information includes the “results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations” (UNECE 2013). The GHS “tiered approach provides guidance on how to organize existing information on a chemical and to make a weight of evidence decision about hazard assessment and hazard classification” (UNECE 2013).
Chemicals classified based on standard animal test data can be placed in one of three categories: (a) Category 1 (skin corrosion) is comprised of chemicals that cause “destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure for ≤ 4h” (UNECE 2013). Category 1 can be subdivided into three sub-categories (1A, 1B, 1C) if more than one
corrosion designation is required. Corrosive responses are noted and observed at specified time periods. For example, in Category 1A, corrosive responses are noted following exposures greater than 3 minutes and up to 1 hour observation. (b) Category 2 (skin irritation) chemicals produce reversible damage to the skin following application for up to 4 hours. Criteria include: mean scores for erythema/eschar or for edema in at least 2 of 3 tested animals at specified time periods after patch removal; or inflammation that persists to the end of the observation period (normally 14 days) in at least 2 animals. Category 3 (mild skin irritation) is used by authorities (e.g., pesticides) that want to have more than one skin irritation category.
The IC2 and BizNGO frameworks use GHS categories with hazard designations assigned by GreenScreen® to provide evidence of the skin corrosion/irritation end point: Very High Hazard = Category 1 (corrosive); High Hazard = Category 2 (irritation); Moderate Hazard = Category 3 (mild irritation); Low Hazard = “Not classified.” Authoritative lists with assigned hazard designations supplement the criteria: Very High Hazard = H314 (causes severe skin burns and eye damage); High Hazard = H315 (causes skin irritation).
The DfE framework uses criteria derived from the Office of Pesticide Programs Acute Toxicity Categories to provide evidence of skin irritation/corrosivity: Very High Hazard = Corrosive; High Hazard = Severe irritation at 72 hours; Moderate Hazard = Moderate irritation at 72 hours; Low Hazard = Not irritating. The DfE guidance document did not provide a rationale or reason for the use of the Office of Pesticides Programs criteria in the framework instead of the GHS criteria. One possible disadvantage is the inability to link the criteria to the EU hazard statements, H314 and H315.
In the TURI framework, information obtained from HSDB, NIOSH, and MSDSs provide evidence of skin irritation/corrosion. The information above under “Skin Sensitization” regarding the use of HSDB and MSDSs also applies to the use of these resources in providing evidence for skin irritation/corrosion. Information from NIOSH provides a source of existing human and animal toxicity studies on chemicals that have undergone a weight of evidence evaluation, consistent with GHS criteria. In addition, a search of the NIOSH Pocket Guide to Chemical Hazards (available online) using the key phrases “irrit skin” and “skin burns” under “SY” (Symptoms) identifies chemicals that cause skin irritation and skin corrosion, respectively (NIOSH 2005).
Based on the results of animal tests, GHSclassified chemicals are placed into one of two categories. Chemicals in Category 1 (serious eye damage/irreversible effects on the eye) produce: “(a) in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period (normally 21 days); and/or (b) in at least 2 of 3 tested animals, a positive response of corneal opacity and/or iritis for up to 72 hours after instillation of the test material” (UNECE 2013). Chemicals in Category 2/2A (eye irritation/reversible effects on the eye) “produce in at least 2 or 3 tested animals a positive response of: (a) corneal opacity; and/or (b) iritis; and/or (c) conjunctival redness; and/or (d) conjunctival oedma (chemosis)” for up to 72 hours after instillation of the chemical, which fully reverses within an observation period (usually 21 days) (UNECE 2013). Category 2B (mildly irritating) is comprised of Category 2A chemicals for which the effects are fully reversible within 7 days of observation.
IC2 and BizNGO use the following GHS categories with hazard designations assigned by GreenScreen® as evidence that a chemical causes eye corrosion or irritation: Very High Hazard = Category 1 (irreversible damage); High = Category 2 (irritating). Hazard designations assigned to EU statements supplement the criteria: Very High Hazard = H318 (causes severe eye damage); High Hazard = H319 (causes serious irritation). The ECHA database (harmonized classifications) lists 543 H318 substances and 431 H319 substances as of 2/14/2014, the most recent update of the database.
In the DfE framework, hazard designations (assigned by DfE) to the EPA OPPT categories (EPA 2011b) provide evidence of eye irritation and corrosivity. Very High = Irritation persists for > 21 days or corrosive; High = Clearing in 8-21 days, severely irritating; Moderate = Clearing in 7 days or less, moderately irritating; irritating; Low = Clearing in less than 24 hours, mildly irritating; Very Low = Not irritating. Although the DfE and GHS criteria for identifying eye irritants and corrosives as “Very High Hazard” and “High Hazard” do not appear to be substantially different, the DfE framework does not suggest using the H318 and H319 as authoritative lists to classify chemicals. It is not clear whether this means that the DfE considers the GHS and DfE
criteria to be significantly different, and that chemicals classified as H318 and H319 do not meet the DfE criteria for the eye corrosion/irritation.
The REACH and the TURI frameworks identify respiratory irritation as a health endpoint. The REACH framework uses the GHS criteria for the hazard class specific target organ toxicity (single exposure) to provide evidence of the end point. Category 3 of the criteria addresses transient target organ effects that “adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function”(29CFR1910.1200 ).
The specific GHS criteria for respiratory tract irritation as Category 3 are: (a) Respiratory irritant effects “include effects that impair function with symptoms such as cough, pain, choking, and breathing difficulties. The evaluation is based primarily on human data; (b) Subjective human observations can be supported by objective measurements of clear respiratory tract irritation (e.g., electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids); (c) The symptoms observed in humans should also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction of response triggered only in individuals with hypersensitive airways” (29CFR 1910.1200 ); (d) There are currently no validated animal tests that deal specifically with respiratory tract irritation; however, single and repeated inhalation toxicity may provide useful information.
The REACH framework provides guidance regarding potential sources of existing information that can be used as evidence of respiratory irritation (ECHA 2013). The guidance indicates that on a case-by-case basis, information where symptoms have been described associated with occupational exposures can be used. Information from acute and repeated dose inhalation toxicity studies may also be considered sufficient to show that a substance causes respiratory irritation at a specific concentration level or range. The EU hazard statement H335 (may cause respiratory irritation) provides evidence of the end point and supplements the GHS criteria.
The TURI framework’s use of the HSDB, NIOSH, and MSDSs as information sources for providing evidence of the respiratory irritation end point is consistent with the GHS criteria and the REACH framework’s approach to classifying respiratory irritants. The NIOSH Pocket Guide to Chemical Hazards identifies chemicals that cause respiratory irritation with the phrase “irrit resp sys” under “SY” (Symptoms), which can provide evidence of the health end point (NIOSH 2005).
Chemicals that provide evidence of respiratory irritation also can be identified from ATSDR Minimal Risk Levels (MRLs) where the MRL is based on an inhalation study and the respiratory system is listed as the health end point (ATSDR 2013). The Cal/EPA OEHHA acute and chronic inhalation Reference Exposure Levels for which the respiratory system is the target organ (OEHHA 2014) also can identify chemicals that provide evidence of the respiratory irritation end point.
End Point of Concern that is Not Identified as a GHS Health Hazard
Endocrine activity is assessed in several existing frameworks. However, it is not yet identified as a health hazard in the GHS classification system. The criteria the frameworks use to provide evidence of endocrine-related health effects depend on how they define or describe the health end point. The DfE, IC2, and BizNGO frameworks identify the health end point as “endocrine activity.” The German Guide and TURI frameworks describe the end point as “endocrine disruption.” The CA SCP framework uses the term “endocrine toxicity,” which includes endocrine disruption and metabolic syndrome. Endocrine toxicity is characterized by toxicological end points that include adverse effects on endocrine organs and adverse perturbations of the synthesis, secretion, transport, binding, action, or elimination on natural hormones or their receptors (OEHHA 2012). In the REACH framework, based on existing legislation, endocrine disruption per se is not identified as a health end point. Adverse endocrine-related effects on reproduction or disease states like cancer, however, are addressed. Endocrine disrupters can be identified as SVHCs under REACH on the basis that they cause probable serious human health effects that are equivalent to the level of concern for carcinogens, mutagens, and reproductive toxicants (ECHA 2014).
GreenScreen®’s definitions of endocrine activity and endocrine disruption point out differences in the
descriptors. Endocrine active substances are defined as “having the inherent ability to interact or interfere with one or more components of the endocrine system resulting in a biological effect, but need not necessarily cause adverse effects” (EFSA 2013a). An endocrine disruptor is “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations” (Clean Production Action 2013). The European Food and Safety Authority’s definitions are similar: “endocrine active substances are chemicals that interact or interfere with normal hormonal activity; when this leads to adverse effects they are called endocrine disruptors” (EFSA 2013b).
The frameworks use all available data and authoritative lists to provide evidence of endocrine activity and/or disruption. The IC2 and BizNGO frameworks and the DfE framework use different approaches to provide evidence of the endocrine activity health end point. The DfE framework evaluates endocrine activity of chemicals, but does not characterize hazard in terms of endocrine disruption. Based on criteria developed by GreenScreen®, the IC2 and BizNGO frameworks evaluate chemicals for endocrine activity and assign hazard values based on adverse endocrine-related health effects (Clean Production Action 2013).
Classification of Endocrine Activity in the DfE Framework
In assessing endocrine activity, the DfE framework uses data resources that include: “(a) in vitro data such as hormone binding assays or ex vivo assays; (b) in vivo data from studies of intact animals or wildlife (including aquatic organisms); (c) ethically conducted human studies; (d) in vivo short term exposures or altered (e.g., ovariectomized) animal models; (e) structural similarity to known endocrine active substances using SAR tools such as AIM, QSAR, etc.; and (f) additional information from studies that indicate a chemical’s endocrine system interactions, such as changes in hormone profiles or reproductive organ weights” (EPA 2011a).
Using the following criteria, DfE evaluates available data for each chemical for the presence of endocrine activity, noting caveats and limitations: (a) No Data (ND) = No data available to evaluate end point; endocrine activity is unknown, untested; (b) Potentially Endocrine Active = Data show evidence of endocrine activity; (c) No Evidence of Endocrine Activity = Data show no evidence of endocrine activity (no binding, perturbation, or evidence of endocrine-related adverse effects). “In consultation with EPA toxicologists and risk assessors, DfE provides a summary statement of the available data, including the presence of equivocal or conflicting data and any limitations to the available data. The level of confidence in the assessment is also noted” (EPA 2011a).
Classification of Endocrine Activity in IC2 and BizNGO Frameworks
Based on the GreenScreen® tool, the frameworks evaluate chemicals for endocrine activity and designate hazard levels using the following protocol: (a) assign a preliminary hazard level based on searching GreenScreen® specified lists and available data; (b) determine whether there is a plausibly related adverse health effect for chemicals identified as endocrine active; (c) identify the level of hazard associated with the plausibly related adverse effect(s); and (d) assign the final hazard level for endocrine activity using expert judgment and a weight of evidence approach.
IC2 and BizNGO classify chemicals as endocrine active using the following hazard levels: High Hazard = chemical on EU SVHC authorization list for endocrine activity; Moderate / Moderate or High Hazard = (1) indication of endocrine activity in scientific literature; (2) initial assignment of all chemicals with data suggesting endocrine activity associated with adverse effects; (3) listed for endocrine activity on Specified Lists, except EU SVHC list. Further review using scientific literature is required to confirm the list-based classifications (except EU SVHC list). Low Hazard = requires data for multiple endocrine pathways (e.g., androgenicity, anti-androgenicity, thyroid effects, estrogenicity, and anti-estrogenicity).
The frameworks modify the hazard level for endocrine activity from Moderate to High where there is a High (or very High) plausibly-related adverse effect for carcinogenicity, reproductive toxicity, developmental toxicity and/or systemic toxicity (repeated dose, typically thyroid). The endocrine activity level is not modified where an adverse health effect is not plausibly related.
The DfE and GreenScreen® guidance documents do not indicate whether the frameworks have developed (or use existing) guidance or criteria related specifically to identifying endocrine active chemicals to help ensure that the process is consistent and transparent. The use of hazard
identification guidance or criteria, developed a priori and modified as appropriate, may be particularly important for this end point, given the lack of validated tests and the developing nature of the science related to endocrine-related effects of chemicals and their potential adverse health impacts. For example, it is not clear how the various data resources are weighted regarding strength of what data, test results, or combination of test results provide sufficient evidence of endocrine activity.
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