SDSRP Practice - Rubric 4 Health Hazards

Three Rules of Toxicology

1) The dose (or exposure) makes the poison.

2) Chemicals cause specific [adverse] effects.

3) Results of testing using experimental animals are applicable to humans

Additive Health Hazard Categories

- Acute toxicity

- Skin irritation/corrosion (strong acids and bases)

- Eye irritation and serious eye damage

- STOT-SE Category 3 (respiratory tract irritation)

- STOT-SE Category 3 (narcotic effects)

- Aspiration hazard

Bridging Principles

- Dilution

- Batching

- Concentration of high toxic mixtures

- Interpolation within a toxicity class

- Substantially similar mixtures

Dilution

A tested mixture classified as Skin Sensitizer 1A is diluted with non-sensitizer. That mixture is classified as Skin Sensitizer 1A.

Principle of Toxicology: ADME

Absorption: Movement of chemicals across cell membranes and into the body

Distribution: Movement of chemicals within the body.

Metabolism: Biotransformation of chemicals; bioactivation and deactivation

Excretion: Removal of chemicals and/or metabolites from the body.

Dose-Response Relationship

There is a positive relationship between dose and response.

- As dose increases, so does the fraction of individuals within a population that respond or the magnitude of the effect in an individual organism.

Dose is the primary determinant of toxicity.

- A dose-response relationship is a critical element of a cause-effect relationship.

No-Observable-Effect Level (NOEL)

The highest exposure level in a study at which there are no statistically and biologically significant increases in frequency or severity of effects between the exposed population and its appropriate control.

No-Observable-Adverse-Effect Level (NOAEL)

The highest exposure level in a study at which there are no statistically and biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control (effects are produced at this level but are not considered adverse).

Lowest-Observable-Adverse-Effect Level (LOAEL)

The lowest exposure level in a study that produces statistically and biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control.

Immediate Effect

Effects seen within minutes of exposure

Example:

- Chemical burns from HCl

- Asphyxiation from cyanide

- Respiratory tract irritation from ammonia gas

Delayed Effect

Extended period between exposure and onset of adverse effects

Example:

- Asbestosis from asbestos

- Liver damage from carbon tetrachloride

- Cancer from bezene

Local Effect

Manifestation at the site of contact

Example:

- Ocular (eye) irritation from solvents and dilute acids

- Chemical burns of skin from sodium hydroxide

- Respiratory tract irritation from ammonia gas

System Effect

Manifestation at a distant site

Example:

- Renal (kidney) effects of mercury

- Ocular (eye) effects of methanol after ingestion

- Peripheral nervous system damage from n-hexane

Reversible Effect

Potential to reestablish normal structure, function, and capacity

Example:

- Anticholinergic effects of organophosphate insecticides

- Peripheral neuropathy from n-hexane (limited reversibility)

- Eye and skin irritation

Irreversible Effect

Permanent alterations in function, structure, or capacity

Example:

- Brain lesions from inhalation abuse of toluene

- Cirrhosis of the liver from chronic alcohol ingestion

Animal Testing - Three "R"s

Refinement

- Lower pain or distress

Reduction

- Lower numbers of animals

Replacement

- Work toward non-animal systems: in vitro, in chemico, in silico

Weight of Evidence

A system (or approach) for characterizing the extent to which the available data support the hypothesis that an agent causes an adverse health effect in humans.

- Evaluate positive, negative, and equivocal data.

- Approach is used in the GHS classification of most endpoints.

- Statistical and biological significance of the effects are relevant in evaluating study results.

Median Lethal Dose (LD50)

The single dose of a chemical that can be expected to cause death in 50% of the population.

- Usually expressed as mg chemical/kg body weight

Median Lethal Concentration (LC50)

The concentration of a chemical in the air that can be expected to cause death in 50% of the population.

- Usually expressed as ppm of the chemical in air (for gases) or mg/L of air (for vapors and dusts/mists).

- Need to know duration of exposure and the physical state of the chemical (gas, vapor, dust/mist).

Additivity Principle: Heath Hazards

If a mixture contains two or more ingredients with the same or similar hazards, the concentration of the hazardous ingredients shall be added.

- This assumes that each ingredient contributes to the overall toxicity of the mixture in proportion to its potency and concentration.

- Does not apply to non-additive hazard classes (Sensitizers, germ cell mutagens, carcinogens, reproductive toxicants)

Batching

A factory-made lot is tested and classified as Skin Irritant 2. Subsequent factory-made materials are also classified as Skin Irritant 2.

Concentration of High Toxic Mixtures

A tested mixture classified as Acute Toxicity 1 is concentrated. The concentrated mixture is classified as Acute Toxicity 1.

Interpolation within a Toxicity Class

Mixture A contains 25% of chemical X. Mixture B contains 50% of chemical X. Both mixtures are tested and are classified as Eye Irritant 2A. Untested mixture C contains 35% of chemical X. Mixture C is also classified as Eye Irritant 2A.

Substantially Similar Mixtures

A tested mixture (A) is classified as Skin Corrosive 1C due to one ingredient: Chemical Y. An untested mixture (B) contains "essentially the same" concentration of chemical Y, and the balance of ingredients in both mixtures are toxicologically equivalent. Untested Mixture B should also be classified as Skin Corrosive 1C.

Acute Toxicity Estimate (ATE)

Calculation performed if bridging principles cannot apply.

- Include all relevant ingredients with a known acute toxicity and which fall into any of the GHS acute toxicity categories.

- Ignore ingredients that are presumed not acutely toxic (e.g., water, sugar)

- Ignore ingredients if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure) AND do not show acute toxicity.

Skin Corrosion Category 1

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Skin Corrosion Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Skin Corrosion Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Skin Corrosion Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

Acute Toxicity Category 1

Oral: ATE ≤ 5 mg/kg (ATE 0.5)

Dermal: ATE ≤ 50 mg/kg (ATE 5)

Gases: ATE ≤ 100 ppmV (ATE 10)

Vapours: ATE ≤ 0.5 mg/l (ATE 0.05)

Dusts and Mists: ATE ≤ 0.05 mg/l (ATE 0.005)

Acute Toxicity Category 2

Oral: 5 < ATE ≤ 50 mg/kg (ATE 5)

Dermal: 50 < ATE ≤ 200 mg/kg (ATE 50)

Gases: 100 < ATE ≤ 500 ppmV (ATE 100)

Vapours: 0.5 < ATE ≤ 2.0 mg/l (ATE 0.5)

Dusts and Mists: 0.05 < ATE ≤ 0.5 mg/l (ATE 0.05)

Acute Toxicity Category 3

Oral: 50 < ATE ≤ 300 mg/kg (ATE 100)

Dermal: 200 < ATE ≤ 1000 mg/kg (ATE 300)

Gases: 500 < ATE ≤ 2500 ppmV (ATE 700)

Vapours: 2.0 < ATE ≤ 10 mg/l (ATE 3)

Dusts and Mists: 0.5 < ATE ≤ 1.0 mg/l (ATE 0.5)

Acute Toxicity Category 4

Oral: 300 < ATE ≤ 2000 mg/kg (ATE 500)

Dermal: 1000 < ATE ≤ 2000 mg/kg (ATE 500)

Gases: 2500 < ATE ≤ 20000 ppmV (ATE 4500)

Vapours: 10 < ATE ≤ 20 mg/l (ATE 11)

Dusts and Mists: 1.0 < ATE ≤ 5.0 mg/l (ATE 1.5)

Skin Irritation Category 2

a) Mean score of ≥ 2.3 and ≤ 4.0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48, and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

b) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or

c) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.

Serious Eye Damage Category 1

A substance that produces:

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 of normally 21 days; and/or

b) In at least 2 of 3 tested animals, a positive response of:

i) Corneal opacity ≥ 3; and/or

ii) Iritis > 1.5;

calculated as the mean scores following grading at 24, 48,

and 72 hours after instillation of the test material.

Eye Irritation Category 2/2A

Substances that produce in at least 2 of 3 tested animals a positive response of:

a) Corneal opacity ≥ 1; and/or

b) Iritis ≥ 1; and/or

c) Conjunctival redness ≥ 2; and/or

d) Conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48, and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

Eye Irritation Category 2B

Within Category 2A an eye irritant is considered mildly irritating to eyes (Category 2B) when the effects listed above are fully reversible within 7 days of observation.

Respiratory Sensitizer

A substance that will lead to hypersensitivity of the airways following inhalation of the substance.

Skin Sensitizer

A substance that will lead to an allergic response following skin contact with a substance.

Respiratory Sensitizer Category 1

A substance is classified as a respiratory sensitizer:

a) If there is evidence in humans that the substance can lead to specific respiratory hypersensitivity and/or

b) If there are positive results from an appropriate animal test.

Respiratory Sensitizer Sub-Category 1A

Substances showing 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. Severity of reaction may also be considered.

Respiratory Sensitizer Sub-Category 1B

Substances showing 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.

Skin Sensitizer Category 1 (Animal Test Results)

Local lymph node assay: SI ≥ 3

Local lymph node assay (DA): SI ≥ 1.8

Local lymph node assay (BrdU-ELISA): SI ≥ 1.6

Local lymph node assay (BrdU-FCM): SI ≥ 2.7

Adjuvant Guinea pig test method: ≥ 30% responding at any intradermal induction dose

Non-adjuvant Guinea pig test method: ≥ 15% responding at any topical induction dose

Skin Sensitizer Category 1A (Animal Test Results)

Local lymph node assay: EC3 value ≤ 2%

Guinea pig maximization test: ≥ 30% responding at ≤ 0.1% intradermal induction dose or ≥ 60% responding at > 0.1% to ≤ 1.0% intradermal induction dose

Buehler assay: ≥ 15% responding at ≤ 0.2% topical induction dose or ≥ 60% responding at > 0.2% to ≤ 20% topical induction dose

Skin Sensitizer Category 1B (Animal Test Results)

Local lymph node assay : EC3 value > 2%

Guinea pig maximization assay: ≥ 30% to < 60% responding at > 0.1% to ≤ 1% intradermal induction dose or ≥ 30% responding at > 1% intradermal induction dose

Buehler assay: ≥ 15% to < 60% responding at > 0.2% to ≤ 20% topical induction dose or ≥ 15% responding at > 20% topical induction dose.

Mutation

A permanent change in the amount or structure of the genetic material of a cell.

Germ Cell Mutagenicity Category 1

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans

Germ Cell Mutagenicity Category 1A

Substances known to induce heritable mutations in germ cells of humans

Germ Cell Mutagenicity Category 1B

Substances which should be regarded as if they induce heritable mutations in the gem cells of humans

a) Positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

b) Positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. This supporting evidence may, for example, be derived from mutagenicity/genotoxic tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

c) Positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

Germ Cell Mutagenicity Category 2

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans.

Positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

a) Somatic cell mutagenicity tests in vivo, in mammals; or

b) Other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Germ Cell Mutagenicity Classification Note

Substances which are positive in in vitro mammalian mutagenicity assays, and which also show structure activity relationship to known germ cell mutagens, should be considered for classification as Category 2 mutagens.

Carcinogenicity: Factors that affect level of concern

- Tumor type and background incidence

- Reduced tumor latency

- Whether responses are in single or both sexes

- Whether responses are in single or multiple species

- Route of exposure used in animal studies

- Comparison of ADME between humans and animals

- Mode of action in animals and its relevance to humans

Carcinogenicity Category 1

Known or presumed human carcinogen

Carcinogenicity Category 1A

Known to have carcinogenic potential for humans; the placing of the substance is largely based on human evidence.

Carcinogenicity Category 1B

Presumed to have carcinogenic potential for humans; the placing of a substance is largely based on animal evidence.

Carcinogenicity Category 2

Suspected human carcinogens

Reproductive Toxicity

includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

Reproductive Toxicity Category 1

Known or presumed human reproductive toxicant.

Reproductive Toxicity Category 1A

Known human reproductive toxicant; the placing of the substance in this category is largely based on evidence from humans.

Reproductive Toxicity Category 1B

Presumed human reproductive toxicant; the placing of this substance in this category is largely based on evidence from experimental animals.

Reproductive Toxicity Category 2

Suspected human reproductive toxicant; category includes substances for which there is some evidence from humans or experimental animals, but whose studies may contain deficiencies in quality

Effects on or Via Lactation

Hazard allocated to a separate single category. Substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of the breastfed child.

Classification can be assigned on the basis of:

a) Absorption, metabolism, distribution, and excretion studies that would indicate the likelihood the substance would be present in potentially toxic levels in breast milk; and/or

b) Results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

c) Human evidence indicating a hazard to babies during the lactation period.

STOT Single Exposure Category 1

Substances that have produced significant toxicity in humans, or that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to product significant toxicity in humans following single exposure.

STOT Single Exposure Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure.

STOT Single Exposure Category 3

Transient target organ effects. This category only includes narcotic effects and respiratory tract irritation.

A cut-off concentration limit of 20% has been suggested.

Toxic Effects Considered to Support Classification (STOT SE)

- Morbidity from a single exposure

- Significant functional changes in organs or organ systems

- Consistent significant adverse changes in clinical biochemistry, hematology, or urinalysis parameters

- Significant organ damage noted at necropsy

- Multifocal or diffuse necrosis, fibrosis, or granuloma formation in vital organs with regenerative capacity

- Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction

- Evidence of appreciable cell death in vital organs incapable of regeneration

Toxic Effects Considered NOT to Support Classification (STOT SE)

- Lethal effects

- Clinical observations or small changes in body weight, food/water intake... that do not indicate significant toxicity

- Small changes in clinical biochemistry, hematology, or urinalysis parameters

- Changes in organ weights with no evidence of dysfunction

- Adaptive responses that are not considered toxicologically relevant

- Effects via substance-induced species-specific mechanism of toxicity not relevant to human health

STOT Repeated Exposure Category 1

Substances that have produced significant toxicity in humans, or that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

STOT Repeated Exposure Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Toxic Effects Considered to Support Classification (STOT RE)

- Morbidity or death from a repeated or long-term exposure

- Significant functional changes in organs or organ systems

- Consistent significant adverse changes in clinical biochemistry, hematology, or urinalysis parameters

- Significant organ damage noted at necropsy

- Multifocal or diffuse necrosis, fibrosis, or granuloma formation in vital organs with regenerative capacity

- Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction

- Evidence of appreciable cell death in vital organs incapable of regeneration

Toxic Effects Considered to NOT Support Classification (STOT RE)

- Secondary effects

- Clinical observations or small changes in body weight, food/water intake... that do not indicate significant toxicity

- Small changes in clinical biochemistry, hematology, or urinalysis parameters and/or transient effects of doubtful or minimal importance

- Changes in organ weights with no evidence of dysfunction

- Adaptive responses that are not considered toxicologically relevant

- Effects via substance-induced species-specific mechanism of toxicity not relevant to human health

STOT RE Category 1 - LOAEL Guidance values

Based on results of 90-day test

Oral (rat): ≤ 10 mg/kg mw/d

Dermal (rat or rabbit): ≤ 20 mg/kg mw/d

Inhalation (rat) gas: ≤ 50 ppmV/6h/d

Inhalation (rat) vapour: ≤ 0.2 mg/liter/6h/d

Inhalation (rat) dust/mist/fume: ≤ 0.02 mg/liter/6h/d

STOT RE Category 2 - LOAEL Guidance values

Based on results of 90-day test

Oral (rat): 10 < C ≤ 100 mg/kg mw/d

Dermal (rat or rabbit): 20 < C ≤ 200 mg/kg mw/d

Inhalation (rat) gas: 50 < ≤ 250 ppmV/6h/d

Inhalation (rat) vapour: 0.2 ≤ 1.0 mg/liter/6h/d

Inhalation (rat) dust/mist/fume: 0.02 ≤ 0.2 mg/liter/6h/d

Aspiration Category 1

Chemicals known to cause human aspiration toxicity hazard or to be regarded as if they cause human aspiration toxicity hazard.

Classified in Category 1:

a) Based on reliable and good quality human evidence; or

b) If it is a hydrocarbon and has a kinematic viscosity of ≤ 20.5 mm²/s, measured at 40 °C.

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