The combination of the toxic effects of two substances may be significantly greater than the toxic effect of either substance alone.

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1 Summary 4 Chapter 3 Prudent Practices, p also 1. Week 4, paper 1 An Introduction to Toxicology 2. Safety in Academic Chemistry Labs (SACL), P. 1, Toxicology is the study of chemicals that can cause harm to organisms by chemical action and the ways in which harm is caused. The risk of toxic effects is related to both the extent of exposure and the inherent toxicity of a chemical. Harm may be due to: poisoning, tissue destruction (ex. acid burn), contaminated air, displacement of oxygen (ex CO), injury after being absorbed through intact skin or through a cut, injury by penetrating through orifices (ear eye socket, etc.) Exposure: The extent of exposure is determined by the dose, the duration and frequency of exposure, and the route of exposure. For most substances, the route of exposure (through the skin, the eyes, the gastrointestinal tract, or the respiratory tract) is also an important consideration in risk assessment. In the case of chemicals that are systemic toxicants, the internal dose to the target organ is a critical factor. The combination of the toxic effects of two substances may be significantly greater than the toxic effect of either substance alone. Dose For all substance the toxicity depends on the dose One way to evaluate the acute toxicity (i.e., the toxicity occurring after a single exposure) of laboratory chemicals involves consideration of their lethal dose 50 (LD 50 ) or lethal concentration 50 (LC 50 ) value. The LD 50 is defined as the amount of a chemical that when ingested, injected, or applied to the skin of a test animal under controlled laboratory conditions will kill one half (50%) of the animals. The LD 50 is usually expressed in units of milligrams or grams per kilogram of body weight. See Table 3.1. Duration and Frequency of Exposure Toxic effects of chemicals can occur after single (acute), intermittent (repeated), or long term, repeated (chronic) exposure. An acutely toxic substance can cause damage as the result of a single, short duration exposure. Chronic toxins include all carcinogens, reproductive toxins, and certain heavy metals (e.g., mercury, lead) and their compounds. Many chronic toxins are extremely dangerous because of their long latency periods: the cumulative effect of low exposures to such substances may not become apparent for many years. Routes of Exposure Exposure to chemicals in the laboratory can occur by several different routes: (1) inhalation odorless gases, dusts, mists, gases, vapors the most rapid means of entry into the body, causing harmful effects most rapidly. Predominant route of exposure to toxic substances lungs are 75 m 2 of surface area. Gases or vapors that are highly water soluble, such as methanol, acetone, hydrogen chloride, and ammonia, dissolve predominantly in the lining of the nose and windpipe (trachea) and therefore tend to be absorbed from those regions. Reactive gases with low water solubility, such as ozone, phosgene, and nitrogen dioxide, penetrate farther into the respiratory tract and thus come into contact with the smaller tubes of the airways.

2 Gases and vapors that are not water soluble but are more fat soluble, such as benzene, methylene chloride, and trichloroethylene, are not completely removed by interaction with the surfaces of the nose, trachea, and small airways. As a result, these gases penetrate the airways down into the deep lung, where they can diffuse across the thin lung tissue into the blood. The more soluble a gas is in the blood, the more of it will be dissolved and transported to other organs Inhaled solid chemicals if and where a particle will be deposited in the respiratory tract depends on its size. One generalization is that the largest particles (³5 microns (µm)) are deposited primarily in the nose, smaller particles (1 to 5 µm) in the trachea and small airways, and the smallest particles in the lungs. Particles that are water soluble will dissolve within minutes or days, and chemicals that are not watersoluble but have a moderate degree of fat solubility will also clear rapidly into the blood. Those that are not water soluble or highly fat soluble will not dissolve and will be retained in the lungs for long periods of time. Metal oxides, asbestos, and silica are examples of water insoluble inorganic particles that might be retained in the lungs for years. Factors which affect the airborne concentrations of chemicals. 1. Vapor pressure the tendency to form vapor. Vapor pressure increases as temperature increases. However, even if a substance has a low VP if it is very toxic it can cause harm 2. Find dusts and aerosols tend to remain ariborne (2) contact with skin or eyes may be slow so individual is unaware. Faster through a cut May cause skin irritation and allergic skin reactions. Many chemicals are absorbed through the skin in sufficient quantity to produce toxicity (principle of the patch). (3) ingestion don t eat or drink in the lab. Toxins that enter the gastrointestinal tract must be absorbed into the blood to produce a systemic injury. More chemical will be absorbed if the chemical remains in the intestine for a long time. If a chemical is in a relatively insoluble, solid form, it will have limited contact with gastrointestinal tissue, and its rate of absorption will be low. If it is an organic acid or base, it will be absorbed in that part of the gastrointestinal tract where it is most fat soluble. Fat soluble chemicals are absorbed more rapidly and extensively than water soluble chemicals. (4) injection sharp edges of broken glass intravenous route of administration is especially dangerous because it introduces the toxins directly into the bloodstream. Custodial workers or waste handlers, must be protected from this form of exposure by putting all "sharps" in special trash containers. (5) other orifices in the body eyes to bloodstream or nose or mouth Types of Toxins Exposure to a harmful chemical can result in local toxic effects, systemic toxic effects, or both. Local effects involve injury at the site of first contact. Systemic effects, by contrast, occur after the toxicant has been absorbed from the site of contact into the bloodstream and distributed throughout the body. Toxic effects can be further classified as reversible or irreversible. Irritants

3 Irritants are noncorrosive chemicals that cause reversible inflammatory (swelling and redness) at the site of contact. Corrosive Substances Corrosive substances cause destruction of living tissue by chemical action at the site of contact and can be solids, liquids, or gases. Corrosive effects can occur not only on the skin and eyes, but also in the respiratory tract and, in the case of ingestion, in the gastrointestinal tract as well. Corrosive liquids strong acids and HF, bromine, strong bases, strong ammonia solutions, strong dehydrating agents such as phosphorous pentoxide and calcium oxide, strong oxidizing agents such as hydrogen peroxide, etc. Corrosive gases chlorine ammonia, nitrogen dioxide Corrosive solids phenol, sodium hydroxide pellets, phosphorous Allergens A chemical allergy is an adverse reaction by the immune system to a chemical. Such allergic reactions result from previous sensitization to that chemical or a structurally similar chemical. Once sensitization occurs, allergic reactions can result from exposure to extremely low doses of the chemical. Allergic reactions can be immediate, occurring within a few minutes after exposure. Anaphylactic shock is a severe immediate allergic reaction that can result in death if not treated quickly. Examples of substances that may cause allergic reactions in some individuals include diazomethane, dicyclohexylcarbodiimide, formaldehyde, various isocyanates, benzylic and allylic halides, and certain phenol derivatives. Asphyxiants Asphyxiants are substances that interfere with the transport of an adequate supply of oxygen to the vital organs of the body. The brain is the organ most easily affected by oxygen starvation, and exposure to asphyxiants can lead to rapid collapse and death. Simple asphyxiants are substances that displace oxygen from the air being breathed to such an extent that adverse effects result. Acetylene, carbon dioxide, argon, helium, ethane, nitrogen, and methane are common asphyxiants. Carcinogens A carcinogen is a substance capable of causing cancer. The current thinking is that some chemicals interact directly with DNA to produce permanent alterations. Carcinogens are chronically toxic substances. Reproductive and Developmental Toxins Reproductive toxins are substances that have adverse effects on various aspects of reproduction, including fertility, gestation, lactation, and general reproductive performance. Developmental toxins are substances that act during pregnancy to cause adverse effects on the embryo or fetus. Male reproductive toxins can in some cases lead to sterility. Two well known male reproductive toxins are ethylene dibromide and dibromochloropropane. Neurotoxins Neurotoxic chemicals can induce an adverse effect on the structure or function of the central and/or peripheral nervous system, which can be permanent or reversible.

4 Toxins Affecting Other Organs Target organs outside the reproductive and neurological systems can also be affected by toxic substances found in the laboratory. Most of the chlorinated hydrocarbons, benzene, other aromatic hydrocarbons, some metals, carbon monoxide, and cyanides, among others, can produce one or more effects in target organs. Phototoxicity local irritation when a chemical is exposed to sunlight Assessing Risks Due to the Toxic Effects of Laboratory Chemicals 1. Select Carcinogens 2. Acute Toxicity 3. Corrosive 4. Flammable Explosive Acute Toxicants Acute toxicity is the ability of a chemical to cause a harmful effect after a single exposure. Acutely toxic agents can cause local toxic effects, systemic toxic effects, or both, and this class of toxicants includes corrosive chemicals, irritants, and allergens (sensitizers). Among the most useful parameters for assessing the risk of acute toxicity of a chemical are its LD 50 and LC 50 values, selected with due regard for the possible routes of exposure ACGIH TLV; The TLV TWA (threshold limit value time weighted average) refers to the concentration safe for exposure during an entire 8 h workday, while the TLV STEL (threshold limit value short term exposure limit) is a higher concentration to which workers may be exposed safely for a 15 min period. OSHA defines the permissible exposure limit (PEL) Corrosive Substances, Irritants, and Allergens special attention should be paid to the identification of irritant chemicals by consulting LCSSs, MSDSs, and other sources of information. Carcinogens known to pose the greatest carcinogenic hazard; are referred to as "select carcinogens," and they constitute another category of substances that must be handled as "particularly hazardous substances" according to the OSHA Laboratory Standard. See tables. 3.4 and 3.5. Reproductive and Developmental Toxins Reproductive toxins are defined by the OSHA Laboratory Standard as substances that cause chromosomal damage (mutagens) and substances with lethal or teratogenic (malformation) effects on fetuses defects. Embryotoxins have the greatest impact during the first trimester of pregnancy. FLAMMABLE, REACTIVE, AND EXPLOSIVE HAZARDS In addition to the hazards due to the toxic effects of chemicals, hazards due to flammability, explosibility, and reactivity need to be considered in risk assessment. Flammable Substances Flammable substances, those that readily catch fire and burn in air, may be solid, liquid, or gaseous. The most common fire hazard in the laboratory is a flammable liquid or the vapor produced from such a liquid. For a fire to occur, three conditions must exist simultaneously: an oxidizing atmosphere, usually air; a

5 concentration of flammable gas or vapor that is within the flammable limits of the substance; and a source of ignition. Flammability Characteristics Flash Point The flash point is the lowest temperature at which a liquid has a sufficient vapor pressure to form an ignitable mixture with air near the surface of the liquid. Note that many common organic liquids have a flash point below room temperature: for example, acetone ( 18 C), benzene ( 11.1 C), diethyl ether ( 45 C). Ignition Temperature The ignition temperature (autoignition temperature) of a substance, whether solid, liquid, or gaseous, is the minimum temperature required to initiate or cause self sustained combustion independent of the heat source. The lower the ignition temperature, the greater the potential for a fire started by typical laboratory equipment. A spark is not necessary for ignition when the flammable vapor reaches its autoignition temperature Limits of Flammability Each flammable gas and liquid (as a vapor) has two fairly definite limits of flammability defining the range of concentrations in mixtures with air that will propagate a flame and cause an explosion. At the low extreme, the mixture is oxygen rich but contains insufficient fuel. The lower flammable limit (lower explosive limit (LEL)) is the minimum concentration (percent by volume) of the fuel (vapor) in air at which a flame is propagated when an ignition source is present. The upper flammable limit (upper explosive limit (UEL)) is the maximum concentration (percent by volume) of the vapor in air above which a flame is not propagated. Classes of Flammability Several systems are in use for classifying the flammability of materials. Some (e.g., Class I flammable liquid, etc.) apply to storage or transportation considerations. Another (Class A, B, C paper, liquid, electrical fire) concerns the type of fire extinguisher to be used Causes of Ignition Spontaneous Combustion Spontaneous ignition (autoignition) or combustion takes place when a substance reaches its ignition temperature without the application of external heat. Examples of materials susceptible to spontaneous combustion include oily rags, dust accumulations, organic materials mixed with strong oxidizing agents (e.g., nitric acid, chlorates, permanganates, peroxides, and persulfates), alkali metals (e.g., sodium and potassium), finely divided pyrophoric metals, and phosphorus. Ignition Sources Potential ignition sources in the laboratory include the obvious torch and Bunsen burner, as well as a number of less obvious, electrically powered, sources The vapors of most flammable liquids are heavier than air and capable of traveling considerable distances. There are many sources of static electricity, particularly in cold, dry atmospheres, and caution should be exercised. Oxidants Other Than Oxygen

6 The most familiar fire involves a combustible material burning in air. However, the oxidant driving a fire or explosion need not be oxygen itself, depending on the nature of the reducing agent Special Hazards Compressed or liquefied gases present hazards in the event of fire because the heat will cause the pressure to increase and the container may rupture Reactive Hazards 3.D.2.1 Water Reactives Water reactive materials are those that react violently with water. Alkali metals (e.g., lithium, sodium, and potassium), many organometallic compounds, and some hydrides react with water to produce heat and flammable hydrogen gas, which can ignite or combine explosively with atmospheric oxygen. Some anhydrous metal halides (e.g., aluminum bromide), oxides (e.g., calcium oxide), and nonmetal oxides (e.g., sulfur trioxide) and halides (e.g., phosphorus pentachloride) react exothermically with water, and the reaction can be violent if there is insufficient coolant water to dissipate the heat produced. Pyrophorics For pyrophoric materials, oxidation of the compound by oxygen or moisture in air proceeds so rapidly that ignition occurs. Many finely divided metals are pyrophoric, and their degree of reactivity Incompatible Chemicals Accidental contact of incompatible substances could result in a serious explosion or the formation of substances that are highly toxic or flammable or both. Explosives An explosive is any chemical compound or mechanical mixture that, when subjected to heat, impact, friction, detonation, or other suitable initiation, undergoes rapid chemical change, evolving large volumes of highly heated gases that exert pressure on the surrounding medium. Table 3.11 lists a number of explosive compounds. Organic peroxides are among the most hazardous substances handled in the chemical laboratory. They are generally low power explosives that are sensitive to shock, sparks, or other accidental ignition. Dusts Suspensions of oxidizable particles (e.g., flour, coal dust, magnesium powder, zinc dust, carbon powder, and Explosive Boiling Not all explosions result from chemical reactions. A dangerous, physically caused explosion can occur if a hot liquid or a collection of very hot particles comes into sudden contact with a lower boiling point material. Sudden boiling eruptions occur when a nucleating agent (e.g., charcoal, ''boiling chips") is added to a liquid heated above its boiling point.

7 TABLE 3.1 Acute Toxicity Hazard Level Hazard Toxicity Oral LD 50 Skin Contact LD 50 Inhalation LC 50 (Rats, Inhalation LC 50 (Rats, Level Rating (Rats, per kg) (Rabbits, per kg) ppm for 1 h) mg/m 3 for 1 h) High Highly toxic <50 mg <200 mg <200 <2,000 Medium Moderately toxic 50 to 500 mg 200 mg to 1 g 200 to 2,000 2,000 to 20,000 Low Slightly toxic 500 mg to 5 g 1 to 5 g 2,000 to 20,000 20,000 to 200,000 TABLE 3.2 Probable Lethal Dose for Humans Toxicity Rating Animal LD 50 (per kg) Lethal Dose When Ingested by 70 kg (150 lb) Human Extremely toxic Less than 5 mg A taste (less than 7 drops) Highly toxic 5 to 50 mg Between 7 drops and 1 teaspoonful Moderately toxic 50 to 500 mg Between 1 teaspoonful and 1 ounce Slightly toxic 500 mg to 5 g Between 1 ounce and 1 pint Practically nontoxic Above 5 g Above 1 pint SOURCE: Modified, by permission, from Gosselin et al. (1984). Copyright 1984 by Williams & Wilkins, Baltimore. TABLE 3.4 Examples of Select Carcinogens 2 Acetylaminofluorene Dimethyl sulfate Acrylamide Ethylene dibromide Acrylonitrile Ethylene oxide Aflatoxins Ethylenimine 4 Aminobiphenyl Formaldehyde Arsenic and certain arsenic compounds Hexamethylphosphoramide Asbestos Hydrazine Azathioprine Melphalan Barium chromate 4,4' Methylene bis[2 chloroaniline] Benzene Mustard gas (bis(2 chloroethyl)sulfide) Benzidine N,N Bis(2 chloroethyl) 2 naphthylamine Bis(chloromethyl)ether (chloraphazine) 1,4 Butanediol dimethylsulfonate (myleran) a Naphthylamine Chlorambucil ß Naphthylamine Chloromethyl methyl ether Nickel carbonyl Chromium and certain chromium compounds 4 Nitrobiphenyl Cyclophosphamide N Nitrosodimethylamine 1,2 Dibromo 3 chloropropane ß Propiolactone 3,3' Dichlorobenzidine (and its salts) Thorium dioxide Diethylstilbestrol Treosulfan 4 Dimethylaminoazobenzene Vinyl chloride NOTE: Compounds on this list are classified as select carcinogens on the basis of OSHA Laboratory Standard criteria. See accompanying text for details.

8 TABLE 3.5 Classes of Carcinogenic Substances Alkylating agents a Halo ethers Bis(chloromethyl) ether Methyl chloromethyl ether Sulfonates 1,4 Butanediol dimethanesulfonate (myleran) Diethyl sulfate Dimethyl sulfate Ethyl methanesulfonate Methyl methanesulfonate Methyl trifluoromethanesulfonate 1,3 Propanesultone Epoxides Ethylene oxide Diepoxybutane Epichlorohydrin Propylene oxide Styrene oxide Aziridines Ethylenimine 2 methylaziridine Diazo, azo, and azoxy compounds 4 Dimethylaminoazobenzene Electrophilic alkenes and alkynes Acrylonitrile Acrolein Ethyl acrylate Acylating agents ß Propiolactone ß Butyrolactone Dimethylcarbamyl chloride Organohalogen compounds 1,2 Dibromo 3 chloropropane Mustard gas (bis(2 chloroethyl)sulfide) Vinyl chloride Carbon tetrachloride Chloroform 3 Chloro 2 methylpropene 1,2 Dibromoethane 1,4 Dichlorobenzene 1,2 Dichloroethane 2,2 Dichloroethane 1,3 Dichloropropene Hexachlorobenzene Methyl iodide Tetrachloroethylene Trichloroethylene 2,4,6 Trichlorophenol Hydrazines Hydrazine (and hydrazine salts) 1,2 Diethylhydrazine 1,1 Dimethylhydrazine 1,2 Dimethylhydrazine N Nitroso compounds N Nitrosodimethylamine N Nitroso N alkylureas Aromatic amines 4 Aminobiphenyl Benzidine (4, 4' diaminobiphenyl) a Naphthylamine ß Naphthylamine Aniline o Anisidine (2 methoxyaniline) 2,4 Diaminotoluene o Toluidine Aromatic hydrocarbons Benzene Benz[a]anthracene Benzo[a]pyrene Natural products (including antitumor drugs) Adriamycin Aflatoxins Bleomycin Cisplatin Progesterone Reserpine Safrole Miscellaneous organic compounds Formaldehyde (gas) Acetaldehyde 1,4 Dioxane Ethyl carbamate (urethane) Hexamethylphosphoramide 2 Nitropropane Styrene Thiourea Thioacetamide Miscellaneous inorganic compounds Arsenic and certain arsenic compounds Chromium and certain chromium compounds Thorium dioxide Beryllium and certain beryllium compounds Cadmium and certain cadmium compounds Lead and certain lead compounds Nickel and certain nickel compounds Selenium sulfide

9 TABLE 3.8 Examples of Oxidants Gases: fluorine, chlorine, ozone, nitrous oxide, steam, oxygen hydrogen peroxide, nitric acid, perchloric acid, bromine, sulfuric acid, water Liquids: Solids: nitrites, nitrates, perchlorates, peroxides, chromates, dichromates, picrates, permanganates, hypochlorites, bromates, iodates, chlorites, chlorates

10 TABLE 3.9 Partial List of Incompatible Chemicals (Reactive Hazards) Substances in the left hand column should be stored and handled so that they cannot accidentally contact corresponding substances in the right hand column under uncontrolled conditions. Acetic acid Chromic acid, nitric acid, peroxides, permanganates Acetic anhydride Hydroxyl containing compounds such as ethylene glycol, perchloric acid Acetone Concentrated nitric and sulfuric acid mixtures, hydrogen peroxide Acetylene Chlorine, bromine, copper, silver, fluorine, mercury Alkali and alkaline earth metals, such as Carbon dioxide, carbon tetrachloride, other chlorinated sodium, potassium, lithium, magnesium, hydrocarbons (also prohibit the use of water, foam, and dry calcium, powdered aluminum chemical extinguishers on fires involving these metals dry sand should be employed) Ammonia (anhydrous) Mercury, chlorine, calcium hypochlorite, iodine, bromine, hydrogen fluoride Ammonium nitrate Acids, metal powders, flammable liquids, chlorates, nitrites, sulfur, finely divided organics, combustibles Aniline Nitric acid, hydrogen peroxide Bromine Ammonia, acetylene, butadiene, butane, other petroleum gases, sodium carbide, turpentine, benzene, finely divided metals Calcium oxide Water Carbon, activated Calcium hypochlorite, other oxidants Chlorates Ammonium salts, acids, metal powders, sulfur, finely divided organics, combustibles Chromic acid and chromium trioxide Acetic acid, naphthalene, camphor, glycerol, turpentine, alcohol, other flammable liquids Chlorine Ammonia, acetylene, butadiene, butane, other petroleum gases, hydrogen, sodium carbide, turpentine, benzene, finely divided metals Chlorine dioxide Ammonia, methane, phosphine, hydrogen sulfide Copper Acetylene, hydrogen peroxide Fluorine Isolate from everything Hydrazine Hydrogen peroxide, nitric acid, any other oxidant Hydrocarbons (benzene, butane, Fluorine, chlorine, bromine, chromic acid, peroxides propane, gasoline, turpentine, etc.) Hydrocyanic acid Nitric acid, alkalis Hydrofluoric acid (anhydrous) Ammonia (aqueous or anhydrous) Hydrogen fluoride

11 Hydrogen Copper, chromium, iron, most metals or their salts, any flammable liquid, combustible peroxide materials, aniline, nitromethane Hydrogen sulfide Fuming nitric acid, a oxidizing gases Iodine Acetylene, ammonia (anhydrous or aqueous) Mercury Acetylene, fulminic acid,a ammonia Nitric acid Acetic acid, acetone, alcohol, aniline, chromic acid, hydrocyanic acid, hydrogen sulfide, (concentrated) flammable liquids, flammable gases, nitratable substances Nitroparaffins Inorganic bases, amines Oxalic acid Silver and mercury and their salts Oxygen Oils, grease, hydrogen, flammable liquids, solids, gases Perchloric acid Acetic anhydride, bismuth and its alloys, alcohol, paper, wood, grease, oils (all organics) Peroxides, organic Acids (organic or mineral), (also avoid friction, store cold) Phosphorus Air, oxygen (white) Phosphorus Alcohols, strong bases, water pentoxide Potassium chlorateacids (see also chlorates) Potassium Acids (see also perchloric acid) perchlorate Potassium Glycerol, ethylene glycol, benzaldehyde, sulfuric acid permanganate Silver and silver Acetylene, oxalic acid, tartaric acid, fulminic acid, a ammonium compounds salts Sodium See alkali metals (above) Sodium nitrite Ammonium nitrate and other ammonium salts Sodium peroxide Any oxidizable substance, such as ethanol, methanol, glacial acetic acid, acetic anhydride, benzaldehyde, carbon disulfide, glycerol, ethylene glycol, ethyl acetate, methyl acetate, furfural Sulfuric acid Chlorates, perchlorates, permanganates a Produced in nitric acid ethanol mixtures. SOURCE: Reproduced, by permission, from Hazards in the Chemical Laboratory, 4th edition, L. Bretherick, Ed. (1986).

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