© Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 1 Topic 2 Toxic Chemicals and Toxic Effects Objectives After studying this topic you should:  Be able to find and use various sources of toxicological data including RTECS, Cheminfo.  Know how to read a MSDS.  Understand the main types of toxic effects, sites of toxic action and their time courses.  Be aware of the main methods of measuring toxicity, including the use of in-vivo and in-vitro testing.  Know the terminology applied to different types of toxic effects including LD50 and LC50.  Be familiar with "risk phrases" used for toxic substances. Contents 2.1 Introduction ...................................................................................................................... 1 2.2 Data on Toxic Substances .............................................................................................. 2 2.3 Toxic Effects .................................................................................................................... 4 2.3.1 Site of toxic action ........................................................................................................ 4 2.3.2 Types of toxic effects ............................................................................................... 5 2.3.3 Time course of toxic effects ..................................................................................... 6 2.4 Measurement of Toxicity ................................................................................................. 7 2.4.1 Animal testing (in-vivo)............................................................................................. 7 2.4.2 Non-animal tests (in-vitro) ........................................................................................ 8 2.5 Toxicity and “Risk Phrases” ............................................................................................ 9 Key concepts and Information ............................................................................................... 9 References .......................................................................................................................... 10 Acknowledgment ................................................................................................................. 10 Appendix 1. Extracts from a typical Material Safety Data Sheet (MSDS). .......................... 11 2.1 Introduction In Topic 1 we learned that all chemicals are potentially toxic, depending on their dose. Some chemicals are much more toxic than others which means that the dose required to cause harm is much less. For example it requires several hundred grams of pure alcohol (ethanol) to kill an average human, but less than a milligram of ricin* is fatal. Hence, ricin is several hundred thousand times more toxic that ethanol. *Ricin is a two-chain protein obtained from castor beans. It is extremely poisonous as a result of being able to enter cells and block protein synthesis. http://www.ansci.cornell.edu/plants/toxicagents/ricin (Please let us know if this, or any other web address in the notes, does not work and we will try to provide a new link. Organisations often change their web sites and while we try to keep our information current we cannot always update our notes immediately). © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 2 Whenever we are dealing with the potential toxic effects of a substance there are certain key pieces of information that are required in order to assess the risk, including, how it gets into a person or animal, what toxic effects it has, how long they take to occur and what dose is required to cause those effects. In this topic we will examine how we can obtain toxicity data and learn about the main types of toxic effects, their time course, and measures of toxicity. 2.2 Data on Toxic Substances There are a vast number of chemical substances and this presents us with a daunting challenge when dealing with their toxicity. Little direct information is available on the toxicity of most known chemical substances. Of the 5 million or so known chemical substances only around 8,000 (0.16%) have been adequately tested toxicologically (table 2.1). Table 2.1 —The number of known and toxicologically uncharacterised chemicals is very large. number of chemicals in ACS register* ~5,000,000 number of chemicals which are in ‘common use’ worldwide** ~60,000 number of chemicals in ‘common use’ in Australia***. ~30,000 number of chemicals tested adequately for toxicity ~8,000 number of new chemicals identified or synthesised each year ~1,000 number of chemicals known to cause cancer in test animals ~800 number of chemicals known as human carcinogens ~100  ACS register = American Chemical Society, Chemical Abstracts *  US Food and Drugs Administration (FDA) Environment Protection Agency (EPA) *  Worksafe Australia * Information on toxic chemicals is available from a number of sources. The best source of information on toxic chemicals is the general scientific literature. However, there are thousands of research papers on many chemicals and it is difficult and time consuming to track these down and summarise them. Fortunately, for several thousand of the more important toxic chemicals summaries have already been written and they are the best starting point. We will mention three of these here: Registry of Toxic Effects of Chemical Substances (RTECS), CHEMINFO and Material Safety data Sheets (MSDS). RTECS Summary information on several thousand chemicals is available on databases such as the Registry of Toxic Effects of Chemical Substances (RTECS) supported by the US Centre for Disease Control and Prevention. Registry of Toxic Effects of Chemical Substances (RTECS) RTECS is a compendium of data extracted from the open scientific literature. The data are recorded in the format developed by the RTECS staff and arranged in alphabetical order by prime chemical name. Six types of toxicity data are included in the file: (1) primary irritation; (2) mutagenic effects; (3) reproductive effects; (4) tumorigenic effects; (5) acute toxicity; and (6) other multiple dose toxicity. Specific numeric toxicity values such as LD50, LC50, TDLo, and TCLo (Note*) are noted as well as species studied and route of administration used. For each citation, the bibliographic source is listed thereby enabling the user to access the actual studies cited. No attempt has been made to evaluate the studies cited in RTECS. The user has the responsibility of making such assessments. http://www.cdc.gov/niosh/rtecs/default.html. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 3 (Note* these terms are described later in this topic) A typical RTECS entry for a single substance contains many lines of information in a table, each one of which contains a very brief summary of a research finding. A single entry for benzene is shown below. RTECS can be accessed through the Deakin University Library. Type of Test Route of Exposure Species Observed Dose Data Reaction Severity Reference LD50 - Lethal dose, 50 percent kill Oral Rodent - mouse 4700 mg/kg Details of toxic effects not reported other than lethal dose value HYSAAV Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964- 71. Discontinued. Volume (issue)/page/year: 32(3), 349, 1967 There are many other entries in RTECS table for benzene and as you can see they are very brief. It is necessary to obtain the original references if full details are required. CHEMINFO Another useful database is CHEMINFO which contains information on about 1,300 chemicals used in industry. CHEMINFO contains much more information than RTECS, but it does not contain references to all the sources of information that are summarised in the database. Extract of CHEMINFO Entry for Benzene showing just the Effects of Acute Exposure Inhalation: Short-term exposure causes depression of the central nervous system (CNS), marked by drowsiness, dizziness, headache, nausea, loss of coordination, confusion and unconsciousness. No effects are expected at 25 ppm. Exposure to 50 to 150 ppm produces headache, and tiredness.(4) Nose and throat irritation have also been reported following short-term exposure. A period of feeling excited or giddy may precede the onset of other symptoms. Exposure to approximately 20,000 ppm for 5 to 10 minutes may result in death.(1,8) In general, blood and immune system effects have not been documented in humans following short-term exposures, although these effects have been seen in animals. A 1992 report describes blood system effects in workers exposed to high levels of benzene (estimated to be above 60 ppm) for several days. In addition to CNS symptoms experienced during the exposure, 9 of the 15 workers had at least 1 blood system abnormality when followed up 4 months later. One year later, 6 workers still had changes in the blood system (numerous large granular lymphocytes).(8) Skin Contact: Animal evidence has shown that benzene is moderately irritating. Human studies have demonstrated that absorption of liquid benzene or its vapours occurs only to a small extent, but can contribute to overall exposure.(1) There are no reports of skin sensitization. Eye Contact: The vapour can be irritating to the eyes.(8) Animal evidence indicates that splashes of benzene in the eyes will be moderately irritating but will not cause permanent injury. Ingestion: Benzene is readily absorbed following ingestion producing CNS depression with symptoms as described under inhalation.(1,3) There are no human reports of blood or immune system effects resulting from ingestion, although these effects have been observed in animal experiments. In one case report, accidental ingestion and/or attempted suicide with benzene produced pneumonitis (probably caused by aspiration of benzene into the lungs) as one of the symptoms.(1) Based on this observation, the physical properties (viscosity and surface tension) and the fact that benzene is a petroleum distillate, benzene can probably be aspirated. Aspiration is the inhalation of a material into the lungs during ingestion or vomiting. Severe lung irritation, damage to the lung tissues and death may result. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 4 MSDS Yet another source of information on toxic chemicals are the Material Safety Data Sheets provided by manufacturers and suppliers of chemicals. Companies that import, manufacture or distribute any industrial substances in Australia are legally obliged to provide information in the form of MSDS to users. MSDS contain information on toxicity of the substance and other hazards including fire and explosion, corrosion and chemical reactivity. MSDS are required by law to be up to date but they need not contain the references to the information that they contain. The first two pages of a typical MSDS (from a Canadian manufacturer) is shown in Appendix 1. There are many sources of MSDS including manufacturers and several large databases in Australia. Most of these require a subscription before access can be obtained. Some Canadian MSDS can be obtained through an open access database through a Deakin University library subscription: http://ccinfoweb.ccohs.ca.ezproxy-f.deakin.edu.au/msds/search.html. Clinical Toxicology Information Services Most countries have national or state poisons information services that are for the use of hospitals, physicians and emergency medical services. These services provide information on the emergency treatment of poisoning, diagnosis, assays and antidotes. Some countries have online databases of clinical toxicology that can be accessed 24 hours a day. These are usually accessible only to registered users in the medical profession. In Australia, each state has a poisons information service that provides some online information as well as an emergency telephone service. In Victoria this service is provided by the Victorian Poisons Information Centre (VPIC, http://www.rch.org.au/poisons/). 2.3 Toxic Effects The toxic effect of a substance is dependent on many factors including the nature of the chemical, route of exposure, site of action, metabolic pathway and the dose. Fundamentally, all toxic effects involve a molecular mechanism and can only be understood if that mechanism is known. The poison starts by interacting with a biochemical "target" such as a transport protein, enzyme, cell-wall lipid, receptor site or DNA to compromise a biochemical process. For example, carbon monoxide reacts with haemoglobin to form a complex (carboxyhaemoglobin). The chemical changes then lead to alterations in function - (e.g. carboxyhaemoglobin fails to transport oxygen in the blood). The consequences of the change in function can be altered performance of a physiological system, or cell death leading to organ damage. 2.3.1 Site of toxic action The toxic action of chemical substances may be dependent on the site of contact. Some chemicals are locally-acting and exert their toxic effect at the point of interaction (local toxicity), while others may show effects at another part or parts of the body (systemic toxicity). Local toxic effects are those that occur at the site of first contact, such as corrosive burns on the skin, and may arise from contact with corrosive substances such as acids or alkalis. Systemic toxic effects are those that occur as a result of the absorption and distribution of the chemical from the point of entry, to a distant site at which the deleterious effect occurs. Typical of systemic effects are the effects of solvents and organophosphate pesticides on the central nervous system. Such effects are frequently predominantly evident in one or two organs, known as the target organs or target systems for that chemical. For example, the main target organs for many heavy metals are the kidneys. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 5 Important target areas for systemic toxicity include:  central nervous system (CNS)  peripheral nervous system (PNS)  cardiovascular system (CVS)  blood and blood forming tissues  liver  kidneys Skin, bone and muscle are less commonly a target of systemic toxicity and are more commonly affected by local toxic effects. A toxic substance may be able to exert both local and systemic toxic effects from the same dose. 2.3.2 Types of toxic effects Mechanisms involving toxic chemicals are complex and often seem to involve multiple chemical events. The biochemical changes that result from small doses might go unobserved and involve no pathological or histological changes. However, it might be possible to measure some biological changes such as the concentrations of carboxy-haemoglobin and acetylcholine esterase. When the dose of a toxic substance is high enough clinical changes occur and these might be observed as various types of toxic effects. Important examples of toxic effects are: irritation, allergic reaction, specific organ effects, cancer, and reproductive effects. Irritations Irritation of the skin or mucous membranes is a common local toxic effect of industrial chemicals. It should not be assumed that irritation can only arise from the local effects of chemicals. While irritation at the point of contact is the most likely outcome, systemic distribution of chemicals ingested or inhaled can cause reversible irritation of both the skin and eyes. Problems may occur when the respiratory epithelium is affected in people with compromised respiratory function, such as asthmatics. In this case respiratory arrest and death is possible. Allergic reaction (hypersensitivity) Allergic reaction or hypersensitivity is the adverse response resulting from prior sensitisation to the chemical or to a similarly structured one. These reactions may occur at extremely low doses and responses may vary markedly between individuals. Hypersensitivity is typified by the first exposure to the chemical having little adverse effect while later exposures, even to much lower doses, cause significant and rapid responses. Hypersensitivity reactions result from the interaction of the chemical with the immune system. Specific organ effects All organ systems can be the target of toxic chemicals as will be dealt with more thoroughly later in the course. It is important, however, to note that in industrial toxicology the lungs, skin and eyes are frequent sites of contact, while the liver, kidney, nervous and respiratory systems are frequently sites of damage. Specific toxic substances may also cause damage to the cardiovascular and haematopoietic systems. Cancer A number of substances are capable of causing cancer in humans or other animals. Such chemicals are known as carcinogens. Carcinogenesis is generally a slow multi-stage process. In humans it might take many years following a period of exposure to a carcinogenic chemical for the development of cancer. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 6 Reproductive effects The effects of chemicals on both the male and female reproductive systems has recently begun to receive increased attention. To date most reproductive studies have focused on the teratogenic effects (birth defects) to the foetus from chemical exposure to the mother prior to and during pregnancy. However, of equal importance are the effects on both male and female fertility and genetic damage to sperm and ova. 2.3.3 Time course of toxic effects While some toxic effects are rapid, others can take many years to develop, and some reproductive results are evident only after one or two generations. Acute (short-term) toxicity Acute toxicity relates to the effect of a single dose or multiple doses over a short period such as 24-hours. The acute toxic effects may be either local or systemic and generally they occur shortly after exposure, although in some cases clinical signs may be delayed. An example acute poisoning is cyanide poisoning. A single high dose of cyanide can cause severe illness or death. Small doses delivered over a long period may have no effect because cyanide does not build up in the body. Chronic toxicity Some toxic chemicals may cause adverse effects only after prolonged or repeated exposures. For example exposure to tobacco smoke over many years may result in a vast range of toxic effects which are rarely evident in the early stages of exposure. Such effects are known as chronic (long-term). Some toxic compounds which cause acute toxicity can also have chronic effects such as cancer. Another example of chronic toxicity is lead poisoning from contaminated foodstuffs. The lead content of even severely lead-contaminated food or water is very rarely sufficient to cause acute poisoning. However, if the contaminated food or water is consumed over a long period (e.g months) the body burden increases until clinical (symptomatic) lead poisoning results. Delayed (latent) toxic effects Some chemicals may cause changes which have long latency periods until their effects become evident. For example mutagenic effects may occur in only one cell and hence will remain indiscernible until that cell has undergone multiple divisions. Cancer is the typical example of a delayed toxic effect with a long latency period. Reversible/irreversible effects The effect of a chemical may be reversible or irreversible. Reversible effects are those which cause a temporary change in the function of the organ or system, such as local anaesthesia, however the function returns to normal following the removal of the chemical. Irreversible changes are those which result in a permanent change in the biological system and these do not return to normal on the removal of the chemical. The liver has a strong capability to regenerate following toxic damage and hence its function may be able to be restored. Its structure however may be permanently affected and with persistent injury liver function can eventually be affected significantly. The capability of organs to recover varies widely however, with organs such as the brain and kidney possessing little capacity for recovery from toxic damage. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 7 2.4 Measurement of Toxicity The toxicity of a chemical can only be accurately assessed through testing in a biological system. It may be possible to make an educated deduction about the toxic effects of a substance by considering its molecular structure. For example, a compound that has a molecular structure similar to a known poison may have a similar toxic effect. This is the "Structure-Activity Relationship". It is also possible to obtain some information by testing the substance in cells in culture; however, the only reliable way to measure the toxicity of a substance is to test it in animals or humans. 2.4.1 Animal testing (in-vivo) Most measurements of toxicity are carried out on experimental animals such as rats, rabbits or mice. Occasionally larger animals such as dogs or primates are used, but this can be very expensive and the advantages are not usually significant. A number of specially-bred laboratory animals are used in each test, including a number of "controls" that are not given the test substance but are subjected to all other test conditions. A range of doses are used and the test substance may be administered in a number of ways such as by an oral gavage in which a feeding tube is placed down the animal's throat, intravenous injection, implantation, skin application or by inhalation if the substance is a gas or fine mist. Short term tests are conducted in order to measure acute toxicity effects such as lethality. The dose which results in the short-time period death of 50% of the test animals is known as the LD50 and the concentration responsible for the deaths of 50% the test animals over the test period is known as the LC50. Long term animal experiments are necessary to investigate chronic toxic effects and multi-generational studies are also required for the investigation of reproductive consequences. The following are all measures that can be derived from experimentation of the acute or short- term effects of chemicals on test groups of animals  LD50 -Dose causing death of 50% of the test group  LDLO -Least dose at which death of any of the test group occurs  LC50 -Concentration (for example in air or water) causing the death of 50% of the test group  LCLO -Least concentration (for example in air or water) at which death of any of the test group occurs  ED50 -Effective dose at which the required (therapeutic) effect occurs in 50% of the test group.  ED90 -Effective dose at which the required (therapeutic) effect occurs in 90% of the test group. In practical terms, however, none of these measures give any information about the chronic effects, delayed effects, or the effects of low doses of the chemical in question. The first three are measures of the acute toxic effects of the chemical, while the later two are measures of the effects of an immediate or sustained dose of the chemical or drug. The most commonly used measure of toxicity is the median acute lethal dose (LD50). This tells us the acute dose that could cause death, but it does not tell us anything about the effects of lower doses that result in chronic toxicity. Examples of acute lethal toxicity data are given in table 2.2. Note that the toxic dose is expressed in terms of mass of the toxic substance per kilogram of body weight which allows comparisons to be made between animals of different weight. You should also note that not all the animals die at the same dose, even though laboratory animals are usually inbred and very similar. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 8 Table 2.2 —Approximate ~LD50s (median doses) of selected chemicals. Chemical Animal Species Route LD50 in mg/kg Common Sugar rat o. 30,000 Ethyl alcohol mouse o. 10,000 Sodium Chloride mouse i.p. 4,000 Ferrous sulfate rat o. 900 Morphine sulfate rat o. 900 Phenobarbitone rat o. 150 DDT rat o. 100 Picrotoxin rat s.c. 5 Strychnine sulfate rat i.p. 2 Nicotine* rat i.v. 1 d~Tubocurarine* rat i.v. 0.5 Hemicholinium-3 rat i.v. 0.2 Tetrodotoxin* rat i.v. 0.10 Dioxin’ (TCDD) G/pig i.v. 0.001 Botulinus* rat i.v. 0.00001 Polonium-10 human (estimate) o. 0.00001 * Some of the more toxic natural compounds. ** The LD50 is the dosage required to kill 50% of the exposed group. o.= oral, i.p. = intraperitoneal, s.c. = subcutaneous, i.v. = intravenous. What should you learn from Table 2.2? Do not try to remember most of the data. If you need to find this information it is readily available in RTECS. The key concept is that toxic substances have an enormous range of toxicity. For example botulinus toxin is 200,000 times more toxic than strychnine and one billion times more toxic than ethanol. The data in table 2.2 only applies to the particular species and route of administration indicated. Some substances can be very toxic to one species but much less so to another and the route of administration is also important, a substance might have a different degree of toxicity if inhaled or injected rather than being taken orally. 2.4.2 Non-animal tests (in-vitro) Non-animal toxicity testing systems are being used with increasing frequency to study the potentially harmful effects of chemicals. This is especially important for the genetic toxicity effects of the chemical. However, a large body of information needs to be developed before the toxicologists or regulators will accept the predictive power of such systems for overall human toxicity. Toxicity testing is dealt with in greater detail in later topics. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 9 2.5 Toxicity and “Risk Phrases” Sometimes the toxicity of chemicals is classified using phrases such as non-toxic, toxic, very toxic or extremely toxic; however, different authorities use different terminology, which can lead to confusion. In Australia the Australian Government, National Occupational Health and safety Commission, [NOHSC] has published three official phrases for use in Material Safety Data Sheets (MSDS) based on the acute oral LD50 in rats, as shown in table 2.3. Table 2.3 —Official "Risk Phrases" used in Australia to describe the acute lethal toxicity of chemicals in Material Safety Data Sheets (MSDS). LD50 oral, rat Risk phrase 200 to 2000 mg/kg. Harmful if swallowed 25 to 200 mg/kg Toxic if swallowed less than 25 mg/kg Very toxic if swallowed Approved Criteria for Classifying Hazardous Substances, Australian Government, National Occupational Health and Safety Commission, [NOHSC:1008(2004)] 3rd Edition October 2004. Key concepts and Information  Local toxic effects are those that occur at the site of first contact  Systemic toxic effect are those that occur as a result of the absorption and distribution of the chemical from the point of entry, to a distant site at which the deleterious effect occurs.  A toxic substance may be able to exert both local and systemic toxic effects from the same dose.  Changes to biochemical systems are often the first level of systemic effects.  While some toxic effects are rapid, others can take many years to develop, and some reproductive results are evident only after one or two generations.  Acute toxicity relates to the effect of a single dose or multiple doses over a short period such as 24-hours.  Chronic toxicity relates to the effect of prolonged or repeated exposures.  Some toxic compounds which cause acute toxicity can also have chronic effects such as cancer.  Reversible effects are those which cause a temporary change in the function of the organ or system, such as local anaesthesia. Irreversible changes are those which result in a permanent change in the biological system.  LD50 is the dose in milligram of the toxic substance per kilogram of body weight that would kill 50% of the individuals in a test population.  LC50 Concentration (for example in air or water) causing death of 50% of the individuals in the test group  ED50 Effective dose at which the required (therapeutic) effect occurs in 50% of the test group.  Non-animal toxicity testing systems are being used with increasing frequency to study the potentially harmful effects of chemicals. This is especially important for the genetic toxicity effects of the chemical.  Sometimes the toxicity of chemicals is classified using phrases such as non-toxic, toxic, very toxic or extremely toxic. Different authorities use different terminology, leading to possible confusion.  Official "Risk Phrases" used in Australia to describe the acute lethal toxicity of chemicals in Material Safety Data Sheets (MSDS). LD50 oral, rat Risk phrase 200 to 2000 mg/kg. Harmful if swallowed 25 to 200 mg/kg Toxic if swallowed less than 25 mg/kg Very toxic if swallowed © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 10 References Mangas S, Visvanathan R, van Alphen M, Lead Poisoning from Homemade Wine: A Case Study. Environ Health Perspect 109:433-435 (2001). NOHSC, Approved Criteria for Classifying Hazardous Substances, Australian Government, National Occupational Health and Safety Commission, [NOHSC:1008(2004)] 3rd Edition October 2004. NOVA Chemicals, Benzene Material Safety Data Sheet, http://www.novachemicals.com/productservices/docs/Benzene_MSDS_EN.pdf Acknowledgment The section on the fields of toxicology was based on notes prepared by Tony Morgan. © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 11 Appendix 1. Extracts from a typical Material Safety Data Sheet (MSDS). Material Safety Data Sheet Material Name: Benzene MSDS ID: NOVA-0011 Issue Date: January 21, 2005 Revision: 2.14 Print Date: 13-Mar-06 Section 1 - Product and Company Identification Synonyms: Benzene, benzol Chemical Name: Benzene Chemical Family: Aromatic hydrocarbons Material Use: Petrochemical industry: Solvent, raw material for petrochemicals Chemical Formula: (C6H6) NOVA Chemicals In Case of Emergency: P.O. Box 2518, Station M Calgary, Alberta, Canada T2P 5C6 1-800-561-6682, 1-403-314-8767 (NOVA Chemicals)(24 hours) 1-800-424-9300 (CHEMTREC-USA) Product Information: 1-412-490-4063 1-613-996-6666 (Canutec-Canada)(24 hours) General Comments This product has been assigned a CAS# of 71-43-2 Section 2 - Composition / Information on Ingredients CAS # Component Percent by Wt. 71-43-2 Benzene 99.85 Not Available Other hydrocarbons 0.1-1 Additional Information This product is considered hazardous under 29 CFR 1910.1200 (Hazard Communication). This material is a controlled product under Canadian WHMIS regulations. This material is regulated under DOT and TDG as a flammable liquid for transportation. See Section 8 for applicable exposure limits. See Section 11 for applicable toxicity data. Section 3 - Hazards Identification HMIS Ratings: Health: 2* Fire: 3 Physical Hazard: 0 Personal Protection: chemical goggles, gloves, respirator, apron Hazard Scale: 0 = Minimal 1 = Slight 2 = Moderate 3 = Serious 4 = Severe * = Chronic hazard NFPA Ratings: Health: 2 Fire: 3 Reactivity: 0 Hazard Scale: 0 = Minimal 1 = Slight 2 = Moderate 3 = Serious 4 = Severe Emergency Overview DANGER: TOXIC! FLAMMABLE! CANCER HAZARD! Product is a clear liquid at room temperature with a sweet, solvent-like odor. Flammable liquid and vapor can accumulate static charge - distant ignition and flashback are possible. Product will float on water and may travel to distant locations and/or spread fire; product vapor is heavier than air and may also spread long distances. This product is considered harmful by inhalation, ingestion, and © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 12 dermal exposure routes. This product is irritating to the eyes and skin. Excessive inhalation may result in heartbeat irregularities and adverse central nervous system effects including headache, sleepiness, dizziness, nausea, loss of coordination, tremors, and in extreme conditions, coma and death. Systemic absorption effects may include long-term damage to the blood-forming system, kidney and liver damage, and/or cancer (leukemia). Ingestion may also cause adverse central nervous system effects, blood disorders, kidney and/or liver damage. Potential Health Effects: Eyes Contact with liquid and high concentrations of this product's vapors are irritating to the eyes. Potential Health Effects: Skin Product may be rapidly absorbed through the skin. Prolonged and/or repeated skin contact may cause mild to severe irritation/dermatitis and chemical blistering. Prolonged contact may also cause skin sensitization and secondary skin infections. Potential Health Effects: Ingestion This product may be harmful if swallowed. Ingestion of this product may result in adverse central nervous system effects including headache, sleepiness, dizziness, nausea, loss of coordination, and in extreme conditions coma and/or death. Ingestion may also cause kidney and liver damage and blood disorders. Small amounts of this product, if aspirated into the lungs, may cause mild to severe pulmonary injury. Potential Health Effects: Inhalation This product may be harmful if inhaled. Excessive inhalation may result in heartbeat irregularities and adverse central nervous system effects including headache, sleepiness, dizziness, nausea, loss of coordination, and in extreme conditions, coma and death. Additional adverse inhalation effects may also include long-term damage to blood-forming system, kidney and liver damage, and/or cancer (leukemia). Small amounts of this product, if aspirated into the lungs, may cause mild to severe pulmonary injury. Section 4 - First Aid Measures First Aid: Eyes Immediately flush eyes with lukewarm water for at least 15 minutes, while holding eyelids open. Remove contact lenses, if worn. Seek medical attention at once. First Aid: Skin Remove contaminated clothing and immediately wash skin with large amounts of warm water and an oil emulsifying soap or shampoo. Seek immediate medical attention if extensive skin exposure has occurred and/or if irritation persists. First Aid: Inhalation Move affected individual to a well-ventilated area as soon as possible. Loosen any restrictive clothing such as a collar, tie, belt or waistband on the individual to facilitate breathing. Seek immediate medical attention if the individual is not breathing. WARNING: Contact through mouth-to-mouth resuscitation may pose a secondary exposure risk to the rescuer. Avoid mouth-to-mouth contact by using mouth shield or guard to perform artificial respiration. Immediately transport affected individual to an emergency facility. First Aid: Ingestion If ingestion occurs and exposed individual is unconscious, maintain an open airway by gently lifting chin and tilting head back. DO NOT INDUCE VOMITING. If vomiting occurs naturally, have victim lean forward to reduce risk of aspiration. Seek medical attention immediately. First Aid: Notes to Physician An Emergency Medical Response Protocol is available for this product. These are available to first responders and medical personnel. 1-800-561-6682 (24 hours, NOVA Chemicals Emergency Response). Ensure thorough eye and skin decontamination. Treat unconsciousness, nausea, hypotension, seizures and cardiac arrhythmias in the conventional manner. Aspiration of this product during induced emesis can result in lung injury. If evacuation of stomach contents is considered necessary use the method least likely to cause aspiration, such as gastric lavage after protecting the airway. Observe hospitalized patients for delayed chemical pneumonia, acute tubular necrosis, encephalopathy and dysrhythmias. Monitor for urinary phenol within © Deakin University SLE312 Toxicology TOPIC 2 TOXIC CHEMICALS AND TOXIC EFFECTS 13 72 hours of acute exposure. Sections 5 to 10 have been omitted They deal with: 5 Fire fighting, 6 Accidental release, 7 Handling and storage, 8 Exposure controls / personal protection, 9 Physical and Chemical properties and 10 Stability and reactivity information. Section 11 - Toxicology A: Acute Toxicity - General Information Benzene primarily poses an inhalation exposure hazard. It is absorbed rapidly and extensively following inhalation or ingestion and preferentially distributes into bone marrow and tissues (esp. fat, brain, kidney liver). Potential adverse health effects include CNS depression, pneumonia (following aspiration), respiratory failure, coma and death. Benzene is a skin irritant that is rapidly absorbed through the skin; absorption is more rapid through abraded skin. Aspiration of small amounts of benzene will cause immediate damage to the lungs and death may result. B: Acute Toxicity - LD50/LC50 Benzene (71-43-2) Inhalation LC50 Rat: 10,000 mg/m3/7 hour Dermal LD50 Rabbit: > 9400 microlitre/kg C: Chronic Toxicity - General Material Information Bone marrow is the main target organ of benzene. Long-term overexposure to benzene has been associated with certain types of leukemia in humans. The International Agency for Research on Cancer (IARC) and OSHA (US Occupational Safety and Health Administration) identify benzene as a human carcinogen. Chronic exposure to benzene has also been reported to cause adverse blood effects including anemia. Progressive deterioration of hematopietic (blood forming) function expressed as a decrease in absolute lymphocyte count is the most sensitive indicator of benzene exposure. Benzene may also cause fetotoxicity and teratogenicity. Chromosomal aberrations have been noted in animal tests. D: Chronic Toxicity - Carcinogenic Effects ACGIH, IARC, OSHA and NTP carcinogen lists have been checked for selected similar materials or those components with CAS registry numbers. Benzene (71-43-2) ACGIH: A1 Confirmed Human Carcinogen OSHA: Present (Regulated Carcinogen); Present (Select Carcinogen) NTP: Known Carcinogen (Select Carcinogen) IARC: Supplement 7, 1987; Monograph 29, 1982 (Group 1 (carcinogenic to humans)) Special Remarks on Chronic Effects Benzene may pose a cancer hazard and may cause adverse birth and reproductive effects. Bone marrow abnormalities, leukemia, multiple myelomas, fetotoxicty, teratogenicity (exencephaly, angulated ribs and dilated brain ventricles) have been linked to benzene exposure). Sections 12 to 16 have been omitted. They deal with: 12 Ecological information, 13 Disposal information, 14 Transportation information, 15 Regulatory information, 16 Other information. What you should learn from this MSDS: Do not try to remember any of the detail. The key information is that all industrial chemicals and those manufactured, imported or distributed for commercial are required under law to have a MSDS. These contain a summary of all of the information related to the hazards of the substance including the toxicity. MSDS do not usually contain references to the sources of the information they contain. End of Topic