Safety Data Sheet: Section 11: Toxicological Information-Warfarin

SECTION 11: TOXICOLOGICAL INFORMATION (13 - 25)

No adverse health effects expected if the product is handled in accordance with this Safety Data Sheet and the product label. Route of entry: Absorbed through the skin (Dermal contact) and inhalation and/or ingestion. Toxicological effects: Potential acute health effects in humans: When Warfarin comes into contact with skin it may cause skin irritation. It can be absorbed into the skin in toxic amounts with systemic effects similar to ingestion. It can cause eye irritation. It may be absorbed also through inhalation though the respiratory tract but may lead to irritation of the respiratory tract. Ingestion of the product may be fatal if swallowed. The major effect is prolongation of prothrombin time, leading to haemorrhage. A wide range of Warfarin induced symptoms include: causes tissue/skin necrosis, skin discolouration, dermatitis, uncontrolled bleeding, hypotension, haemorrhage in the retina, epitaxis (nosebleeds), chest tightness, upper airway occlusion and dyspnoea (shortness of breath) or asphyxiation due to haemorrhage into the soft tissue of the neck and pulmonary/alveolar haemorrhage, coughing up blood, and paralysis from intracerebral haemorrhage, abdominal pain, vomiting, gastrointestinal bleeding, bloody or dark stools, easy bruising, abdominal and back pain, bleeding lips, shock, and rupture of the spleen, normocytic anemia (changes in red blood cell count), urinary system (hematuria). General symptoms of poisoning which begin after a few days or weeks or repeated exposure. It may also affect behaviour/central nervous system (somnolence and convulsions). Body accumulation can result from repeated exposures. Individuals with blood clotting disorders may be more susceptible to overexposure effects. Potential chronic health effects in humans: Ingestion or skin contact-Warfarin has a cumulative toxicity; it can cause abnormal bleeding following chronic skin contact. Chronic exposure may also produce alopecia and calcification of the cartilaginious rings in the trachea and bronchi. It may also affect the liver and absorption by the lungs may result in haemorrhage effects. Warfarin has been established as a human teratogen, because it causes birth defects in the offspring of women receiving clinical doses of the compound during any trimester of pregnancy. A fetal disorder caused by exposure of a fetus to warfarin (Coumadin), a drug used therapeutically as an anticoagulation chemical (inhibits synthesis of vitamin K dependent clotting factors, including factors II, VII, IX, and X, and the anticoagulant proteins C and S.1). The exact teratogenic effect of fetal damage from warfarin therapy during pregnancy is difficult to determine with variable impact on several different systems depending on the developmental window. Some examples include: nasal hypoplasia or stippled epiphyses, central nervous system abnormalities, and maternal and fetal haemorrhage. Acute toxicity values in humans: Toxicity values for humans exposed to Warfarin an oral-woman TD1o of 15 mg/kg/21 weeks intermittent: 10,200 ug/kg oral-man TDlo; and 6,667 mg/kg oral-human LDlo. A dose of Warfarin at 200 mg/m3 is considered highly toxic and immediately dangerous to life or health. Acute toxicity values in rats: The amount of Warfarin that is lethal to one-half (50%) of experimental animals fed the material is referred to its acute oral lethal dose fifty, or LD50. The acute oral toxicity for Warfarin in rats is variously reported to be 3 mg/kg. In female rats it is found to be 58 mg/kg. The acute oral LD50 for rats over 4-5 days is 1 mg/kg/day. There was no development of ingestion tolerance indicated regardless of rodent sex or age. The acute oral LD50 for technical sodium Warfarin in rats was 323 mg/kg for males and 58 mg/kg for females. A single larger dose of Warfarin is about as toxic as a single, small dose. On a multiple-dose basis, the reported LD100 for rats is 0.2 mg/kg for 5 days. The dermal LD50 for rats was 1,400 mg/kg; 420 mg/kg intraperitoneal and 320 mg/m3 inhalation LC50. The same source indicated the acute oral LD50 for mice was 60 mg/kg; 800 mg/kg subcutaneous LDlo; and 165 mg/kg intravenous LD50. Mutagenicity- Negative in the Ames Assay and in mammalian cells. Negative for direct DNA damage and for vitro and for potential to cause chromosomal aberrations in-vitro (in Chinese Hamster Ovary cells) or to induce micronuclei in bone marrow in rats (dosages up to 600 mg/kg/day for three days) Carcinogenicity- Negative in two year oral bioassays in rats and mice. Acute toxicity values in other animals: An oral LD50 for cats of 2.5-20 mg/kg: an acute oral LD50 for 35 mg/kg for a single dose of 3 mg/day/ per 5 days; and 12 mg/kg oral LDlo.  The acute oral LD50 for dogs exposed to Warfarin was 3 mg/kg/ per 5 days. Technical sodium Warfarin in dogs had an LD50 of 200-300 mg/kg. The acute oral LD50 for Warfarin in cattle was 200 mg/kg/day for 5 days. The LD50 for technical sodium Warfarin in guinea pigs was 182 mg/kg. The oral LDl0 for Warfarin in pigs was reported to be 1,200 ug/kg. Death followed 5 daily doses of 1mg/kg for pigs. Studies done on rabbits indicated the dermal LD50 to be greater than 8g/kg. Technical sodium Warfarin in rabbits had an LD50 of 800 mg/kg. Rabbits exhibit mild to slight conjunctival irritation in response to technical Warfarin.

Health and Safety Report on Warfarin

To identify the nature and extent of the probability of risk/harm to a pregnant woman due to occupational exposure to the chemical agent Warfarin

Data collection

 It has been well established via numerous data sources that Warfarin needs to be directly consumed to cause an effect on a patient. However, it is difficult to establish the exact risk during the different stages of pregnancy. There is no clear data collection because this would involve administrating Warfarin directly into pregnant women. Much of the evidence relies on data which is specifically in relation to Warfarin being administered to Women as an oral anticoagulant. In this instance, the dosage varies from person to person and as a result has to be carefully monitored in order to prevent varied side effects such as uncontrollable bleeding (haemorrhage). “Acceptable Exposure Levels (AELs) were derived from data because NO Observable Adverse Effect Levels (NOAEL) for Warfarin could be derived from rodent repeated dose studies because of the particular susceptibility of rodents to anticoagulants effects”. Directive 98/8/EC Concerning the Placing of Biocidal Products on the Market pp.11.

Evaluating Prenatal Effects of Warfarin

There is a risk to both Mother and Progeny, it has been noted that during week six to nine of the pregnancy in particular are associated with Warfarin specific embryopathy (first trimester). However, the exposure to cause such affects would need to be administrated directly into a pregnant woman to cause the effect that Haly and Bernotts’ claim “Throughout gestastion and into the neonatal period, many organ systems are maturing and substantial cell-cell interactions are occurring especially in organ systems like the central nervous system, endocrine system, immune system, and urogential system” (1987:273). Warfarin disrupts normal embryonic and or foetal development (teratogenic effects). The second and third trimesters are associated with optic atrophy and dilation of the central ventricles associated with blindness, microcephaly and mental retardation. Therefore, it can be said that direct contact/exposure to Warfarin during any stage of pregnancy is extremely dangerous. Any hypothesis presented on the basis of indirect contact with Warfarin in an occupational setting could be said to be inconclusive.

Review of Risk Assessment

A new risk assessment is now in place and additional and necessary controls, rigorous policies and standards are in place to protect you and your unborn baby. I am satisfied that no harm will come to you or the baby as adequate controls are in place. To have any adverse effect, a person would have to be in physical contact with the agent (skin contact) or ingest it. I have looked over your training files and you are competent and adequately trained in the use of Personal Protective Equipment (PPE) (respirator/dust mask, gloves, overalls, goggles/face shield). Distance is a great protector and because you are not in direct contact you do not need to be removed from the laboratory.

Recommendations

As part of the updated Risk Assessment wider conditions were considered laboratory work is characterised as requiring long periods of standing and thus I would strongly advise you to liaise with the Human Resources Department to ensure you get regular rest breaks or to be repositioned in another department such as Administration where you would not be required to stand for the duration of your shift.

A. Murphy

Anita Murphy

Health and Safety Officer

Date: 10^th Oct 2011