TERIFLUNOMIDE

Alembic Pharmaceuticals Limited Chemwatch Hazard Alert Code: 3

Chemwatch: 27-5375 Issue Date: 13/04/2020
Version No: 3.1 Print Date: 07/08/2023
Safety Data Sheet [Link]

SECTION 1 Identification of the substance / mixture and of the company / undertaking

Product Identifier
Product name TERIFLUNOMIDE
Chemical Name teriflunomide
C12-H9-F3-N2-O2; (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide; (Z)-2-cyano-
a',a',a'-trifluoro-3-hydroxy-p-crotonotoluidide; 2-butenamide, 2-cyano-3-hydroxy-
Synonyms N-[4-(trifluoromethyl)phenyl]-, (2Z)-; N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide; DMARD;
Aubagio; Flucyamide; HMR 1726; SU 20; teriflunomide metabolite; A77-1726 (CAS RN: 108605-62-5);
A771726; teriflunomide, A77 1726; A77-1726-d4 (CAS RN: 1185240-22-5)
Proper shipping name MEDICINE, SOLID, TOXIC, N.O.S. (contains teriflunomide)
Chemical formula C12-H9-F3-N2-O2
Other means of
Not Available
identification
CAS number 163451-81-8

Relevant identified uses of the substance or mixture and uses advised against
The active metabolite of leflunomide. Medication of the DMARD (disease-modifying antirheumatic drug)
type, used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine
synthesis inhibitor. Given by mouth. Leflunomide is an immunomodulatory drug inhibiting dihydroorotate
dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) (abbreviation DHODH). Genuine
antiproliferative activity has been proven. In addition, several experimental models (both in vivo and in
vitro) have demonstrated an anti-inflammatory effect. This double action is supposed to slow progression
of the disease and to cause remission/relief of symptoms of rheumatoid arthritis and psoriatic arthritis
such as joint tenderness and decreased joint and general mobility in human patients. Leflunomide has
been assigned orphan drug status for the prevention of solid-organ rejection after allograft
transplantations when co-administered with commonly used first-line agents (USA only). Most experience
Relevant identified exists with liver and renal transplations. The efficacy and safety of leflunomide has not been completely
uses assessed so far in well-controlled and adequate studies Upon administration of leflunomide, 70% of the
drug administered converts into teriflunomide. The only difference between the molecules is the opening
of the isoxazole ring. This is considered a simple structural modification and a technically simple one-step
synthetic transformation. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide
is opened and teriflunomide is formed. "Regardless of the substance administered (leflunomide or
teriflunomide), it is the same molecule (teriflunomide) - the one exerting the pharmacological,
immunological or metabolic action in view of restoring, correcting or modifying physiological functions,
and does not present, in clinical use, a new chemical entity to patients." (EMA). Because of this, the
European Medicines Agency (EMA) initially had not considered teriflunomide being a new active
substance Therapeutic or pharmacologically-active agent.
Dihydroorotate dehydrogenase (DHODH) inhibitor

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TERIFLUNOMIDE

As an enzyme associated with the electron transport chain, DHODH links mitochondrial bioenergetics,
cell proliferation, reactive oxygen species (ROS)production, and apoptosis in certain cell types. DHODH
depletion also resulted in increased ROS production, decreased membrane potential and cell growth
[Link], due to its role in DNA synthesis, inhibition of DHODH may provide a means to regulate
transcriptional elongation.
In humans, it is a mitochondrial protein identified as a drug target in cancer and immunological disorders.
Prokaryotic DHODH is also a target for antiviral and antibacterial [Link] of pyrimidine
metabolism by selectively targeting DHODHs has been exploited in the development of new therapies
against cancer, immunological disorders, bacterial and viral infections, and parasitic disease.
Human DHODH is a mitochondrial protein located on the outer surface of the inner mitochondrial
membrane (IMM). Inhibitors of this enzyme are used to treat autoimmune diseases such as rheumatoid
arthritis and multiple sclerosis.
DHODH is essential for the de novo production of pyrimidines starting with the generation of uridine
monophosphate (UMP), and small molecule inhibitors of DHODH are highly effective in vitro and in vivo in
pre-clinical models of malignancy. DHODH is an unlikely cancer target, as it is ubiquitously expressed
and is not known to be mutated or overexpressed in cancer. However, malignant cells seem to be more
metabolically-dependent on de novo pyrimidine production, forming the potential basis of a therapeutic
window. The use of DHODH inhibitors in solid tumor malignancies has been clinically disappointing.
However, the use of DHODH inhibitors in the treatment of acute myeloid leukemia (AML) has been more
recently shown to have both a cytotoxic and a pro-differentiation effect, making AML an attractive new
disease indication. When starved of pyrimidines, the acute myeloid leukemic blasts demonstrated both
cell death and differentiation as shown by morphology, cell surface-marker expression, and gene
expression. Furthermore, the surviving cells were functionally more differentiated, as demonstrated by the
loss of leukemia-initiating cell activity. While early trials focus on the population of relapsed and refractory
patients with AML, it seems likely that trials in myelodysplastic syndrome (MDS) and other hematologic
malignancies will follow
In mammalian species, DHODH catalyzes the fourth step in de novo pyrimidine biosynthesis, which
involves the ubiquinone-mediated oxidation of dihydroorotate to orotate and the reduction of FMN to
dihydroflavin mononucleotide (FMNH2).
The immunomodulatory drugs teriflunomide and leflunomide have been shown to inhibit DHODH. Human
DHODH has two domains: an alpha/beta-barrel domain containing the active site and an alpha-helical
domain that forms the opening of a tunnel leading to the active site. Leflunomide has been shown to bind
in this tunnel. Leflunomide is being used for treatment of rheumatoid and psoriatic arthritis, as well as
multiple sclerosis Its immunosuppressive effects have been attributed to the depletion of the pyrimidine
supply for T cells or to more complex interferon or interleukin-mediated pathways
Additionally, DHODH may play a role in retinoid N-(4-hydroxyphenyl)retinamide (4HPR)-mediated cancer
suppression. Inhibition of DHODH activity with teriflunomide or expression with RNA interference resulted
in reduced ROS generation in, and thus apoptosis of, transformed skin and prostate epithelial cells
Mutations in the DHODH gene have been shown to cause Miller syndrome, also known as Genee-
Wiedemann syndrome, Wildervanck-Smith syndrome or post-axial acrofacial dystosis
Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of
inflammatory arthritides including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing
spondylitis (AS). They can also be used to in the treatment of other disorders including connective tissue
disease such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and Sjogren syndrome
(SS), as well as in treatment of inflammatory myositis, vasculitis, uveitis, inflammatory bowel disease, and
some types of cancers.
DMARDs are immunosuppressive and immunomodulatory agents and are classified as either
conventional DMARDs or biologic DMARDs. Commonly used conventional DMARDs include
methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Biologic DMARDs are usually
prescribed after the failure of conventional DMARD therapy (ongoing disease activity, or clinical or
radiographic disease progression). Some biologic agents include infliximab, adalimumab, etanercept,
rituximab, abatacept, rituximab, tocilizumab, tofacitinib, among others. Biologic DMARDs are highly
specific and target a specific pathway of the immune system. Some of these drugs are monoclonal
chimeric humanized fusions antibodies, while others are receptors that have been fused to a part of the
human immunoglobulin or small molecules such as Janus kinase (JAK) inhibitors.
An OAT inhibitor:

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Organic anion transporters (OATs) mediate the body disposition of a diverse array of environmental toxins
and clinically important drugs.
The isoforms, OAT1 and 3 share many common substrates and inhibitors, and are generally both
implicated in drug-drug interactions (DDIs) and renal toxicology. The classical clinical inhibitor of OAT1-3
is the uricosuric drug probenecid (which is also a substrate). Other inhibitors include rifampicin,
novobiocin, and the HIV integrase inhibitor cabotegravir.
Modulation of OAT1-3 expression under disease conditions can modify the renal excretion of substrate
drugs. Decrease in renal secretion and clearance may produce an increase in systemic drug exposure,
thereby resulting in clinically significant changes in the overall drug pharmacokinetics (PKs). Clinically
relevant changes in the clearance of therapeutics can occur when OAT1-3 transporter activity is inhibited.
Renal tubular secretion of drugs is inhibited by the co-administration of probenecid which, by
simultaneous inhibition of OAT1 and 3, increases the circulating levels of OAT substrates such as
penicillin, cephalosporin, pravastatin, fexofenadine, and some antiviral drugs by 10-260%. Mercuric
conjugates, too, are transported by OAT1 and 3, contributing to the renal toxicity of these compounds.
Probenecid can be used to reduce nephrotoxicity of therapeutics by inhibiting transport of potentially
nephrotoxic drugs into the renal proximal tubular cells.
Organic anions are a large group of both endogenous and exogenous compounds including bile acids,
bilirubin, fatty acids, anionic drugs, and environmental toxins. OATs do not directly utilize ATP as the
driving force for substrate translocation. OATs operate as anion exchangers, coupling the uptake of an
organic anion to the release of another organic anion from within the cell
Common to all so far functionally characterized OATs is their broad substrate specificity and their ability to
exchange extracellular against intracellular organic anions. One prominent feature of the OAT system is
its interaction with and transport of a wide variety of clinically important anionic drugs, including
beta-lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), anti-HIV therapeutics,
anti-cancer drugs, and inhibitors of angiotensin-converting enzymes. As a consequence of the multi-
specific substrate recognition of the transporter, drug-drug interactions can take place at the transporter
molecules. Drugs coexisting in the plasma may compete for the transporter processes, thus mutually
influencing each other s pharmacological and toxicological profile. Such drug-drug interactions are an
important consideration in drug development and therapy. Several classes of drugs interact with human
OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase
inhibitors, beta-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs and toxins such
as ochratoxin A. OAT1 also transports some neutral and cationic compounds (e.g., cimetidine), but with a
lower affinity.
It was suggested that all investigational drugs should be evaluated in vitro to determine whether they are
a substrate of the isoforms OAT1, OAT3 or the organic cation transporter 2 (OCT2) when renal active
secretion contributes to most of its elimination.
Excretory tissue/organ such as liver, kidneys and intestine protect the human body against possibly
harmful effects of variety of endogenous and exogenous organic anion and cation substances mainly by
either biotransformation of them into less active metabolites or by the excretory transport process called
organic anion and cation transporters
OATs facilitate the cellular uptake of a wide range of structurally diverse small hydrophilic organic anions.
Several clinically important anionic drugs are OAT substrates, such as beta-lactam antibiotics, diuretics,
and nonsteroidal anti-inflammatories (NSAIDs).
All OAT family members are expressed in the kidney where they play key roles in renal organic anion
secretion. OAT2 (SLC22A7) is the only OAT family member that is highly expressed in the liver. There are
at least six OAT members (OAT1–6). In terms of tissue location, OAT1, OAT2, and OAT3 are expressed
(mostly) in the basolateral membrane of the renal proximal tubules, mediating the uptake of drug
substrates from the blood into the proximal tubule cells; OAT4, in contrast, is located at the apical side of
the renal proximal tubule, functioning in the secretion of drug substrates into urine . OAT1, OAT2, and
OAT3 are responsible for the uptake of drugs into the tubular cells, and OAT4 mediates their secretion
into the renal tubule. Additionally, OAT1 is an example of transporter-related toxicity. Different studies
have shown that OAT1 substrates, such as cephaloridine and beta-lactam antibiotics, sometimes cause
nephrotoxicity.
OAT2 when it was demonstrated to have sequence homology and functional similarities to renal OAT1. It
is localized to the basolateral membrane of hepatocytes where it mediates sodium-independent uptake of
organic anions. OAT2 has a very broad substrate specificity, transporting methotrexate, prostaglandin E2,

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cAMP, a-ketoglutarate, azidodeoxythymidine (AZT), prostaglandin F2a, tetracycline, p-amminohippurate

(PAH), bumetanide, estrone sulfate, glutarate, DHEAS, allopurinol, 5-fluorouracil, paclitaxel, and
l-ascorbic acid
Organic anion transporters (OATs) are the secondary/tertiary active transporter proteins that regulate
anion balance in the body. They are primarily expressed in the kidney and liver and control the excretion
of common drugs, toxins, and endogenous metabolites into the urine. They utilize the electrochemical
gradient of substrate or other ions to operate. The OATs have been identified to contain 12 alpha-helical
transmembrane domains (TMDs). Several isoforms of the transporters exist because of genetic variation.
.
OATs are reported to play an important role in transport of several organic anions in brain. There are
various OAT which are specific for the transport of peptides and are known as OATPs such as rOatp1
(SLC21A1) and rOtp2 (SLC21A4) in rats and hOatp-A (SLC21A3) in humans.
OATPs are tissue-specific and, in intestine, Oatp-B is the predominant type. Although the role of Oatp-B
in brain is not clear, some reports showed that it transports simvastatin and lovastatin that are known
inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and are used for the treatment of sleeping
disorders

Details of the manufacturer or supplier of the safety data sheet

Registered company
Alembic Pharmaceuticals Limited
name
Address Vadadora Gujarat India
Telephone +91-265-228-0550
Fax Not Available
Website [Link]
Email Not Available

Emergency telephone number

Association /
Alembic Pharmaceuticals Limited CHEMWATCH EMERGENCY RESPONSE (24/7)
Organisation
Emergency telephone
+91-265-228-0550 +918000403230
numbers
Other emergency
Not Available +61 3 9573 3188
telephone numbers

Once connected and if the message is not in your preferred language then please dial 01

SECTION 2 Hazards identification

Classification of the substance or mixture

NFPA 704 diamond
Note: The hazard category numbers found in GHS
classification in section 2 of this SDSs are NOT to be
used to fill in the NFPA 704 diamond. Blue = Health Red
= Fire Yellow = Reactivity White = Special (Oxidizer or
water reactive substances)

Acute Toxicity (Oral) Category 3, Acute Toxicity (Inhalation) Category 5, Skin Corrosion/Irritation Category
2, Serious Eye Damage/Eye Irritation Category 2A, Carcinogenicity Category 2, Reproductive Toxicity
Classification
Category 1B, Specific Target Organ Toxicity - Single Exposure (Respiratory Tract Irritation) Category 3,
Hazardous to the Aquatic Environment Long-Term Hazard Category 4

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Label elements

Hazard pictogram(s)

Signal word Danger

Hazard statement(s)
H301 Toxic if swallowed.
H333 May be harmful if inhaled.
H315 Causes skin irritation.
H319 Causes serious eye irritation.
H351 Suspected of causing cancer.
H360 May damage fertility or the unborn child.
H335 May cause respiratory irritation.
H413 May cause long lasting harmful effects to aquatic life.

Precautionary statement(s) Prevention

P201 Obtain special instructions before use.
P264 Wash all exposed external body areas thoroughly after handling.
P270 Do not eat, drink or smoke when using this product.
P271 Use only outdoors or in a well-ventilated area.
P280 Wear protective gloves, protective clothing, eye protection and face protection.
P261 Avoid breathing dust/fumes.
P273 Avoid release to the environment.

Precautionary statement(s) Response

P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/physician/first aider.
P308+P313 IF exposed or concerned: Get medical advice/ attention.
P330 Rinse mouth.
IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy
P305+P351+P338
to do. Continue rinsing.
P304+P312 IF INHALED: Call a POISON CENTER/doctor/physician/first aider if you feel unwell.
P337+P313 If eye irritation persists: Get medical advice/attention.
P302+P352 IF ON SKIN: Wash with plenty of water.
P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing.
P332+P313 If skin irritation occurs: Get medical advice/attention.
P362+P364 Take off contaminated clothing and wash it before reuse.

Precautionary statement(s) Storage

P405 Store locked up.
P403+P233 Store in a well-ventilated place. Keep container tightly closed.

Precautionary statement(s) Disposal

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TERIFLUNOMIDE

Dispose of contents/container to authorised hazardous or special waste collection point in accordance

P501
with any local regulation.

SECTION 3 Composition / information on ingredients

Substances
CAS No %[weight] Name
163451-81-8 >98 teriflunomide

Mixtures
See section above for composition of Substances

SECTION 4 First aid measures

Description of first aid measures

If this product comes in contact with the eyes:
Immediately hold eyelids apart and flush the eye continuously with running water.
Ensure complete irrigation of the eye by keeping eyelids apart and away from eye and moving the
eyelids by occasionally lifting the upper and lower lids.
Eye Contact
Continue flushing until advised to stop by the Poisons Information Centre or a doctor, or for at least 15
minutes.
Transport to hospital or doctor without delay.
Removal of contact lenses after an eye injury should only be undertaken by skilled personnel.
If skin contact occurs:
Immediately remove all contaminated clothing, including footwear.
Skin Contact
Flush skin and hair with running water (and soap if available).
Seek medical attention in event of irritation.
If fumes or combustion products are inhaled remove from contaminated area.
Lay patient down. Keep warm and rested.
Prostheses such as false teeth, which may block airway, should be removed, where possible, prior to
Inhalation initiating first aid procedures.
Apply artificial respiration if not breathing, preferably with a demand valve resuscitator, bag-valve mask
device, or pocket mask as trained. Perform CPR if necessary.
Transport to hospital, or doctor, without delay.
Give a slurry of activated charcoal in water to drink. NEVER GIVE AN UNCONSCIOUS PATIENT
WATER TO DRINK.
At least 3 tablespoons in a glass of water should be given.
Although induction of vomiting may be recommended (IN CONSCIOUS PERSONS ONLY), such a first
aid measure is dissuaded due to the risk of aspiration of stomach contents. (i) It is better to take the
patient to a doctor who can decide on the necessity and method of emptying the stomach. (ii) Special
circumstances may however exist; these include non-availability of charcoal and the ready availability
of the doctor.
NOTE: If vomiting is induced, lean patient forward or place on left side (head-down position, if possible) to
Ingestion maintain open airway and prevent aspiration.
NOTE: Wear protective gloves when inducing vomiting.
REFER FOR MEDICAL ATTENTION WITHOUT DELAY.
In the mean time, qualified first-aid personnel should treat the patient following observation and
employing supportive measures as indicated by the patient's condition.
If the services of a medical officer or medical doctor are readily available, the patient should be placed
in his/her care and a copy of the SDS should be provided. Further action will be the responsibility of
the medical specialist.
If medical attention is not available on the worksite or surroundings send the patient to a hospital

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TERIFLUNOMIDE

together with a copy of the SDS. (ICSC20305/20307)

Indication of any immediate medical attention and special treatment needed

There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well
tolerated by healthy subjects. Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomides
activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of
teriflunomide In the event of a significant overdose or toxicity of leflunomide, cholestyramine or charcoal administration is
recommended to accelerate elimination. Following oral administration, leflunomide is metabolized to an active metabolite
teriflunomide (A77 1726 - hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of
leflunomide are occasionally seen, at very low levels. Following oral administration, peak levels of the active metabolite, M1,
occurred between 6 - 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was
used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that
attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations
following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional. Studies with both
hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not
dialyzable
As in all cases of suspected poisoning, follow the ABCDEs of emergency medicine (airway, breathing, circulation, disability,
exposure), then the ABCDEs of toxicology (antidotes, basics, change absorption, change distribution, change elimination).
For poisons (where specific treatment regime is absent):
--------------------------------------------------------------
BASIC TREATMENT
--------------------------------------------------------------
Establish a patent airway with suction where necessary.
Watch for signs of respiratory insufficiency and assist ventilation as necessary.
Administer oxygen by non-rebreather mask at 10 to 15 L/min.
Monitor and treat, where necessary, for pulmonary oedema.
Monitor and treat, where necessary, for shock.
Anticipate seizures.
DO NOT use emetics. Where ingestion is suspected rinse mouth and give up to 200 ml water (5 ml/kg recommended) for dilution
where patient is able to swallow, has a strong gag reflex and does not drool.
--------------------------------------------------------------
ADVANCED TREATMENT
--------------------------------------------------------------
Consider orotracheal or nasotracheal intubation for airway control in unconscious patient or where respiratory arrest has
occurred.
Positive-pressure ventilation using a bag-valve mask might be of use.
Monitor and treat, where necessary, for arrhythmias.
Start an IV D5W TKO. If signs of hypovolaemia are present use lactated Ringers solution. Fluid overload might create
complications.
Drug therapy should be considered for pulmonary oedema.
Hypotension with signs of hypovolaemia requires the cautious administration of fluids. Fluid overload might create complications.
Treat seizures with diazepam.
Proparacaine hydrochloride should be used to assist eye irrigation.
BRONSTEIN, A.C. and CURRANCE, P.L.
EMERGENCY CARE FOR HAZARDOUS MATERIALS EXPOSURE: 2nd Ed. 1994

SECTION 5 Firefighting measures

Extinguishing media
Foam.
Dry chemical powder.
BCF (where regulations permit).
Carbon dioxide.
Water spray or fog - Large fires only.

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Special hazards arising from the substrate or mixture

Avoid contamination with oxidising agents i.e. nitrates, oxidising acids, chlorine bleaches, pool chlorine
Fire Incompatibility
etc. as ignition may result

Advice for firefighters

Alert Fire Brigade and tell them location and nature of hazard.
Wear full body protective clothing with breathing apparatus.
Prevent, by any means available, spillage from entering drains or water course.
Use fire fighting procedures suitable for surrounding area.
Fire Fighting
Do not approach containers suspected to be hot.
Cool fire exposed containers with water spray from a protected location.
If safe to do so, remove containers from path of fire.
Equipment should be thoroughly decontaminated after use.
Combustible solid which burns but propagates flame with difficulty; it is estimated that most organic
dusts are combustible (circa 70%) - according to the circumstances under which the combustion
process occurs, such materials may cause fires and / or dust explosions.
Organic powders when finely divided over a range of concentrations regardless of particulate size or
shape and suspended in air or some other oxidizing medium may form explosive dust-air mixtures and
result in a fire or dust explosion (including secondary explosions).
Avoid generating dust, particularly clouds of dust in a confined or unventilated space as dusts may
form an explosive mixture with air, and any source of ignition, i.e. flame or spark, will cause fire or
explosion. Dust clouds generated by the fine grinding of the solid are a particular hazard;
accumulations of fine dust (420 micron or less) may burn rapidly and fiercely if ignited - particles
exceeding this limit will generally not form flammable dust clouds; once initiated, however, larger
particles up to 1400 microns diameter will contribute to the propagation of an explosion.
In the same way as gases and vapours, dusts in the form of a cloud are only ignitable over a range of
concentrations; in principle, the concepts of lower explosive limit (LEL) and upper explosive limit (UEL)
are applicable to dust clouds but only the LEL is of practical use; - this is because of the inherent
difficulty of achieving homogeneous dust clouds at high temperatures (for dusts the LEL is often called
the "Minimum Explosible Concentration", MEC).
When processed with flammable liquids/vapors/mists,ignitable (hybrid) mixtures may be formed with
combustible dusts. Ignitable mixtures will increase the rate of explosion pressure rise and the
Minimum Ignition Energy (the minimum amount of energy required to ignite dust clouds - MIE) will be
Fire/Explosion Hazard lower than the pure dust in air mixture. The Lower Explosive Limit (LEL) of the vapour/dust mixture will
be lower than the individual LELs for the vapors/mists or dusts.
A dust explosion may release of large quantities of gaseous products; this in turn creates a
subsequent pressure rise of explosive force capable of damaging plant and buildings and injuring
people.
Usually the initial or primary explosion takes place in a confined space such as plant or machinery, and
can be of sufficient force to damage or rupture the plant. If the shock wave from the primary explosion
enters the surrounding area, it will disturb any settled dust layers, forming a second dust cloud, and
often initiate a much larger secondary explosion. All large scale explosions have resulted from chain
reactions of this type.
Dry dust can be charged electrostatically by turbulence, pneumatic transport, pouring, in exhaust ducts
and during transport.
Build-up of electrostatic charge may be prevented by bonding and grounding.
Powder handling equipment such as dust collectors, dryers and mills may require additional protection
measures such as explosion venting.
All movable parts coming in contact with this material should have a speed of less than 1-meter/sec.
A sudden release of statically charged materials from storage or process equipment, particularly at
elevated temperatures and/ or pressure, may result in ignition especially in the absence of an apparent
ignition source.
One important effect of the particulate nature of powders is that the surface area and surface structure
(and often moisture content) can vary widely from sample to sample, depending of how the powder

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TERIFLUNOMIDE

was manufactured and handled; this means that it is virtually impossible to use flammability data
published in the literature for dusts (in contrast to that published for gases and vapours).
Autoignition temperatures are often quoted for dust clouds (minimum ignition temperature (MIT)) and
dust layers (layer ignition temperature (LIT)); LIT generally falls as the thickness of the layer increases.
Combustion products include:
carbon monoxide (CO)
carbon dioxide (CO2)
hydrogen fluoride
nitrogen oxides (NOx)
other pyrolysis products typical of burning organic material.
May emit poisonous fumes.

SECTION 6 Accidental release measures

Personal precautions, protective equipment and emergency procedures

See section 8

Environmental precautions
See section 12

Methods and material for containment and cleaning up

Clean up waste regularly and abnormal spills immediately.
Avoid breathing dust and contact with skin and eyes.
Wear protective clothing, gloves, safety glasses and dust respirator.
Use dry clean up procedures and avoid generating dust.
Vacuum up or sweep up. NOTE: Vacuum cleaner must be fitted with an exhaust micro filter (H-Class
Minor Spills
HEPA type) (consider explosion-proof machines designed to be grounded during storage and
use). H-Class HEPA filtered industrial vacuum cleaners should NOT be used on wet materials or
surfaces.
Dampen with water to prevent dusting before sweeping.
Place in suitable containers for disposal.
Clear area of personnel and move upwind.
Alert Fire Brigade and tell them location and nature of hazard.
Wear full body protective clothing with breathing apparatus.
Prevent, by any means available, spillage from entering drains or water course.
Stop leak if safe to do so.
Contain spill with sand, earth or vermiculite.
Major Spills Collect recoverable product into labelled containers for recycling.
Neutralise/decontaminate residue (see Section 13 for specific agent).
Collect solid residues and seal in labelled drums for disposal.
Wash area and prevent runoff into drains.
After clean up operations, decontaminate and launder all protective clothing and equipment before
storing and re-using.
If contamination of drains or waterways occurs, advise emergency services.

Personal Protective Equipment advice is contained in Section 8 of the SDS.

SECTION 7 Handling and storage

Precautions for safe handling

Avoid all personal contact, including inhalation.
Wear protective clothing when risk of exposure occurs.
Safe handling
Use in a well-ventilated area.
Prevent concentration in hollows and sumps.

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TERIFLUNOMIDE

DO NOT enter confined spaces until atmosphere has been checked.

DO NOT allow material to contact humans, exposed food or food utensils.
Avoid contact with incompatible materials.
When handling, DO NOT eat, drink or smoke.
Keep containers securely sealed when not in use.
Avoid physical damage to containers.
Always wash hands with soap and water after handling.
Work clothes should be laundered separately. Launder contaminated clothing before re-use.
Use good occupational work practice.
Observe manufacturer's storage and handling recommendations contained within this SDS.
Atmosphere should be regularly checked against established exposure standards to ensure safe
working conditions are maintained.
Organic powders when finely divided over a range of concentrations regardless of particulate size or
shape and suspended in air or some other oxidizing medium may form explosive dust-air mixtures and
result in a fire or dust explosion (including secondary explosions)
Minimise airborne dust and eliminate all ignition sources. Keep away from heat, hot surfaces, sparks,
and flame.
Establish good housekeeping practices.
Remove dust accumulations on a regular basis by vacuuming or gentle sweeping to avoid creating
dust clouds.
Use continuous suction at points of dust generation to capture and minimise the accumulation of
dusts. Particular attention should be given to overhead and hidden horizontal surfaces to minimise the
probability of a "secondary" explosion. According to NFPA Standard 654, dust layers 1/32 in.(0.8 mm)
thick can be sufficient to warrant immediate cleaning of the area.
Do not use air hoses for cleaning.
Minimise dry sweeping to avoid generation of dust clouds. Vacuum dust-accumulating surfaces and
remove to a chemical disposal area. Vacuums with explosion-proof motors should be used.
Control sources of static electricity. Dusts or their packages may accumulate static charges, and static
discharge can be a source of ignition.
Solids handling systems must be designed in accordance with applicable standards (e.g. NFPA
including 654 and 77) and other national guidance.
Do not empty directly into flammable solvents or in the presence of flammable vapors.
The operator, the packaging container and all equipment must be grounded with electrical bonding
and grounding systems. Plastic bags and plastics cannot be grounded, and antistatic bags do not
completely protect against development of static charges.
Empty containers may contain residual dust which has the potential to accumulate following settling. Such
dusts may explode in the presence of an appropriate ignition source.
Do NOT cut, drill, grind or weld such containers.
In addition ensure such activity is not performed near full, partially empty or empty containers without
appropriate workplace safety authorisation or permit.
Store in original containers.
Keep containers securely sealed.
Store in a cool, dry, well-ventilated area.
Other information
Store away from incompatible materials and foodstuff containers.
Protect containers against physical damage and check regularly for leaks.
Observe manufacturer's storage and handling recommendations contained within this SDS.

Conditions for safe storage, including any incompatibilities

Glass container is suitable for laboratory quantities
Lined metal can, lined metal pail/ can.
Plastic pail.
Suitable container Polyliner drum.
Packing as recommended by manufacturer.
Check all containers are clearly labelled and free from leaks.
For low viscosity materials

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TERIFLUNOMIDE

Drums and jerricans must be of the non-removable head type.

Where a can is to be used as an inner package, the can must have a screwed enclosure.
For materials with a viscosity of at least 2680 cSt. (23 deg. C) and solids (between 15 C deg. and 40 deg
C.):
Removable head packaging;
Cans with friction closures and
low pressure tubes and cartridges
may be used.
-
Where combination packages are used, and the inner packages are of glass, there must be sufficient
inert cushioning material in contact with inner and outer packages *.
-
In addition, where inner packagings are glass and contain liquids of packing group I and II there must be
sufficient inert absorbent to absorb any spillage *.
-
* unless the outer packaging is a close fitting moulded plastic box and the substances are not
incompatible with the plastic.
Storage
Avoid reaction with oxidising agents
incompatibility

SECTION 8 Exposure controls / personal protection

Control parameters

Occupational Exposure Limits (OEL)

INGREDIENT DATA
Not Available

Emergency Limits

Ingredient TEEL-1 TEEL-2 TEEL-3

TERIFLUNOMIDE Not Available Not Available Not Available

Ingredient Original IDLH Revised IDLH

teriflunomide Not Available Not Available

Occupational Exposure Banding

Ingredient Occupational Exposure Band Rating Occupational Exposure Band Limit

teriflunomide E ≤ 0.01 mg/m³
Notes: Occupational exposure banding is a process of assigning chemicals into specific categories or bands
based on a chemical's potency and the adverse health outcomes associated with exposure. The output of
this process is an occupational exposure band (OEB), which corresponds to a range of exposure
concentrations that are expected to protect worker health.

MATERIAL DATA
CEL TWA: 0.006 mg/m3 (cf Sanofi OEL for leflunamide)
Airborne particulate or vapour must be kept to levels as low as is practicably achievable given access to modern engineering
controls and monitoring hardware. Biologically active compounds may produce idiosyncratic effects which are entirely unpredictable
on the basis of literature searches and prior clinical experience (both recent and past).

Exposure controls
For potent pharmacological agents:
Appropriate Powders
engineering controls To prevent contamination and overexposure, no open handling of powder should be allowed.

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TERIFLUNOMIDE

Powder handling operations are to be done in a powders weighing hood, a glove box, or other
equivalent ventilated containment system.
In situations where these ventilated containment hoods have not been installed, a non-ventilated
enclosed containment hood should be used.
Pending changes resulting from additional air monitoring data, up to 300 mg can be handled outside of
an enclosure provided that no grinding, crushing or other dust-generating process occurs.
An air-purifying respirator should be worn by all personnel in the immediate area in cases where
non-ventilated containment is used, where significant amounts of material (e.g., more than 2 grams)
are used, or where the material may become airborne (as through grinding, etc.).
Powder should be put into solution or a closed or covered container after handling.
If using a ventilated enclosure that has not been validated, wear a half-mask respirator equipped with
HEPA cartridges until the enclosure is validated for use.
Solutions Handling:
Solutions can be handled outside a containment system or without local exhaust ventilation during
procedures with no potential for aerosolisation. If the procedures have a potential for aerosolisation, an
air-purifying respirator is to be worn by all personnel in the immediate area.
Solutions used for procedures where aerosolisation may occur (e.g., vortexing, pumping) are to be
handled within a containment system or with local exhaust ventilation.
In situations where this is not feasible (may include animal dosing), an air-purifying respirator is to be
worn by all personnel in the immediate area. If using a ventilated enclosure that has not been
validated, wear a half-mask respirator equipped with HEPA cartridges until the enclosure is validated
for use.
Ensure gloves are protective against solvents in use.
Enclosed local exhaust ventilation is required at points of dust, fume or vapour generation.
HEPA terminated local exhaust ventilation should be considered at point of generation of dust, fumes or
vapours.
Barrier protection or laminar flow cabinets should be considered for laboratory scale handling.
A fume hood or vented balance enclosure is recommended for weighing/ transferring quantities
exceeding 500 mg.
When handling quantities up to 500 gram in either a standard laboratory with general dilution ventilation
(e.g. 6-12 air changes per hour) is preferred. Quantities up to 1 kilogram may require a designated
laboratory using fume hood, biological safety cabinet, or approved vented enclosures. Quantities
exceeding 1 kilogram should be handled in a designated laboratory or containment laboratory using
appropriate barrier/ containment technology.
Manufacturing and pilot plant operations require barrier/ containment and direct coupling technologies.
Barrier/ containment technology and direct coupling (totally enclosed processes that create a barrier
between the equipment and the room) typically use double or split butterfly valves and hybrid
unidirectional airflow/ local exhaust ventilation solutions (e.g. powder containment booths). Glove bags,
isolator glove box systems are optional. HEPA filtration of exhaust from dry product handling areas is
required.
Fume-hoods and other open-face containment devices are acceptable when face velocities of at least 1
m/s (200 feet/minute) are achieved. Partitions, barriers, and other partial containment technologies are
required to prevent migration of the material to uncontrolled areas. For non-routine emergencies
maximum local and general exhaust are necessary. Air contaminants generated in the workplace possess
varying "escape" velocities which, in turn, determine the "capture velocities" of fresh circulating air
required to effectively remove the contaminant.

Type of Contaminant: Air Speed:

0.25-0.5 m/s
solvent, vapours, etc. evaporating from tank (in still air)
(50-100 f/min.)
aerosols, fumes from pouring operations, intermittent container filling, low speed 0.5-1 m/s
conveyer transfers (released at low velocity into zone of active generation) (100-200 f/min.)
direct spray, drum filling, conveyer loading, crusher dusts, gas discharge (active 1-2.5 m/s
generation into zone of rapid air motion) (200-500 f/min.)

Within each range the appropriate value depends on:

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TERIFLUNOMIDE

Lower end of the range Upper end of the range

1: Room air currents minimal or favourable to capture 1: Disturbing room air currents
2: Contaminants of low toxicity or of nuisance value only. 2: Contaminants of high toxicity
3: Intermittent, low production. 3: High production, heavy use
4: Large hood or large air mass in motion 4: Small hood-local control only

Simple theory shows that air velocity falls rapidly with distance away from the opening of a simple
extraction pipe. Velocity generally decreases with the square of distance from the extraction point (in
simple cases). Therefore the air speed at the extraction point should be adjusted, accordingly, after
reference to distance from the contaminating source. The air velocity at the extraction fan, for example,
should be a minimum of 1-2.5 m/s (200-500 f/min.) for extraction of gases discharged 2 meters distant
from the extraction point. Other mechanical considerations, producing performance deficits within the
extraction apparatus, make it essential that theoretical air velocities are multiplied by factors of 10 or more
when extraction systems are installed or used.
The need for respiratory protection should also be assessed where incidental or accidental exposure is
anticipated: Dependent on levels of contamination, PAPR, full face air purifying devices with P2 or P3
filters or air supplied respirators should be evaluated.
The following protective devices are recommended where exposures exceed the recommended exposure
control guidelines by factors of:
10; high efficiency particulate (HEPA) filters or cartridges
10-25; loose-fitting (Tyvek or helmet type) HEPA powered-air purifying respirator.
25-50; a full face-piece negative pressure respirator with HEPA filters
50-100; tight-fitting, full face-piece HEPA PAPR
100-1000; a hood-shroud HEPA PAPR or full face-piece supplied air respirator operated in pressure
demand or other positive pressure mode.
Individual protection
measures, such as
personal protective
equipment
For laboratory, larger scale or bulk handling or where regular exposure in an occupational setting occurs:
Chemical goggles. [AS/NZS 1337.1, EN166 or national equivalent]
Face shield. Full face shield may be required for supplementary but never for primary protection of
eyes
Contact lenses may pose a special hazard; soft contact lenses may absorb and concentrate irritants. A
written policy document, describing the wearing of lens or restrictions on use, should be created for
Eye and face
each workplace or task. This should include a review of lens absorption and adsorption for the class of
protection
chemicals in use and an account of injury experience. Medical and first-aid personnel should be
trained in their removal and suitable equipment should be readily available. In the event of chemical
exposure, begin eye irrigation immediately and remove contact lens as soon as practicable. Lens
should be removed at the first signs of eye redness or irritation - lens should be removed in a clean
environment only after workers have washed hands thoroughly. [CDC NIOSH Current Intelligence
Bulletin 59].
Skin protection See Hand protection below
The selection of suitable gloves does not only depend on the material, but also on further marks of quality
which vary from manufacturer to manufacturer. Where the chemical is a preparation of several
substances, the resistance of the glove material can not be calculated in advance and has therefore to be
checked prior to the application.
The exact break through time for substances has to be obtained from the manufacturer of the protective
Hands/feet protection gloves and has to be observed when making a final choice.
Personal hygiene is a key element of effective hand care. Gloves must only be worn on clean hands.
After using gloves, hands should be washed and dried thoroughly. Application of a non-perfumed
moisturiser is recommended.
Suitability and durability of glove type is dependent on usage. Important factors in the selection of gloves
include:

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TERIFLUNOMIDE

· frequency and duration of contact,

· chemical resistance of glove material,
· glove thickness and
· dexterity
Select gloves tested to a relevant standard (e.g. Europe EN 374, US F739, AS/NZS 2161.1 or national
equivalent).
· When prolonged or frequently repeated contact may occur, a glove with a protection class of 5 or higher
(breakthrough time greater than 240 minutes according to EN 374, AS/NZS 2161.10.1 or national
equivalent) is recommended.
· When only brief contact is expected, a glove with a protection class of 3 or higher (breakthrough time
greater than 60 minutes according to EN 374, AS/NZS 2161.10.1 or national equivalent) is
recommended.
· Some glove polymer types are less affected by movement and this should be taken into account when
considering gloves for long-term use.
· Contaminated gloves should be replaced.
As defined in ASTM F-739-96 in any application, gloves are rated as:
· Excellent when breakthrough time > 480 min
· Good when breakthrough time > 20 min
· Fair when breakthrough time < 20 min
· Poor when glove material degrades
For general applications, gloves with a thickness typically greater than 0.35 mm, are recommended.
It should be emphasised that glove thickness is not necessarily a good predictor of glove resistance to a
specific chemical, as the permeation efficiency of the glove will be dependent on the exact composition of
the glove material. Therefore, glove selection should also be based on consideration of the task
requirements and knowledge of breakthrough times.
Glove thickness may also vary depending on the glove manufacturer, the glove type and the glove model.
Therefore, the manufacturers technical data should always be taken into account to ensure selection of
the most appropriate glove for the task.
Note: Depending on the activity being conducted, gloves of varying thickness may be required for specific
tasks. For example:
· Thinner gloves (down to 0.1 mm or less) may be required where a high degree of manual dexterity is
needed. However, these gloves are only likely to give short duration protection and would normally be just
for single use applications, then disposed of.
· Thicker gloves (up to 3 mm or more) may be required where there is a mechanical (as well as a
chemical) risk i.e. where there is abrasion or puncture potential
Gloves must only be worn on clean hands. After using gloves, hands should be washed and dried
thoroughly. Application of a non-perfumed moisturiser is recommended.
Rubber gloves (nitrile or low-protein, powder-free latex, latex/ nitrile). Employees allergic to latex
gloves should use nitrile gloves in preference.
Double gloving should be considered.
PVC gloves.
Change gloves frequently and when contaminated, punctured or torn.
Wash hands immediately after removing gloves.
Protective shoe covers. [AS/NZS 2210]
Head covering.
Body protection See Other protection below
For quantities up to 500 grams a laboratory coat may be suitable.
For quantities up to 1 kilogram a disposable laboratory coat or coverall of low permeability is
recommended. Coveralls should be buttoned at collar and cuffs.
For quantities over 1 kilogram and manufacturing operations, wear disposable coverall of low
permeability and disposable shoe covers.
Other protection
For manufacturing operations, air-supplied full body suits may be required for the provision of
advanced respiratory protection.
Eye wash unit.
Ensure there is ready access to an emergency shower.

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TERIFLUNOMIDE

For Emergencies: Vinyl suit

Respiratory protection
Type -P Filter of sufficient capacity. (AS/NZS 1716 & 1715, EN 143:2000 & 149:2001, ANSI Z88 or national equivalent)

Selection of the Class and Type of respirator will depend upon the level of breathing zone contaminant and the chemical nature of
the contaminant. Protection Factors (defined as the ratio of contaminant outside and inside the mask) may also be important.

Required minimum Maximum gas/vapour concentration present in air Half-face Full-Face

protection factor p.p.m. (by volume) Respirator Respirator
up to 10 1000 -AUS / Class1 P2 -
up to 50 1000 - -AUS / Class 1 P2
up to 50 5000 Airline * -
up to 100 5000 - -2 P2
up to 100 10000 - -3 P2
100+ Airline**

* - Continuous Flow ** - Continuous-flow or positive pressure demand

A(All classes) = Organic vapours, B AUS or B1 = Acid gasses, B2 = Acid gas or hydrogen cyanide(HCN), B3 = Acid gas or hydrogen
cyanide(HCN), E = Sulfur dioxide(SO2), G = Agricultural chemicals, K = Ammonia(NH3), Hg = Mercury, NO = Oxides of nitrogen, MB
= Methyl bromide, AX = Low boiling point organic compounds(below 65 degC)

· Respirators may be necessary when engineering and administrative controls do not adequately prevent exposures.
· The decision to use respiratory protection should be based on professional judgment that takes into account toxicity information,
exposure measurement data, and frequency and likelihood of the worker's exposure - ensure users are not subject to high thermal
loads which may result in heat stress or distress due to personal protective equipment (powered, positive flow, full face apparatus
may be an option).
· Published occupational exposure limits, where they exist, will assist in determining the adequacy of the selected respiratory
protection. These may be government mandated or vendor recommended.
· Certified respirators will be useful for protecting workers from inhalation of particulates when properly selected and fit tested as part
of a complete respiratory protection program.
· Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN143) dust masks. Use respirators
and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU)
· Use approved positive flow mask if significant quantities of dust becomes airborne.
· Try to avoid creating dust conditions.

SECTION 9 Physical and chemical properties

Information on basic physical and chemical properties

White to off-white crystalline solid; does not mix well with water. Teriflunomide is the only active
metabolite of leflunomide, completely responsible for its therapeutic actions. It results from the reaction of
Appearance isoxazole ring opening, which occurs in vivo. Teriflunomide then can interconvert between the E and Z
enolic forms (and the corresponding keto-amide), the Z-enol being the most stable and therefore most
predominant form.

Relative density
Physical state Divided Solid Not Applicable
(Water = 1)
Partition coefficient
Odour Not Available 2.922
n-octanol / water
Auto-ignition
Odour threshold Not Available Not Available
temperature (°C)
Decomposition
pH (as supplied) Not Applicable Not Available
temperature (°C)

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TERIFLUNOMIDE

Melting point /
229 Viscosity (cSt) Not Applicable
freezing point (°C)
Initial boiling point Molecular weight
Not Applicable 270.21
and boiling range (°C) (g/mol)
Flash point (°C) Not Available Taste Not Available
Evaporation rate Not Applicable Explosive properties Not Available
Flammability Not Available Oxidising properties Not Available
Upper Explosive Limit Surface Tension
Not Available Not Applicable
(%) (dyn/cm or mN/m)
Lower Explosive Limit Volatile Component
Not Available Negligible
(%) (%vol)
Vapour pressure
Negligible Gas group Not Available
(kPa)
Solubility in water Partly miscible pH as a solution (1%) Not Applicable
Vapour density (Air =
Not Applicable VOC g/L Not Applicable
1)

SECTION 10 Stability and reactivity

Reactivity See section 7

Unstable in the presence of incompatible materials.
Chemical stability Product is considered stable.
Hazardous polymerisation will not occur.
Possibility of
See section 7
hazardous reactions
Conditions to avoid See section 7
Incompatible
See section 7
materials
Hazardous
decomposition See section 5
products

SECTION 11 Toxicological information

Information on toxicological effects

Evidence shows, or practical experience predicts, that the material produces irritation of the respiratory
system, in a substantial number of individuals, following inhalation. In contrast to most organs, the lung is
able to respond to a chemical insult by first removing or neutralising the irritant and then repairing the
damage. The repair process, which initially evolved to protect mammalian lungs from foreign matter and
antigens, may however, produce further lung damage resulting in the impairment of gas exchange, the
primary function of the lungs. Respiratory tract irritation often results in an inflammatory response
involving the recruitment and activation of many cell types, mainly derived from the vascular system.
Inhaled
Inhalation of dusts, generated by the material during the course of normal handling, may be damaging to
the health of the individual.
Persons with impaired respiratory function, airway diseases and conditions such as emphysema or
chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.
If prior damage to the circulatory or nervous systems has occurred or if kidney damage has been
sustained, proper screenings should be conducted on individuals who may be exposed to further risk if
handling and use of the material result in excessive exposures.

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Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes
(ALT and AST), alopecia and rash Up to 20% of patients experience stomach and bowel side effects
when taking leflunomide. These effects can include excessive wind, bowel discomfort, loss of appetite,
nausea (feeling sick) and diarrhoea. Up to 10% of patients may have other common side effects such as
skin rash, reversible thinning of hair, increase in blood pressure or dizziness. There are some rare but
potentially serious side effects with leflunomide. Blood counts: Leflunomide can cause a drop in the
number of white blood cells, which are needed to fight infection. It can also cause a drop in the number of
platelets, which help to stop bleeding. Infections: There is an increased risk of developing some
infections, especially herpes zoster (chicken pox and shingles). Liver enzymes: Leflunomide can cause
liver test to rise, which may be due to hepatitis (liver inflammation). There have been rare reports of
Ingestion
numbness (neuropathy) in patients taking leflunomide. There have been rare reports of lung inflammation
in patients taking leflunomide. In mouse and rat acute toxicology studies, the minimally toxic dose for oral
leflunomide was 200 - 500 mg/kg and 100 mg/kg, respectively (approximately > 350 times the maximum
recommended human dose, respectively).
Toxic effects may result from the accidental ingestion of the material; animal experiments indicate that
ingestion of less than 40 gram may be fatal or may produce serious damage to the health of the
individual.
At sufficiently high doses the material may be hepatotoxic (i.e. poisonous to the liver). Signs may include
nausea, stomach pains, low fever, loss of appetite, dark urine, clay-coloured stools, jaundice (yellowing of
the skin or eyes)

Evidence exists, or practical experience predicts, that the material either produces inflammation of the
skin in a substantial number of individuals following direct contact, and/or produces significant
inflammation when applied to the healthy intact skin of animals, for up to four hours, such inflammation
being present twenty-four hours or more after the end of the exposure period. Skin irritation may also be
present after prolonged or repeated exposure; this may result in a form of contact dermatitis (nonallergic).
The dermatitis is often characterised by skin redness (erythema) and swelling (oedema) which may
Skin Contact progress to blistering (vesiculation), scaling and thickening of the epidermis. At the microscopic level
there may be intercellular oedema of the spongy layer of the skin (spongiosis) and intracellular oedema of
the epidermis.
The material may accentuate any pre-existing dermatitis condition
Open cuts, abraded or irritated skin should not be exposed to this material
Entry into the blood-stream through, for example, cuts, abrasions, puncture wounds or lesions, may
produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure
that any external damage is suitably protected.
Evidence exists, or practical experience predicts, that the material may cause eye irritation in a
substantial number of individuals and/or may produce significant ocular lesions which are present
twenty-four hours or more after instillation into the eye(s) of experimental animals.
Eye
Repeated or prolonged eye contact may cause inflammation characterised by temporary redness (similar
to windburn) of the conjunctiva (conjunctivitis); temporary impairment of vision and/or other transient eye
damage/ulceration may occur.
There have been reports of chronic overdose in patients taking Arava (leflunomide) at daily dose up to
five times the recommended daily dose and reports of acute overdose in adults or children. There were
no adverse events reported in the majority of case reports of overdose
On the basis, primarily, of animal experiments, concern has been expressed that the material may
produce carcinogenic or mutagenic effects; in respect of the available information, however, there
presently exists inadequate data for making a satisfactory assessment.
Long-term exposure to respiratory irritants may result in disease of the airways involving difficult breathing
Chronic
and related systemic problems.

There is sufficient evidence to provide a strong presumption that human exposure to the material may
result in impaired fertility on the basis of: - clear evidence in animal studies of impaired fertility in the
absence of toxic effects, or evidence of impaired fertility occurring at around the same dose levels as
other toxic effects but which is not a secondary non-specific consequence of other toxic effects.
There is sufficient evidence to provide a strong presumption that human exposure to the material may

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TERIFLUNOMIDE

result in developmental toxicity, generally on the basis of:

- clear results in appropriate animal studies where effects have been observed in the absence of marked
maternal toxicity, or at around the same dose levels as other toxic effects but which are not secondary
non-specific consequences of the other toxic effects.
CAUTION: May produce immunosuppression in individuals occupationally exposed to the material.
Exposure to immunosuppressives may aggravate infectious diseases.
Chronic exposure to therapeutic doses of compounds which produce immunosuppression has been
associated with development of lymphomas (occasionally malignant) and mammary tumours. These may
be secondary effects induced by activation of endogenous retroviruses.
Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to
the general population. Furthermore, people who currently have or have already been treated for cancer
have a higher rate of tumor progression and recurrence than patients with an intact immune system.
Patients receiving immunosuppressive regimens involving combinations of drugs, as part of an
immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies,
particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression
rather than to the use of any specific agent
Increased incidences of neoplasms, in mice and humans, have been reported after long-term
immunosuppression by azathioprine and cyclosporin. Cyclosporin has been classified as a human
carcinogen, by IARC, based on development of lymphomas after repeated and prolonged exposures to
therapeutic doses.

Long term exposure to high dust concentrations may cause changes in lung function (i.e.
pneumoconiosis) caused by particles less than 0.5 micron penetrating and remaining in the lung. A prime
symptom is breathlessness. Lung shadows show on X-ray.
Repeated or long-term occupational exposure is likely to produce cumulative health effects involving
organs or biochemical systems.

TOXICITY IRRITATION
teriflunomide
Oral (Mouse) LD50; 100 mg/kg[2] Not Available

Legend: 1. Value obtained from Europe ECHA Registered Substances - Acute toxicity 2. Value obtained from
manufacturer's SDS. Unless otherwise specified data extracted from RTECS - Register of Toxic Effect of
chemical Substances

* Hoechst quoted on Sanofi SDS ** Enzo Life Science SDS for A77-1726 The side-effects of Arava affect
quite a number of organ systems, are frequent and at times severe or even fatal. Most serious is
symptomatic liver damage ranging from jaundice to hepatitis, which can be fulminant, severe liver
necrosis, and liver cirrhosis. Fatalities are known. Liver function studies may or may not precede the
outbreak of clinical disease. The total incidence of severe liver damage is estimated to be as high as
0.5%, according to an internal report of the FDA. The EMEA, the European pendant to FDA, has in 2001
reported 296 cases of hepatotoxicity in 104,000 patient years, with 129 considered as serious, 2 cases of
liver cirrhosis, and 15 cases of liver failure. Nine of the patients died. EMEA findings are that liver damage
is typically seen within the first 6 months of therapy and is partially depending on cofactors, because of
the serious cases 101 (78%) were concomitantly treated with other hepatotoxic drugs; 58% of those with
TERIFLUNOMIDE asymptomatic elevations of liver function studies were cotreated with certain NSARs and/or methotrexate
. In addition, 33% (=27 patients) of the patients with serious damage had other risk factors (history of
alcohol abuse, liver function disturbance, acute heart failure, severe pulmonary disease or pancreatic
carcinoma). Analysis of the data suggested that monitoring of liver function studies and wash-out periods
may have not been fully adhered to. Also very important is a relatively high incidence of
myelosuppression with leukopenia, and/or hypoplastic anemia, and/or thrombocytopenia. Infections,
sometimes as severe as development of active tuberculosis, pneumonia, PCP, and severe viral or
mycotical infections, possibly leading to sepsis, death or permanent damage have been seen. Anemia or
bleeding episodes may also lead to serious complications. Interstitial lung disease may occasionally be
noticed and is recognized by progressive dyspnea and typical X-ray findings. This disease may or may

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TERIFLUNOMIDE

not be reversible upon treatment and may lead to permanent disability or death. Other sites are: GIT, skin
reactions up to life-threatening forms (Stevens-Johnson syndrome and toxic epidermal necrolysis, heart
problems, alopecia (17%), CNS troubles etc Due to its potent immunosuppression, leflunomide has the
potential to promote myeloid/lymphatic malignancies or solid cancers. In postmarketing reports some
cases of lymphoma have been noticed, the absolute number of cases and the case/patient ratio is
unknown. In rheumatoid arthritis patients a several-fold increase of lymphoma is already found in those
patients not treated with any DMARD. Leflunomide, when administered orally to rats during
organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia
and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the
human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a
decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body
weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis
resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the
maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in
rats and rabbits. When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before
mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%)
decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the
human exposure level based on AUC. Arava is a potent drug comparing favourably with other DMARDs
regarding the efficacy as measured by improvements on the ACR scale. Leflunomide met the ACR20
criteria in up to 56% of patients; most other drugs (e.g., methotrexate alone, sulfasalazine, TNF-inhibitors
(infliximab, etanercept, and adalimumab), the latter drugs also in combination with methotrexate) reach
values from 20% only up to approximately 50%. Arava was withdrawn in clinical studies in 36% of
patients due to different reasons (intolerable side-effects, lack of efficacy, unspecified reasons); the
incidence was not higher than observed in the methotrexate control group. However, postmarketing data
regarding the high incidence of severe liver damage, serious myelosuppression, profound
immunosuppression leading to serious or even fatal infections, the possibility that Arava is a human
carcinogen, and the occurrence of interstitial lung disease has led to the forming of patient groups in the
USA and Europe, for example, supported by safety aware physicians. These groups call for the local or
worldwide ban or discontinuation of Arava.
Asthma-like symptoms may continue for months or even years after exposure to the material ends. This
may be due to a non-allergic condition known as reactive airways dysfunction syndrome (RADS) which
can occur after exposure to high levels of highly irritating compound. Main criteria for diagnosing RADS
include the absence of previous airways disease in a non-atopic individual, with sudden onset of
persistent asthma-like symptoms within minutes to hours of a documented exposure to the irritant. Other
criteria for diagnosis of RADS include a reversible airflow pattern on lung function tests, moderate to
severe bronchial hyperreactivity on methacholine challenge testing, and the lack of minimal lymphocytic
inflammation, without eosinophilia. RADS (or asthma) following an irritating inhalation is an infrequent
disorder with rates related to the concentration of and duration of exposure to the irritating substance. On
the other hand, industrial bronchitis is a disorder that occurs as a result of exposure due to high
concentrations of irritating substance (often particles) and is completely reversible after exposure ceases.
The disorder is characterized by difficulty breathing, cough and mucus production.
The severe side effects, narrow therapeutic window, and inconsistent pharmacokinetics of the available
DHODH inhibitors raise the need of new and more efficient human DHODH inhibitor.
Inhibitors of DHODH lead to the rapid depletion of intra-cellular UMP and downstream metabolites. A cell
s capacity to salvage uridine is limited, and no cell can tolerate complete DHODH-inhibition and
pyrimidine starvation indefinitely.
Pyrimidine starvation secondary to DHODH inhibition results in death-from-starvation as compared to the
death-from-cumulative-damage that one might expect from cytotoxic chemotherapeutic agents.
Cumulative damage in normal tissues ([Link], gastrointestinal) results in dose-limiting clinical
side-effects. Indeed, in the short-term, many chemotherapies are given at the maximum tolerated dose
(MTD) followed by long periods of recovery. In the long-term, cumulative damage results in secondary
malignancies, a devastating consequence in the patient who survives one cancer only to develop a
treatment-related secondary [Link] interesting possibility for DHODH inhibitors is that MTD-level
dosing may not be necessary to derive clinical benefit. It may be possible to achieve the therapeutically-
desired effect of pyrimidine starvation with doses lower than those that are frankly cytotoxic and lead to
cumulative damage.

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TERIFLUNOMIDE

Although most conventional DMARDs have similar adverse effects, there are several adverse effects
unique to each agent.
The most concerning adverse effect of all biologic DMARDs is increased risk of common and serious
infections including bacterial, fungal and viral infections. Reactivation of tuberculosis, herpes zoster and
hepatitis B/C can also occur. Rarely, bone marrow suppression and hepatotoxicity have been reported
with biologic DMARDs. Anti TNF agents can cause worsening of severe congestive heart failure,
drug-induced lupus, demyelinating central nervous system (CNS) diseases. Lymphomas and
non-melanoma skin cancers may be associated with Anti-TNF agents as well. Hyperlipidemia, elevated
liver function test and pancytopenia can be caused by IL-6 inhibitors and JAK inhibitors. Worsening of
chronic obstructive airway disease has been reported secondary to abatacept. IL-17 inhibitors can
cause/worsen inflammatory bowel disease. Progressive multifocal leukoencephalopathy has been
reported in patients treated with rituximab

Acute Toxicity Carcinogenicity

Skin
Reproductivity
Irritation/Corrosion
Serious Eye STOT - Single
Damage/Irritation Exposure
Respiratory or Skin STOT - Repeated
sensitisation Exposure
Mutagenicity Aspiration Hazard

Legend: – Data either not available or does not fill the criteria for classification
– Data available to make classification

SECTION 12 Ecological information

Toxicity

Endpoint Test Duration (hr) Species Value Source

Not
EC50 48h Crustacea >100mg/l
Available
teriflunomide Not
LC50 96h Fish 50-100mg/l
Available
Not
EC50(ECx) 48h Crustacea >100mg/l
Available

Legend: Extracted from 1. IUCLID Toxicity Data 2. Europe ECHA Registered Substances - Ecotoxicological
Information - Aquatic Toxicity 4. US EPA, Ecotox database - Aquatic Toxicity Data 5. ECETOC Aquatic
Hazard Assessment Data 6. NITE (Japan) - Bioconcentration Data 7. METI (Japan) - Bioconcentration
Data 8. Vendor Data

Degradability (2 8 d): ~1% (ThOD - OECD 301 E) - not readily degradable Fish LC50 (96 h): zebra fish 50-100 mg/l (OECD 203)
Daphnia magna EC50 (48 h): >100 mg/l
May cause long-term adverse effects in the aquatic environment.
Do NOT allow product to come in contact with surface waters or to intertidal areas below the mean high water mark. Do not
contaminate water when cleaning equipment or disposing of equipment wash-waters.
Wastes resulting from use of the product must be disposed of on site or at approved waste sites.
DO NOT discharge into sewer or waterways.

Persistence and degradability

Ingredient Persistence: Water/Soil Persistence: Air
No Data available for all ingredients No Data available for all ingredients

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TERIFLUNOMIDE

Bioaccumulative potential
Ingredient Bioaccumulation
No Data available for all ingredients

Mobility in soil
Ingredient Mobility
No Data available for all ingredients

SECTION 13 Disposal considerations

Waste treatment methods

Containers may still present a chemical hazard/ danger when empty.
Return to supplier for reuse/ recycling if possible.
Otherwise:
If container can not be cleaned sufficiently well to ensure that residuals do not remain or if the
container cannot be used to store the same product, then puncture containers, to prevent re-use, and
bury at an authorised landfill.
Where possible retain label warnings and SDS and observe all notices pertaining to the product.
Legislation addressing waste disposal requirements may differ by country, state and/ or territory. Each
user must refer to laws operating in their area. In some areas, certain wastes must be tracked.
A Hierarchy of Controls seems to be common - the user should investigate:
Reduction
Product / Packaging
Reuse
disposal
Recycling
Disposal (if all else fails)
This material may be recycled if unused, or if it has not been contaminated so as to make it unsuitable for
its intended use. Shelf life considerations should also be applied in making decisions of this type. Note
that properties of a material may change in use, and recycling or reuse may not always be appropriate. In
most instances the supplier of the material should be consulted.
DO NOT allow wash water from cleaning or process equipment to enter drains.
It may be necessary to collect all wash water for treatment before disposal.
In all cases disposal to sewer may be subject to local laws and regulations and these should be
considered first.
Where in doubt contact the responsible authority.

SECTION 14 Transport information

Labels Required

Marine Pollutant NO

Land transport (UN)

UN number or ID
3249
number
UN proper shipping
MEDICINE, SOLID, TOXIC, N.O.S. (contains teriflunomide)
name

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TERIFLUNOMIDE

Transport hazard Class 6.1

class(es) Subsidiary risk Not Applicable

Packing group III

Environmental hazard Not Applicable

Special precautions Special provisions 221; 223

for user Limited quantity 5 kg

Air transport (ICAO-IATA / DGR)

UN number 3249
UN proper shipping
Medicine, solid, toxic, n.o.s. (contains teriflunomide)
name

ICAO/IATA Class 6.1

Transport hazard
ICAO / IATA Subrisk Not Applicable
class(es)
ERG Code 6L

Packing group III

Environmental hazard Not Applicable

Special provisions A3
Cargo Only Packing Instructions 677
Cargo Only Maximum Qty / Pack 200 kg
Special precautions
Passenger and Cargo Packing Instructions 670
for user
Passenger and Cargo Maximum Qty / Pack 100 kg
Passenger and Cargo Limited Quantity Packing Instructions Y645
Passenger and Cargo Limited Maximum Qty / Pack 5 kg

Sea transport (IMDG-Code / GGVSee)

UN number 3249
UN proper shipping
MEDICINE, SOLID, TOXIC, N.O.S. (contains teriflunomide)
name

Transport hazard IMDG Class 6.1

class(es) IMDG Subrisk Not Applicable

Packing group III

Environmental hazard Not Applicable

EMS Number F-A, S-A

Special precautions
Special provisions 221 223
for user
Limited Quantities 5 kg

Transport in bulk according to Annex II of MARPOL and the IBC code

Product name Pollution Category Ship Type
Fatty acids, (C12+) Y 2

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TERIFLUNOMIDE

Transport in bulk in accordance with MARPOL Annex V and the IMSBC Code
Product name Group
teriflunomide Not Available

Transport in bulk in accordance with the IGC Code

Product name Ship Type
teriflunomide Not Available

SECTION 15 Regulatory information

Safety, health and environmental regulations / legislation specific for the substance or mixture

teriflunomide is found on the following regulatory lists

Not Applicable

National Inventory Status

National Inventory Status
Australia - AIIC /
Australia Non-Industrial No (teriflunomide)
Use
Canada - DSL No (teriflunomide)
Canada - NDSL No (teriflunomide)
China - IECSC No (teriflunomide)
Europe - EINEC /
No (teriflunomide)
ELINCS / NLP
Japan - ENCS No (teriflunomide)
Korea - KECI No (teriflunomide)
New Zealand - NZIoC No (teriflunomide)
Philippines - PICCS No (teriflunomide)
USA - TSCA No (teriflunomide)
Taiwan - TCSI Yes
Mexico - INSQ No (teriflunomide)
Vietnam - NCI No (teriflunomide)
Russia - FBEPH No (teriflunomide)
Yes = All CAS declared ingredients are on the inventory
Legend: No = One or more of the CAS listed ingredients are not on the inventory. These ingredients may be
exempt or will require registration.

SECTION 16 Other information

Revision Date 13/04/2020

Initial Date 11/12/2016

SDS Version Summary

Date of
Version Sections Updated
Update
Toxicological information - Chronic Health, Hazards identification - Classification,
3.1 13/04/2020

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TERIFLUNOMIDE

Date of
Version Sections Updated
Update
Toxicological information - Toxicity and Irritation (Other), Identification of the substance /
mixture and of the company / undertaking - Use

Other information

Ingredients with multiple cas numbers

Name CAS No
teriflunomide 163451-81-8, 1185240-22-5, 108605-62-5

Classification of the preparation and its individual components has drawn on official and authoritative sources as well as independent
review by the Chemwatch Classification committee using available literature references.

The SDS is a Hazard Communication tool and should be used to assist in the Risk Assessment. Many factors determine whether the
reported Hazards are Risks in the workplace or other settings. Risks may be determined by reference to Exposures Scenarios. Scale
of use, frequency of use and current or available engineering controls must be considered.

Definitions and abbreviations

PC TWA: Permissible Concentration-Time Weighted Average
PC STEL: Permissible Concentration-Short Term Exposure Limit
IARC: International Agency for Research on Cancer
ACGIH: American Conference of Governmental Industrial Hygienists
STEL: Short Term Exposure Limit
TEEL: Temporary Emergency Exposure Limit
IDLH: Immediately Dangerous to Life or Health Concentrations
ES: Exposure Standard
OSF: Odour Safety Factor
NOAEL :No Observed Adverse Effect Level
LOAEL: Lowest Observed Adverse Effect Level
TLV: Threshold Limit Value
LOD: Limit Of Detection
OTV: Odour Threshold Value
BCF: BioConcentration Factors
BEI: Biological Exposure Index
AIIC: Australian Inventory of Industrial Chemicals
DSL: Domestic Substances List
NDSL: Non-Domestic Substances List
IECSC: Inventory of Existing Chemical Substance in China
EINECS: European INventory of Existing Commercial chemical Substances
ELINCS: European List of Notified Chemical Substances
NLP: No-Longer Polymers
ENCS: Existing and New Chemical Substances Inventory
KECI: Korea Existing Chemicals Inventory
NZIoC: New Zealand Inventory of Chemicals
PICCS: Philippine Inventory of Chemicals and Chemical Substances
TSCA: Toxic Substances Control Act
TCSI: Taiwan Chemical Substance Inventory
INSQ: Inventario Nacional de Sustancias Químicas
NCI: National Chemical Inventory
FBEPH: Russian Register of Potentially Hazardous Chemical and Biological Substances

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TERIFLUNOMIDE

This document is copyright.

Apart from any fair dealing for the purposes of private study, research, review or criticism, as permitted under the Copyright Act, no
part may be reproduced by any process without written permission from CHEMWATCH.
TEL (+61 3) 9572 4700.

end of SDS