Toxicity Studies Guidelines

Dr. C. Ronald Darwin., M. Pharm, MBA, PhD.
,
Professor & Head
Department of Pharmacology,
MSAJCP, Chennai-119
08/13/16
General outline
Toxicity is the degree to which
substance can damage an organism.
Types of toxins
General category of toxic entities
Chemical
-- both organic and Inorganic
substance
Biological
-- bacteria and viruses
Physical
--substances that, due to their
physical nature,
interfere with
biological processes
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What is toxicity study?

Study of adverse effects of chemical and
physical agents and the degree to which
a substance can harm human or animals.
Types
of
investigation.
Acute toxicity
Sub acute toxicity
Sub Chronic toxicity
Chronic toxicity
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toxicological
Guidelines for toxicity

studies
OECD Guidelines
US FDA Guidelines
ICH Guidelines
EMA Guidelines
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OECD
Guidelines
Acute toxicity
Acute
Acute
Acute
Acute
Acute
Oral Toxicity 401

Dermal Irritation/Corrosion 404
Oral Toxicity Acute Toxic Class Method 420
Sub acute toxicity

Repeated Dose 28-day Oral Toxicity Study in Rodents (OECD
407)
Repeated Dose 28-day Oral Toxicity Study in Rodents Dermal
(OECD 410)
Repeated Dose 28-day Oral Toxicity Study in Rodents Inhalation
(OECD 412)
Chronic toxicity
Test Guideline 452
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Acute Toxicity Studies OEDC

423
Single dose - rat, mouse (3/sex/dose)
14 day observation
In-life observations (body wt., food consumption, clinical
observations)
Necropsy
no further testing is needed,
dosing of three additional animals, with the same dose
dosing of three additional animals at the next higher or
lower dose level.
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Acute LD50 Values vs

Toxicity
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Subacute Toxicity
28 day study (3 doses and control)

Species - rat (10/sex/dose)
In-life observations
Clinical pathology
Necropsy
Histopathology
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Subchronic Toxicity
13 week study +/- 4 wk recovery (3 doses and
control)
Species - rat (10/sex/dose)
In-life observations (+/- ophthalmology)
Clinical pathology
Necropsy
Histopathology
Used to set doses for carcinogenicity studies
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Chronic Toxicity
1 year study +/- 4-13 wk recovery (3 doses and
control)
Species - rat (10-15/sex/dose), dog or monkey
(2-3 /sex/dose)
In-life observations including ophthalmology
Necropsy
Histopathology
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Carcinogenicity Study
2 years (3 doses and control)

Species - rats and mice (50/sex/dose)
In-life observations
Toxicokinetic studies
Clinical pathology (rats, optional)
Necropsy
Histopathology
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CPCSEA guidelines for laboratory

animal facilities
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Conflicting Views
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Need of CPCSEA
To ensure that lab animals are well maintained
and experiments are conducted according to
ethical norms.
To promote humane care of animals used in
biomedical and behavioral research.
To enhance animal well being and quality .
To improve laboratory animal facility
To enhance biological knowledge that is relevant
to humans and animals.
14
Governing Body
It is established under the provision of
Prevention of cruelty act of 1960.
The Experiments on animals amendment
rules(1998) and Breeding of and experiments
on animals(1998) gave powers to the CPCSEA.
Objectives
To make rules in relation to the conduct of
experiments on animals.
To authorize any of its officers to inspect any
place at any time.
To prohibit a person or an institute from
carrying out experiments on animals.
15
GUIDELINES
Veterinary care
Animal procurement
Quarantine,Stabilization and Separation
Surveillance,Diagnosis,t/t and control of diseases
Animal care and technical personnel
Personal hygiene
Animal experiments involving hazardous agents
Multiple surgical procedures on single animal
Duration of experiments
Environment
Food and water
Sanitation and cleanliness
Waste disposal
Pest control
Record keeping
Personnel and training
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GUIDELINES
Veterinary care
Daily observation of animals.
Reviewing protocols and proposals
Establishment of appropriate policies and procedures
for animal husbandry.

To maintain zoonosis control programmes.
Animal procurement
Animals are procured from CPCSEA registered
breeders.
Quarantine
Quarantine is the separation of newly received
animals from those already in the animal facility.

It determines microbial status of newly received
animals.
Minimizes the chance for introduction of pathogens
into an established colony.
Duration- small animals 1 week
Large animals- 6 week.
17
Stabilization and separation

Physiological, psychological and nutritional
stabilization is needed.
Separation is based on species to prevent
diseases and transmission.
Animal care and technical personnel

Animal care programmes should be conducted.
People trained in animal science should be
appointed.
Personal hygiene
Showers, changing rooms, footwares.
Clothing.
Use disposable wear such as gloves ,masks,
head covers, coats, shoe covers.

Avoid eat, drink and smoke in animal facility.
18
Animal experimentation involving hazardous

agents
Procedures and facilities involving hazardous agents
should be reviewed by,

Institutional Bio-safety Committee .
Institutional Animal Ethics Committee(IAEC).
Multiple surgical procedures on single animal

No animal should be used for experimentation for
more than 3 years unless adequate justification is

provided.
Physical restraint
for examination , collection of samples and surgical
operations.
Accomplished by manually or by devices.
Devices should be suitable in size design for the
animal being held and operated properly to minimize
stress and avoid injury to the human.
Period of restraint should be minimum.
Less restrictive systems should be used.
19
Animal facility`
Separated from personnel areas such as offices
and most laboratories.

Located as far away from human habitations as
possible.
Not exposed to dust ,smoke, noise , wild
rodents, insects and birds.
Sharp fluctuations in temperature, humidity,
light, sound and ventilation should be avoided.
Functional areas
Separate areas for food, bedding, surgery
,treatment, storage, washing.

Area for repairing cages and equipment.
Specialized laboratories.
20
Environment
Temperature - 18-29O C .
Humidity- 30-70 %.
Ventilation- air conditioning systems.
Power and lighting- fluorescent lights,
emergency power.
Animal husbandry
Adequate space, maintenance of body temp
,urination, defecation and reproduction.

Keep the animals dry and clean.
Polypropylene, polycarbonate and stainless steel
cages should be used.
Easy for inspection.
Social environment
Population density can affect reproduction,
metabolism, immune responses and behaviour.

21
Food
Palatable, non contaminated and nutritionally
adequate.
Should contain crude fibe,r crude protein,
essential vitamins, minerals ,fat and
carbohydrates for providing appropriate
nutrition.
Bedding
Absorbent, free of toxic chemicals.
Change the bedding twice a week.
Optimizes normal animal behaviour.
Water
fresh, potable, uncontaminated.
Pest control
Pest control programmes.
Emergency weekend and holiday care

Everyday care is essential
Personnel and training

Animal facility staff is critical component in the
management.
22
Sanitation and cleanliness

Cages should be sanitized before the animal is
placed.
Cages and water bottles can be disinfected by
rinsing at a temperature of 82.20 C or by
chemical agents such as hypochlorite to destroy
pathogenic microbes.
Autoclave or gas sterilizers can be used.
Record keeping
Animal house plans.
Staff record.
Standard operating procedures(SOP)
Health records.
Breeding, stock, purchase and sales records.
Death record
Records of experiments on animals.
Clinical record of sick animals.
Waste analysis report.
23
Guidelines for Use of Anaesthesia

Useful for painful procedures.
At no stage of experiment the animal is
conscious to perceive the pain.

If any irrepairable injury occurs , the
animal should be sacrificed.
Overnight fasting.
Use pre-anaesthetics were ever
applicable.
Local or general anaesthetics may be
used.
Side effects such as excessive salivation,
convulsions, excitation and disorientation.
24
Euthanasia
Painless killing.
Animal is required to sacrificed on
termination of an experiment or
otherwise for ethical reasons, death
without causing anxiety, pain with
minimum time lag phase.
Location should be separated from
animal rooms.
Tranquillizers should be given for larger
animals such as monkeys, dogs, cats
before an euthanasia procedure.
25
26
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Discussion
08/13/16
08/13/16

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Dr. C. Ronald Darwin., M. Pharm, MBA, PhD.

What is toxicity study?

Guidelines for toxicity

Oral Toxicity 401

Sub acute toxicity

Acute Toxicity Studies OEDC

Acute LD50 Values vs

28 day study (3 doses and control)

2 years (3 doses and control)

CPCSEA guidelines for laboratory

for animal husbandry.

animals from those already in the animal facility.

Stabilization and separation

Animal care and technical personnel

head covers, coats, shoe covers.

Animal experimentation involving hazardous

should be reviewed by,

Multiple surgical procedures on single animal

more than 3 years unless adequate justification is

and most laboratories.

,treatment, storage, washing.

,urination, defecation and reproduction.

metabolism, immune responses and behaviour.

Emergency weekend and holiday care

Personnel and training

Sanitation and cleanliness

Guidelines for Use of Anaesthesia

conscious to perceive the pain.

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