gives detailed information about the differences between the different toxicity studies

1. Difference
between Toxicity
Studies
Aasifa S

2. Acute toxicity study
 Five OECD Test guidelines (TGs 402, 403, 420, 423, and 425) describe acute systemic testing.
1. FixedDoseProcedure(420)-
o Testing in1 sex usually females is considered sufficient.
o Reproducible procedure.
o Causes less suffering to the animals.
o Uses only moderately toxic doses, doses expected to be lethal should be avoided.

3. 2. Acute Toxic Class method (423) –
o Substance administered orally to 2 groups of animals at defined doses .
o 3 animals per step of single sex (normally females).
o Ld50 cut off values are indicated .
3. Up‐and‐Down Procedure (425)- [ Limit test at 2000 or 5000 mg/kg]
o Only one animal is used for study

4. 4. Acute Dermal Toxicity(402)
5. Acute inhalation toxicity (403)
– Acute toxicityinclude toxicometric value determination (LD50, LD 100) 14 days after
singleadministration of drugfor assignment to a particular classof danger, registration
of bodyweight 1-7-14d, mortalityand autopsywithorgan weight

5. Six OECD TG describe short‐term repeat‐dose toxicity testing:
– Repeated Dose 28‐day Oral Toxicity Study in Rodents (TG 407)
– Repeated Dose 90‐DayOral Toxicity Studyin Rodents(TG408)
– Repeated Dose Dermal Toxicity: 21/28‐day Study (TG 410)
– SubchronicDermal Toxicity:90‐day Study (TG411)
– Repeated Dose Inhalation Toxicity: 28‐day or 14‐day Study (TG 412)
– SubchronicInhalationToxicity:90‐day Study (TG413)
SUBACUTE AND CHRONIC TOXICITY TESTING

6. Subacute toxicity study
– The GloballyHarmonizedSystem (GHS)defines it as "specific target organ/systemic toxi
city arising from a repeated exposure"
– Subacute administration of drug from 1 to 21-28days with registration of mortality, body
weight 1-7-14-21-28d: hematological, biochemical and urinalysis assay, may be with
registration of pharmacology safety (respiration, heart rate, behavioural in open field)
autopsy with organ weight
– Doses are selected on the basis of ED50 and LD50.

7. Chronic toxicity study
– Repeated dose toxicity testing using oral administration of a test substance in rod
ents for 28 and90 days is used to evaluate chronic toxic effects, primarily effects o
n various organ systems, and to establish a no observed effect level.
– The endpoints for repeat dose testing consist of an evaluation of clinical observatio
ns, blood analysis, whole body gross necropsy, and microscopic examination of al
l organs and tissues (histopathology)

8. Description of the method
– Selectionof animal species (animals not exceeding 9weeks old for both subacute and
chronic toxicity study)
– Housingand feedingconditions (same for both)
– Preparation of animals :
o In subacutetesting- At least 5 animals per sex per group should normally be used at
each dose level.
o In chronic testing - At least 20 animals per sex per group should normally be used at
each dose level, while for non-rodents a minimum of 4 per sex per group is
recommended.

9. – Preparationof doses
– Observations
 Ophthalmological examination, Body weight, food/water consumption and food efficiency ,
Haematology and clinical biochemistry , Pathology, gross necropsy, Histopathology
– Test report
– Results
– Statistical treatment of results
– Conclusions

10. Provision for interim kills, satellite groups and sentinel animals
– The study may make provision for interim kills (at least 10
animals/sex/group), e.g. at 6 months, to provide information on
progression of toxicological changes and mechanistic information, if
scientifically justified.
– An additional group of sentinel animals (typically 5 animals per sex) may
also be included for monitoring of disease status, if necessary, during the
study (Same as in subacute toxicity )

11. Difference between oral/dermal/inhalational chronic toxicity study
 In the case of oral administration, the animals are dosed with the test chemical daily
(sevendays eachweek), normally for a period of 12 months, although a longer duration
may be required depending on regulatory requirements.
– Any other dosing regime, e.g., five days per week, needs to be justified.
– Volume of liquid that is used to administer should not exceed 1 ml/100 g of body weight
(except for aq. Soln. : 2 ml/ 100 g allowed)

12. In the case of dermal administration, animals are normally treated with the test
chemical for at least 6 hours per day, 7 days per week, as specified in TG 410 , for a
period of 12 months.
– Test substance should be applied uniformly over an area approx. 10%of body
weight
– For highly toxic substances , surface area may be less
– Area should be covered with a thin and uniform film

13. – Between applications , the test substance is held in contact with skin using a gauze
dressing/ non-irritating tape
– Cover test site in order to retain gauze dressing
– Ensure that the animal cannot ingest the test substance
 Exposure by the inhalation route is carried out for 6 hours per day,7 days per week, but
exposure for 5 days per week may also be used, if justified. The period of exposure will
normally be for a period of 12 months. should be provided when using an exposure
duration of less than 6 hours per day

14. Remember
– For substances administered via the diet or drinking water it is important to
ensure that the quantities of the test chemical involved do not interfere with
normal nutrition or water balance.
– In long-term toxicity studies using dietary administration, the concentration
of the chemical in the feed should not normally exceed an upper limit of 5% of
the total diet, in order to avoid nutritional imbalances.

15. – When the test chemical is administered in the diet, either a constant
dietary concentration (mg/kg diet or ppm) or a constant dose level in
terms of the animal’s body weight (mg/kg body weight), calculated on
a weekly basis, may be used. The alternative used should be specified.