Inhalation Toxicity Studies- OECD guidelines

SEMINAR 2
PHARMACOLOGICALAND
TOXICOLOGICAL SCREENING METHODS
SUBMITTED BY : CERIN MAREENA PHILIP
SECOND SEMESTER M.PHARM
DEPARTMENT OF PHARMACOLOGY
KMCH COLLEGE OF PHARMACY
SUBMITTED TO :DR.G.VENKATESH
ASSOCIATE PROFESSOR
DEPARTMENT OF PHARMACOLOGY
KMCH COLLEGE OF PHARMACY
DATE:1/08/2019

INHALATION TOXICITY
STUDIES(1981)
ACUTE TOXICITY
{433(2017),403(2009),39}
SUBACUTE TOXICITY(412)
SUBCHRONIC TOXICITY (413)

CONTENT
ACUTE TOXICITY STUDY FOR INHALATION
• INTRODUCTION
• PRINCIPLE
• DESCRIPTION OF METHOD
• EXPOSURE CONDITIONS AND MONITORING
• PROCEDURE
• OBSERVATION
• DATAAND REPORT
• INTERPRETATION
SUBACUTE TOXICITY STUDY FOR INHALATION
SUBCHRONIC TOXICITY STUDY FOR INHALATION
REFERENCE

INTRODUCTION
• Acute toxicity study for inhalation was
documented as document no. 39 as OECD
GUIDELINE FOR THE TESTING OF
CHEMICALS
• This revised Test Guideline 403 (TG 403) has
been designed to be more flexible, to reduce
animal usage, and to fulfill regulatory needs.
• The revised TG 403 features two study types:
• 1. A Traditional LC50 protocol and
• 2. A Concentration * Time (C x t) protocol.

• SELECTION
 of the most appropriate species,strain,sex,mode of
exposure,appropriate test concentrations include
• the identity,
• chemical structure, and physicochemical properties of the test
article;
• results of any in vitro or in vivo toxicity tests;
• anticipated uses and potential for human exposure;
• available (Q)SAR data and toxicological data on structurally
related substance.
• The targeted concentrations should not induce severe
irritation/corrosive effects, yet reach scientific objective of the
test.

• to provide lethality data.
• (e.g. LC50, LC01 and slope) for one or both sexes as needed for
quantitative risk assessments.This Guideline offers two test
methods.
 Traditional protocol
• groups of animals are exposed to a limit concentration (limit test)
• stepwise procedure
• predetermined duration of usually 4 hours.
 (C x t) protocol
• groups of animals are exposed to one (limit concentration)
• multiple concentrations
• multiple durations.
• OECD Guidance Document No. 19
PRINCILPE

DESCRIPTION OF THE METHOD
1. Selection of animal species:-
2. Preparation of animals
3. Animal husbandry
4. Inhalation chambers
 Selection of animal species:-
• Healthy young adult animals of commonly used laboratory
strains should be used.
• The preferred species is the rat and justification should be
provided if other species are used.
• both sex

 Preparation of animals
1. Females should be nulliparous and nonpregnant.
2. On the exposure day, animals should be young adults 8 to 12
weeks of age, and body weights should be within ±20% of the
mean weight for each sex of any previously exposed animals of
the same age.
3. The animals are randomly selected and marked for individual
identification. The animals are kept in their cages for at least 5
days prior to the start of the test.

• Animal husbandry
• The temperature should be 22±3°C.
• The relative humidity should ideally be maintained in the range
of 30 to 70%,
• Before and after exposures, animals generally should be caged
in groups by sex and concentration,
• When animals are to be exposed nose-only, to be acclimated to
the restraining tubes.
• Animals exposed whole-body to an aerosol should be housed
individually during exposure
• Lighting should be artificial, the sequence being 12 hours
light/12 hours dark.

 Inhalation chambers
• The nature of the test article and the objective of the test
should be considered when Selecting an inhalation chamber.
• The preferred mode of exposure snout-only.
• preferred for studies of liquid or solid aerosols and for
vapours that may condense to form aerosols.
• Toensure atmosphere stability when using a whole-body
chamber.

EXPOSURE CONDITIONS:
Administration of concentrations
Particle-size distribution
Test article preparation in a vehicle
Control animals

Administration
of Concentration
Nose-only
exposures may be
any duration up
to 6 hours in rats.
If mice are
exposed nose-
only, exposures
generally should
not exceed 4
hours.
Particle-size
distribution
Particle sizing
should be
performed for all
aerosols and for
vapours that may
condense to form
aerosols.
( metal fumes
may be smaller
than this standard,
and charged
particles, fibres,
and hygroscopic
materials )
Test article
preparation
in a vehicle
vehicle may be
used to generate
an appropriate
concentration and
particle size of
the test in
atmosphere
(water).
Adequate care
should be taken to
not contaminate
the test material.
Control
animals
A concurrent
negative (air)
control group
is not
necessary.

MONITORING OF EXPOSURE CONDITIONS
1. Chamber airflow
2. Chamber temperature and relative humidity
3. Test article: Nominal concentration
4. Test article: Actual concentration
5. Test article: Particle size distribution

1. Chamber Airflow
The flow of air should be
carefully
Controlled,Continuously
monitored,Recorded( at
least hourly during each
exposure).
Oxygen concentration
should be at least 19%
and carbon dioxide
concentration should not
exceed 1%.(if not
measured)
2. Chamber
temperature and
relative humidity
• Chamber temperature
should be maintained at
22±3°C.
• Relative humidity
should be monitored and
recorded at least three
times for durations of up
to 4 hrs, and hourly for
shorter durations.
• The relative humidity
maintained in the range
of 30 to 70%.
3. Test article:
Nominal
concentration
• mass of generated test
• the total volume of air
passed through the
chamber system.
• The nominal exposure
chamber concentration
should be calculated
and recorded.

•
4.Test article:Actual
concentration
The actual concentration is the test
article concentration at the
animals breathing zone in an
inhalation chamber.
Actual concentrations can
be obtained by specific methods
(e.g. direct sampling, adsorptive
or chemical reactive methods, &
analytical characterisation) or by
nonspecific methods such as
gravimetric filter analysis.
the test sample should be stored
under conditions that maintain its
purity, homogeneity, and stability.
5. Test article: Particle
size distribution
determined at least twice during
each 4 hour exposure by using a
cascade impactor or an
aerodynamic particle sizer.
A second device, such as a
gravimetric filter or an
impinger/gas bubbler, should be
used in parallel .
Particle sizing should be
performed for vapours if vapour
condensation may result in the
formation of an aerosol,

PROCEDURE- Traditional
General considerations:
In a Traditional study, groups of animals are exposed to a test article for a fixed period of time (generally 4 hours) in either a
nose-only or whole-body exposure chamber.
Animals are exposed to either a limit concentration (limit test), or to at least three concentrations in a stepwise procedure
(main study).
A sighting study may precede a main study unless some information about the test article already exists, such as a
previously performed TG 436.
2. Sighting study
A sighting study is used to estimate
test article potency, identify sex
differences in susceptibility, and assist
in selecting exposure concentration
levels for the main study or limit test.
When selecting concentration levels
for the sighting study, all available
information should be used
(3 animals/sex may be needed to
establish a sex difference).
A sighting study may consist of a
single concentration, but more
concentrations may be tested if
necessary.
3. Limit test
A limit test is used when the test article
is known or expected to be virtually
non-toxic,
Three animals of both sex each.
In those situations where there is little or
no information about its toxicity, or the
test material is expected to be toxic, the
main test should be performed.
When the GHS Classification System is
used, the limit concentrations for gases,
vapours, and aerosols are 20000 ppm,
20 mg/L, and 5 mg/L, respectively (or
the maximum attainable concentration)
4. Main Test
A main study is typically performed
using five males and five females (or 5
animals of the susceptible sex, if
known) per concentration level, with at
least three concentration levels.
The time interval between exposure
groups is determined by the onset,
duration, and severity of toxic signs.

C X T PROTOCOL
General considerations:
2. Sighting study
3 animal of per sex is used for test
and exposure of animal is done for
single duration mainly 240 min.
When selecting the initial target
concentration , the study director
should consider the mortality
patterns observed in any available
TG 436 studies
3. Initial Concentration
Group of 1 animal/sex is expose to the
test article initial conc for time
interval of 15, 30, 60 , 120 and 240
min
Total 10 animals are used in this test.
When the GHS Classification
System is used, the limit
concentrations for gases, vapours, and
aerosols are 20000 ppm, 20 mg/L
and 5 mg/L, respectively.
If less than 50% lethality occurs at the
maximum attainable concentration, no
further testing is necessary.
Main study

MAIN STUDY
Exposure Session I –Testing at the limit concentration
1 animal/sex per concentration/time point; 10 animals in total a
Target concentration = limit concentration.
Expose five groups of animals at this target concentration for
durations of 15, 30, 60, 120 and 240 minutes, respectively
Exposure Session II – Main Study
1 animal/sex per concentration/time point; 10 animals in total.
Expose five groups of animals at a lower concentration d (1/2L)
with slightly lower duration of exposure.

Exposure Session III – Main Study
1 animal/sex per concentration/time point; 10 animals total.
Expose five groups of animals at a lower concentration d (1/4L) with slightly
longer exposure durations.
Exposure Session IV′ – Main Study
Expose five groups of animals at a lower concentration d
(1/8L) with slightly longer exposure durations
Exposure Session IV – Main Study
Expose five groups of animals at a higher concentration e
(2L) with slightly shorter exposure durations.

OBSERVATION
Once daily for 14 days.
The length of the observation period is not fixed,
The times at which signs of toxicity appear and disappear are important,
individual records being maintained for each animal
Animals found in a moribund condition should be humanely killed for animal
welfare reasons.
Cage-side observations should include changes in the skin and fur, eyes and
mucous membranes,
and also respiratory, circulatory, autonomic and central nervous systems, and
somatomotor activity and behaviour patterns
Attention should be directed to observations of tremors, convulsions, salivation,
diarrhoea, lethargy, sleep and coma.

• Body weights
• Individual animal weights should be recorded once during the
acclimatization period, on the day of exposure prior to exposure
(day 0), and at least on days 1, 3 and 7 (and weekly thereafter),
and at the time of death or euthanasia
• Pathology
• All test animals, including those which die during the test or are
euthanized and removed from the study for animal welfare
reasons, should be subjected to gross necropsy.

DATA AND REPORTING
• Data : Individual animal data on body weights and necropsy
findings should be provided.
• summarized in tabular form, showing for each test group the
number of animals used, the number of animals displaying
specific signs of toxicity, the number and time of animals found
dead during the test or killed for humane reasons, , a
description and time course of toxic effect.

TEST REPORT
• The test report should include the following information, as
appropriate:
• Description of caging conditions, including: number (or change
in number) of animals per cage, bedding material, ambient
temperature and relative humidity, photoperiod, and identification
of diet
• - Species/strain used and justification for using a species
other than the rat
• - Number, age and sex of animals
• - Method of randomization
• - Details of food and water quality (including diet type/source,
water source);
• - Description of any pre-test conditioning including diet,
quarantine, and treatment for disease

RESULTS
• Tabulation of chamber temperature, humidity, and airflow; -
Tabulation of chamber nominal and actual concentration data
• Tabulation of particle size data
• Individual body weights of animals collected on study;
• date and time of death if prior to scheduled euthanasia,
• time course of onset of signs of toxicity and whether these
were reversible for each animal
• Necropsy findings and histopathological findings for each
animal, if available
• Lethality estimates (e.g. LC50, LD01) including 95%
confidence limits, and slope (if provided by the evaluation
method)
• Statistical relation, including estimate for the exponent n
(C x t protocol). The name of the statistical software used
should be provided.

SUBACUTE TOXICITY TESTING AS PER OECD
GUIDELINES (412)

OECD Guidelines No. 412: 28-day inhalation Toxicity Study in
Rodents
 Toxico-kinetics and systemic toxicity study is also studied.
 Provide robust data for quantitative inhalation risk assessments.
Subacute inhalation toxicity studies are primarily used to derive
regulatory concentrations for assessing worker risk in
occupational settings.
(Q)SAR data and toxicological data on structurally related
chemicals.
The data derived from subacute inhalation toxicity studies can
be used for quantitative risk assessments and for the selection
of concentrations for chronic studies.

PRINCIPLE
Accommodate the testing of nanomaterials as well as to reflect the
evolving state-of-the-science for the testing of inhaled gases,
vapours, and aerosols.
Broncho-alveolar lavage fluid (BALF) to be performed for all test
chemicals
POE-BALF analysis and lung burden measurements are
performed. for all test chemicals( 24h) after exposure termination
When testing a solid aerosol, it is useful to have information on
its retention and kinetics in the lung.
Dilutions of corrosive or irritating test chemicals may be tested
at concentrations that will yield the desired degree of toxicity.

1. Selection of Animal Species
Healthy young adult rodents of commonly used laboratory strains should be employed.
The preferred species is the rat. Justification should be provided if other species are
used.
2. Preparation of
Animals
5 males and females should be
exposed at each concentration.
On the day of randomization,
animals should be young adults
7 to 9 weeks of age.
Body weights should be within
± 20% of the mean weight for
each sex.
allow for acclimatization to
laboratory conditions.
3Inhalation Chambers
Subacute inhalation toxicity
studies are always performed in
dynamic inhalation chambers.
The use of a static inhalation
chamber, which has no airflow,
is not acceptable.
1Limit Concentrations
The maximum concentration
tested should consider:
attainable
the need to maintain an
adequate oxygen supply, and/or
animal welfare considerations.
Up to a maximum
concentration of 5 mg/L for
aerosols,20 mg/L for vapors,
and 20,000 ppm for gases
DESCRIPTION OF THE METHOD

Dynamic Inhalation Chamber & Static Inhalation Chamber

2 Range-Finding Study
 To inform the selection of concentration levels for a main study.
 No Observed Adverse Effects Concentration (NOAEC),
Lowest Observed Adverse Effects Concentration (LOAEC),
Maximum Tolerated Concentration (MTC), and/or the
benchmark concentration (BMC) in a main study.
The study director should use a range-finding study to identify the
upper concentration that is tolerated without undue stress to the
animals.
A range-finding study should last a minimum of 5 days and
generally no more than 14 days, and may include a post-exposure
period and animal numbers should be adjusted accordingly.

When testing poorly soluble particles, it may be necessary for
a range-finding study to be longer than 14 days to allow for a
robust assessment of test chemical solubility and lung burden.
The rationale for the selection of concentrations for the main
study should be provided in the study report.
3 Main Study
The main study consists of at least three test chemical
concentration levels and concurrent negative (air) or vehicle
controls.
This guideline differentiates two study designs depending
on the nature of the test chemical.
Option A, which is generally used for test chemicals (as
gas,vapour, aerosol, or a mixture thereof), option B is used
when testing chemicals that are likely to be retained in the lungs.

OBSERVATIONS
Bronchoalveolar Lavage
• BAL should be performed at PEO-1 (within 24h at termination of
exposure) and at one post-exposure interval (PEO-2)
• When testing a poorly soluble aerosol, BAL should be performed at PEO-1
(within 24 hours of exposure termination) in both sexes and in female
animals at PEO-2 if a recovery group is scheduled.
• The right lung is generally preferred for lavage. The duration of the
post-exposure period and the timing of the PEOs are determined by the
study director based on findings in the range-finding study and other
available, relevant information.
• The mandatory BALF analysis encompasses the following parameters:
Lactate dehydrogenase (LDH) Total protein or albumin Cell counts and
differentials for alveolar macrophages, lymphocytes, neutrophils, and
eosinophils

•Lung Burden
• When testing poorly soluble solid aerosols, measurements of
lung burden can provide clarity on the retained dose.
• Males are used because they have a higher minute volume
than females and may thus have greater lung burdens.
• To obtain clear information on lung clearance kinetics the same
lung (the right lung is recommended) should be measured for
lung burden at all post-exposure time points.
 Ophthalmological Examination
• Refractive media, iris, and conjunctivae.
Gross Pathology And Organ Weights

DATA AND REPORTING
• Individual animal data on body weights, food consumption,
clinical pathology, BALF analysis, gross pathology, organ
weights, lung burden (when evaluated) and histopathology
should be provided for both the range-finding and main
study.
• Clinical observation data should be summarized in tabular form
showing for each test group the number of animals used, the
numberof animals displaying specific signs of toxicity,
• the number of animals found dead during the test or killed for
humane reasons, time of death of individual animals, a
description and time course of toxic effects and reversibility,
and necropsy findings.

DISCUSSION & INTERPRETATION OF
RESULTS
• The respirability of aerosol particles in light of the overall
findings should be addressed, especially if the MMAD
standard could not be met.
• The consistency of methods used to determine analytical and
nominal concentrations, and the relation of analytical
concentrations to nominal concentrations should be included in
the overall assessment of the study.
 The test report must include the following information:
- species/strain used & toxic response data by sex and dose;
- time of death during the study or whether animals survived
or termination;
- Toxic effects and the time of observation of each abnormal
sign and its subsequent course & food and body weight
data.

90-DAY (SUBCHRONIC) INHALATION
TOXICITY STUDY

•INTRODUCTION
•The original subchronic inhalation Test Guideline 413 (TG 413) was adopted in
1981 (2).
•This revision requires specific measurements of bronchoalveolar lavage fluid
(BALF), Measurements of lung burden, should be done when a range-finding
study or other relevant information suggests that inhaled test particles are poorly
soluble and likely to be retained in the lung.
•A range-finding study (or studies), which primarily is (are) performed to assess
concentration levels for the main study should also include BALF analysis, and
may also include lung burden measurements
•Subchronic inhalation toxicity studies are primarily used to derive regulatory
concentrations for assessing worker risk in occupational settings.
•This guideline enables the characterization of adverse effects following repeated
daily inhalation exposure to a test chemical for 90 days.
•Definitions of technical terms used in this Test Guideline can be found in GD 39
(1).
•revising this test guideline was to accommodate the testing of nanomaterials as
well as to reflect the evolving state-of-the-science for the testing of inhaled gases,
vapours, and aerosols.

INITIAL CONSIDERATIONS
•All available information on the test chemical should be considered by the
testing laboratory prior to conducting the main study in order to enhance the
quality of the study, minimize animal usage, and avoid the need to repeat the
study.
•The respirable (or alveolar) fraction of poorly soluble particles that are slowly
cleared can accumulate with each consecutive exposure period.
•Dilutions of corrosive or irritating test chemicals may be tested at
concentrations that will yield the desired degree of toxicity.
•Animals that are moribund obviously in pain or showing signs of severe and
enduring distress should be humanely sacrificed.
•DESCRIPTION OF THE METHOD
• Selection of animal species:-
• Preparation of animals
• Animal husbandry
• Inhalation chambers

TOXICITY STUDIES
Limit Concentrations
Range-Finding Study
• A range-finding study should be performed unless sufficient information
already exists to perform a robust main study.
• A range-finding study may, for example, provide information regarding
analytical methods, particle size distribution, systemic toxicity,
toxicokinetics, test chemical solubility in the lung,BALF data, and
estimates of what may be the No Observed Adverse Effects Concentration
(NOAEC), Lowest Observed Adverse Effects Concentration (LOAEC),
Maximum Tolerated Concentration (MTC), and/or the benchmark
concentration (BMC) in a main study.
• A range-finding study may consist of one or more test chemical
concentration levels and a control group. Depending on the endpoints
chosen, typically no more than 5 males and 5 females should be exposed at
each concentration level.
• should last a minimum of 5 days and generally no more than 28 days,

The main study
•The main study consists of at least three test chemical concentration
levels and concurrent negative (air) or vehicle controls
•Each group consists of a minimum of 10 male and 10 female rodents that
are exposed to the test chemical for 6 hours per day on a 5 day per week
basis for a period of 13 weeks (total study duration of at least 90 days).
•Animals may also be exposed 7 days per week.
•If rodent species other than rats are exposed nose-only,
•A rationale should be provided when using exposure duration less than 6
hours/day, or when it is necessary to conduct a long duration (e.g. 22
hours/day) whole-body exposure study.
•Feed should be withheld during the exposure period unless exposure
exceeds 6 hours. Water may be provided throughout a whole-body
exposure.
Control Animals

EXPOSURE CONDITIONS
Administration of Concentrations
Test Chemical Preparation in a Vehicle
Control animals
Test Chemical: Aerosol Particle Size Distribution
To ensure sufficient exposure of the lower respiratory tract, an aerosol should
meet the following standard whenever possible: Mass Median Aerodynamic
Diameter (MMAD) ≤2 μm with a geometric standard deviation (σg or GSD) of
1-3 for rats (see GD 39).
MONITORING
1. Chamber airflow
2. Chamber temperature and relative humidity
3. Test article: Nominal concentration
4. Test article: Actual concentration
5. Test article: Particle size distribution

OBSERVATION
•FOOD AND WATER CONSUMPTION
To ensure sufficient exposure of the lower respiratory tract, an aerosol should meet
the following standard whenever possible: Mass Median Aerodynamic Diameter
(MMAD) ≤2 μm with a geometric standard deviation (σg or GSD) of 1-3 for rats
(see GD 39).
•OPHTHALMOLOGICAL EXAMINATION
Using an ophthalmoscope or an equivalent device, ophthalmological examinations of
the fundus, refractive media, iris, and conjunctivae should be performed for all
animals prior to the administration of the test chemical,
•GROSS PATHOLOGY AND ORGAN WEIGHTS
All test animals, including those which die during the test or are removed from the
study for humane reasons should be subjected to complete exsanguination (if
feasible) and gross necropsy
•HISTOPATHOLOGY
A histopathological evaluation of all the organs and tissues listed in Table 2 should
be performed for the control and high concentration groups, and for all animals
which die or are sacrificed during the study.

DATA AND REPORTING
•Individual animal data on body weights, food consumption, clinical
pathology, BALF analysis, gross pathology, organ weights, lung burden
(when evaluated) and histopathology should be provided for both the range-
finding and main study.
•Clinical observation data should be summarized in tabular form showing for
each test group the number of animals used, the number of animals displaying
specific signs of toxicity, the number of animals found dead during the test or
killed for humane reasons, time of death of individual animals, a description
and time course of toxic effects and reversibility, and necropsy findings.
• Any generally accepted statistical method may be used and the statistical
methods should be selected during the design of the study.

TEST
REPORT
Test animals
and
husbandry
Test
chemical
Vehicle
Exposure
data
Test
conditions

RESULTS
Tabulation of chamber temperature, humidity, and airflow.
Tabulation of chamber target, analytical, and nominal concentration data.
For aerosols atmospheres with an MMAD >1μm (i.e., fines), information on the aerodynamic diameter size distribution
For aerosols predominantly <100 nm, information on the distribution of thermodynamic equivalent diameter
For aerosols with significant components in both the nano-size range and larger a combination of the above data
Tabulation of response data and concentration level for each animal
Tabulation of individual animal weights.
Tabulation of food consumption
Tabulation of clinical pathology data
Tabulation of bronchoalveolar lavage fluid (BALF) data
Tabulation of lung burden, when measured.
Tabulation of pulmonary function data and body temperatures, when measured.
Organ weights, gross pathology, and histopathological findings for each animal, if available.
Report findings from optional health assessments of systemic toxicity (e.g. immunotoxicity, neurotoxicity, hepatotoxicity, cardiovascular effects).

DISCUSSION AND INTERPRETATION OF RESULTS
Particular emphasis should be given to the description of methods used to meet the
criteria of this test guideline.
The respirability of aerosol particles in light of the overall findings should be
addressed, especially if the MMAD standard could not be met.
The consistency of methods used to determine analytical and nominal
concentrations, and the relation of analytical concentrations to nominal
concentrations should be included in the overall assessment of the study.
The likely cause of death and predominant mode-of-action (systemic versus local)
should be addressed.
An explanation should be provided if there was a need to humanely sacrifice
animals in pain or showing signs of severe and enduring distress, based on the
criteria in the OECD Guidance Document on Humane Endpoints (5).
The target organ(s) should be identified.
The BMC or NOAEC and LOAEC should be determined.
Descriptions of any complications that occurred in the main study that might have
an impact on the results of the study.
If applicable, detailed justification for the inclusion, design and methodology of
post-observation lung burden determinations

REFERENCE
•https://www.piscltd.org.uk/wp-content/uploads/2018/10/Anna-Maione_In-
Vitro-Acute-Inhal-Tox.pdf
•https://www.oecd.org/india/
•"Test No. 413: Subchronic Inhalation Toxicity: 90-day Study." OECD
Guidelines for the Testing of Chemicals, Section 4, 2018.
doi:10.1787/9789264070806-en.
doi:10.1787/9789264070806-en.
doi:10.1787/9789264070806-en.

Inhalation Toxicity Studies- OECD guidelines

Inhalation Toxicity Studies- OECD guidelines

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