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Healthcare Services (P) Ltd

DAPAGLIFLOZIN PROPANEDIOL (ORAL):

DETERMINATION OF PERMISSIBLE DAILY

EXPOSURE (PDE) AND OCCUPATIONAL

EXPOSURE LIMIT (OEL)

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Healthcare Services (P) Ltd Table of Contents

1. BASIC INFORMATION…………………………………………………...………..……3 2. HAZARDS IDENTIFIED…………………………………………………...………...….4 3. SUMMARY OF ASSESSMENT PROCESS (CALCULATIONS OF PDE VALUE)......5 4. IDENTIFIED OF THE ACTIVE SUBSTANCE…………………………………….…...8 5. OBJECTIVE AND SEARCH STRATEGY……………………………………….….......9 6. INTRODUCTION………………………………………………………………….…......97. HAZARD IDENTIFICATION……………………………………………………..……..9

a. Pharmacodynamics Data…………………………………………………………........9 b. Acute Toxicity……………………………………………………………..…...........10 c. Repeated dose toxicity…………………………………………………...……..........10 d. Carcinogenicity…………………………………………………………....................13e. In Vitro / In Vivo Genotoxicity Studies………………………………………...……13 f. Reproductive and Developmental Toxicity………………………………….............14 g. Local tolerance studies…………………………………………………………..…...16

8. IDENTIFICATION OF CRITICAL EFFECTS…………………………………….…...16 a. Most Sensitive Indicator of an Adverse Effect Seen in Clinical Toxicity Data…......16 b. Clinical Therapeutic and Adverse Effects…………………………………….…......16

9. RATIONALE FOR NOEL VALUES SELECTION ………………………………........17 10. APPLICATION OF ADJUSTMENT FACTORS (RATIONALE FOR

THE ADJUSTMENT FACTORS …………………………………………………......17 a. F1: Interspecies Differences…………………………………………………............17 b. F2: Inter-Individual Differences……………………………………………………..17 c. F3: Duration of Exposure……………………………………………………..….......18 d. F4: Nature of Toxicity………………………………………………………….........18 e. F5: Quality of Data…………………………………………………………….…….19

11. PK CORRECTION………………………………………………………………..……..20 12. REFERENCES…………………………………………………………………….…….21

ANNEXURE I: PHARMACOKINETICS AND METABOLISM ……………………….22

ANNEXURE II: Glossary………………………………………………………………........23

ANNEXURE III: Summary of Expert CV..............................................................................29

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Healthcare Services (P) Ltd 2. HAZARDS IDENTIFIED

Yes No Unknown

Genotoxicant

Carcinogen

Reproductive and

Developmental

toxicant

Highly Sensitizing

potential

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Healthcare Services (P) Ltd 3. SUMMARY OF ASSESSMENT PROCESS (CALCULATION OF PDE

VALUE)PDE value 0.333mg/day

OEL value 0.026 mg/m3/day

HAZARD IDENTIFICATION

Pharmacodynamics data Dapagliflozin inhibits the sodium-glucose

contransporter 2(SGLT2), the major transporter

responsible for renal glucose re-absorption which is

primarily located in the proximal tubule of the nephron.

Acute toxicity Oral LD50 was found to be 750 mg/kg in rats and 3000

mg/kg in mice, no mortality but emesis was observed in

the single-dose dog study.

Repeated dose toxicity Repeated dose toxicity studies were performed in rats,

mice and dogs. Decreased activity, abdominal distention

and hunched posture were observed at all doses in the 3-

month mouse toxicity study. In rats the target organs for

toxicity were kidney and bone. Dose related changes

were seen in dogs such as increase in urine volume,

total urine glucose, calcium and phosphorus, increase in

absolute and relative adrenal gland weight (males and

females), liver (males) and kidney (males), decreased

urine osmolality, no organ toxicity was observed even

at very high dose of dapagliflozin.

Carcinogenicity No evidence of carcinogenic potential in 2 years study

in mice and rats.

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Healthcare Services (P) Ltd Genotoxicity studies Dapagliflozin propanediol was not mutagenic or

clastogenic in an in vitro Ames assay or in the in vivo

assays. However, dapagliflozin was clastogenic in the

presence of S9 in multiple in vitro chromosomal

aberration assays. In conclusion there is no evidence for

any clinically relevant genotoxic potential of

Dapagliflozin propanediol.

Reproductive/Developmental

toxicity

Mortality and morbidity was observed in the 300/210

mg/kg high dose male rats in fertility studies. In

embryonic fetal development studies in rats 21-22 late

gestation fetal deaths were reported in 150 and 300

mg/kg dosed group along with reduction of live litter

size and decreased fetal body weights, dose-dependent

significant findings in the offspring were

malformations: in the blood vessels, fused/wavy ribs

and verterbral centra, duplicated manubira and skeletal

variations: reduced ossifications. Incidence and severity

of renal pelvic dilation was increased in the high dose

groups in rat’s prenatal and postnatal studies.

IDENTIFICATION OF CRITICAL EFFECTS

Sensitive indicator of an adverse

effect seen in non-clinical toxicity

data

Target organ toxicities at 150 mg/kg were observed in

rats in the kidney, sternum and femur, trachea, heart and

vessels, spleen and liver, harderian gland. Increase in

absolute and relative adrenal gland weight (males and

females), liver (males) and kidney (males), decreased

urine osmolality was seen in dogs. Incidence and

severity of renal pelvic dilation was increased in the

high dose groups in rat’s prenatal and postnatal studies.

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Healthcare Services (P) Ltd Clinical therapeutic and adverse

effects

FORXIGA (dapagliflozin) was studied as monotherapy

and in combination with other antidiabetic medications,

including metformin, glimepiride, or insulin.

FORXIGA was also studied in patients with type 2

diabetes and cardiovascular disease and in patients with

mild to moderate renal impairment. Adverse effect

reported in at least three (3) FORXIGA 10 mg-treated

patients were renal impairment (0.8%), decrease in

creatinine clearance (0.6%), increased blood creatinine

(0.3%), urinary tract infections (0.2%), and

vulvovaginal mycotic infection (0.1%).

NOAEL NOAEL value of 1 mg/kg is selected from the prenatal

and postnatal development studies in rats.

APPLICATION OF ADJUSTMENT FACTORS

F1: Extrapolation between species 5 For extrapolation from rats to humans.

F2: Inter-individual variability 10 Used for differences between individuals in the

human population. F3: Duration of toxicity 1 For prenatal and postnatal development studies

in rats. F4: Severe toxicity (1-10) 3 A factor of 3 (1 for embryo fetal toxicity with

maternal toxicity and 2 for systemic toxicityF5: NOAEL Vs LOAEL (10 if

LOAEL)

1 NOAEL value is selected from reproductive

toxicity studies in rats.

α (Correction for Bioavailability) 1.28 Oral is the intended route of dapagliflozin

propanediol for population. Considering worst BV ( The volume of air inhaled

during an eight-hour work shift) 10 A healthy adult human can inhale 10 m3 of air

during an eight-hour time

PK correction For PDE calculation, no Pharmacokinetic correction

was carried out, for OEL calculation a factor of 1.28

is used.

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Healthcare Services (P) Ltd 4. IDENTITY OF THE ACTIVE SUBSTANCE:-

Dapagliflozin propanediol is a potent, competitive, reversible, highly selective and orally active

inhibitor of the human sodium-glucose co-transporter 2 (SGLT2), the major transporter

responsible for the renal glucose reabsorption.

IUPAC NAME: (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-

(hydroxymethyl)oxane-3,4,5-triol;(2S)-propane-1,2-diol;hydrate

Chemical Abstract services (CAS) Registry Number: -960404-48-2

Molecular Weight: - 502.985 g/mol

Chemical Formula: -C24H35ClO9

Chemical Description and Physical Properties:-

Dapagliflozin propanediol is a non-hygroscopic, crystalline white to off-white powder which is

soluble in polar solvents.

Figure 1: Structure of Dapagliflozin propanediol (1)

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Healthcare Services (P) Ltd 5. OBJECTIVE AND SEARCH STRATEGY

At present, pharmaceutical companies are investing significant effort to assess and control cross-

contamination risk of drug products that are manufactured in the shared production facilities

(EMA/CHMP/ CVMP/ SWP/169430/2012) (EMA, 2014). Determination of health based

exposure limits for a residual active substance through the derivation of a safe threshold value is

employed to identify the risk posed. The derivation of threshold value like permitted daily

exposure (PDE) or thresholds of toxicological concern are used to determine the risk of the

active pharmaceutical substance. For determination of PDE, all the available pharmacological

and toxicological data including both non-clinical and clinical data should be evaluated. This

involves hazard identification by reviewing all relevant data, identification of critical effects,

determination of NOAEL of the findings that are considered to be critical effects.

In this document, brief summary of pharmacological, pharmacokinetics and toxicity data of

Dapagliflozin propanediol have been presented based on the published data. The data were

extracted from PubMed, PubChem, TOXLINE, Drugdex, RTECS (Registry of Toxic effects of

Chemical Substances), National Toxicology Program (NTP), and FDA.

6. INTRODUCTION

Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor indicated for managing diabetes

mellitus type 2. It helps to improve glycemic control by inhibiting glucose resorption in the

proximal tubule of the nephron and causing glycosuria along with diet and exercise in adult. (2)

Dapagliflozin propanediol falls in the category of anti-diabetic drugs and the ATC code is

A10BD15 (3)

7. HAZARD IDENTIFICATIONa. Pharmacodynamics Data: -Dapagliflozin inhibits the sodium-glucose contransporter

2(SGLT2), the major transporter responsible for renal glucose re-absorption which is

primarily located in the proximal tubule of the nephron. Dapagliflozin lowers plasma glucose

by inhibiting the renal re-absorption of glucose in the proximal tubule, thereby promoting its

urinary excretion. Dapagliflozin increased renal glucose excretion in (healthy, non-diabetic)

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Healthcare Services (P) Ltd experimental animals. This was accompanied, by osmotic diuresis as measured by increased

urine flow. (4)

b. Acute Toxicity: (4, 5)

Table No. 1: Acute toxicity studies of Dapagliflozin propanediol in laboratory animals

Route Species Dose (mg/kg) LD50

(mg/kg/day)

NOAEL

Oral Rats 375,750,

1500, 3000

750 375

Mice 375,750,

1500, 3000

3000 1500

Dogs 200, 500,

1000

- 1000

Dapagliflozin was well tolerated at doses up to 375 mg/kg in rats, 1500 mg/kg in mice, and 1000

mg/kg in dogs, no mortality but emesis was observed in the single-dose dog study.

c. Repeated dose toxicity (4, 5)

Table No. 2: Repeated dose toxicity study in mice

Route Species Strain Duration Dose(mg/kg/day) NOAEL (mg/kg/day)

Oral

gavage

Mice CD-1 1 week 4.1, 25, 43, 75 75

1month 150, 300 -

3 months 50, 150, 250, 400 150

Key Findings

• 1 week study: No drug related effect were seen in any of the dosed group

• 1 month study: one death was reported in the 150 mg/kg/day dose group but No dapagliflozin-

related pathologic changes or cause of death were determined. No death was reported in the

300 mg/kg/day group which suggested that the death at 150 mg/kg/day was not drug related.

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Healthcare Services (P) Ltd Clinical signs reported were rough/urine-stained hair coats at 150 mg/kg/day and polyuria at

150 and 300 mg/kg/day.

• 3 months’ study: The administration of dapagliflozin in the 250 and 400 mg/kg/day dose

groups was not tolerated and was associated with dapagliflozin related deaths. Decreased

activity, abdominal distention and hunched posture were observed at all doses in the 3-month

mouse toxicity study starting on Day 3. The effects generally increased with dose and are most

likely related to off target inhibition of intestinal SGLT1 and the decreased intestinal

absorption of glucose. The clinical observations in the 3-month mouse toxicity study were not

associated with decreases in body weights or food consumption. In fact, dapagliflozin-treated

mice actually exhibited increased food consumption at all doses (26 to 44%) with an increase

in end-of study body-weight gains relative to controls. Pathologic changes were limited to

decreases in absolute prostate weight (20 to 23%) at 150 and 250 mg/kg/day. The NOAEL was

considered to be 150 mg/kg/day.

Table No. 3: Repeated dose toxicity study in rats

Route Species Strain Duration Dose(mg/kg/day) NOAEL

(mg/kg/day)

Oral gavage Rats Sprague

Dawley

4 weeks 5, 50, 300 50

3 months 5, 50, 200 50

6 months 5, 25, 150 25

Key Findings

Mortality was observed at 150 mg/kg dose group but the cause of death was not determined.

There was increase in some parameter in all treatment groups such as: urinary volume, total urine

glucose, calcium and phosphorus, food consumption and water consumption, total urinary

protein. Kidney weight was increased, Serum 1, 25 dihydroxy vitamin D (males only) and

urinary deoxypyridinolene was reduced in all treatment groups. The target organs for toxicity

were kidney and bone. Kidney findings were reactive hyperplasia of collecting duct epithelium,

dilation of cortical and/or medullary tubules, and mineralisation of the collection ducts and

exacerbation of chronic progressive neuropathy (CPN). There were changes indicative of

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Healthcare Services (P) Ltd abnormal bone formation. The mineralization and bone changes were related to increases in

serum calcium. A mechanistic study in rats on a glucose-free diet suggested that these findings

were related to off-target inhibition of intestinal SGLT1 at high doses. No changes in serum

calcium, no renal effects and no mineralisation were observed in rats on glucose-free diet. Liver

enzymes (ALT, AST) were increased with dapagliflozin in rats.

Table No. 4: Repeated dose toxicity study in dogs

Route Species Strain Duration Dose(mg/kg/day) NOAEL

(mg/kg/day)

Oral gavage Dogs Beagle 4 weeks 5, 25, 250 25

3 months 5, 30, 180 30

1 year 5, 20, 120 20

Key Findings

One female from 120 mg/kg was euthanized due to morbidity at study day 172 that was

attributed to acute renal toxicity, and one death was observed in one 5 mg/kg female due to an

aspiration pneumonia dosing accident. There was some dose related changes which included:

increase in urine volume, total urine glucose, calcium and phosphorus, increase in food

consumption and water consumption, increase in absolute and relative adrenal gland weight

(males and females), liver (males) and kidney (males), decreased urine osmolality. Minimal to

slight suburothelial inflammation was present in the renal pelvis of some dosed animals of each

group. No gross microscopy changes were observed. The increased incidence of diarrhea

following dapagliflozin administration is most likely due to the off-target inhibition of SGLT1 in

the intestines and the resulting decreases in intestinal glucose absorption. Administration of high

doses of dapagliflozin was associated with slight increases in total serum cholesterol (≤ 1.6×

relative to controls) in the 1, 3 and 12 months dapagliflozin dog studies. Increases in serum

cholesterol are most likely due to the observed increased food consumption in dogs following

dapagliflozin administration. There was no target organ toxicity observed in the repeat-dose dog

toxicity studies even at very high doses of dapagliflozin.

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Healthcare Services (P) Ltd d. Carcinogenicity(4, 5):

Table No. 5: carcinogenic studies of Dapagliflozin propanediol

Species/route Strain Dose (mg/kg/day) Duration

Mice

Oral gavage

CD-1 M- up to 40

F- up to 20

2 years

Rats

Oral gavage

Sprague-Dawley Up to 10 2 years

The carcinogenicity studies in mice and rats were performed at large exposure multiples in

comparison to clinical exposure. No evidence of carcinogenic potential of Dapagliflozin

propanediol was seen in any of the studies.

e. In Vitro / In Vivo Genotoxicity Studies(4, 5): The following battery of tests were

performed with dapagliflozin

Table No. 6: Genotoxicity studies in vivo and in vitro.

Test system Results

In vitro Ames assay Negative

Rat bone marrow micronucleus assay Negative

Peripheral blood lymphocyte chromosomal aberration assay Negative

Hepatocyte unscheduled DNA synthesis (UDS) assay Negative

In vitro chromosomal aberration assays (in the presence of S9) Positive

In vitro chromosomal aberration assays (in the absence of S9) Negative

Dapagliflozin propanediol was not mutagenic or clastogenic in an in vitro Ames assay or in the

in vivo assays. However, dapagliflozin was clastogenic in the presence of S9 in multiple in vitro

chromosomal aberration assays. The necessity of S9 (rat liver microsomes) to elicit

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Healthcare Services (P) Ltd clastogenicity indicates that an unidentified metabolite or metabolites of dapagliflozin were

causative, not the intact parent molecule. In conclusion there is no evidence for any clinically

relevant genotoxic potential of Dapagliflozin propanediol.

f. Reproductive and Developmental Toxicity :( 4, 5)

Fertility and early embryonic development

Table No. 7: Fertility and early embryonic development study in rats

Route Species Sex Dose (mg/kg/day) NOAEL

Oral gavage Rats M

F

M- 15, 75, 300/210

F- 3, 15, 75

NOAEL for female fertility was 15

mg/kg

NOAEL for embryonic development

was 3 mg/kg

Mortality and morbidity was observed in the 300/210 mg/kg high dose male group between

study days 4-22. In male and female rats, dapagliflozin showed no effects on mating, fertility or

early embryonic development at doses up to 75 mg/kg.

Embryonic Fetal Development

Table No. 8: Embryonic fetal development toxicity study in rats and rabbits

Route Species Sex Study type Dose

(mg/kg/day)

NOAEL

Oral

gavage

Rats F Non-GLP

study

150, 225, 300 NOAEL for embryo-fetal

development in rats was 75

mg/kg. Rats F GLP-compliant

study

37.5, 75, 150,

300

Rabbits F GLP-compliant

study

20, 60, 180 NOAEL for embryo-fetal

development in rats was 180

mg/kg.

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Healthcare Services (P) Ltd Rat study: Three out of 25 high dosed dams were found dead and one was sacrificed, some

critical signs were seen in these animals; dehydration, decreased motor activity, bradypnea,

labored breathing, gasping. Dose-dependent decreases in body weight gain were observed in all

Dapagliflozin propanediol-treated animals during the treatment period, and remained decrease in

the high dose. Total of 21 and 22 late gestation fetal deaths were reported in 150 and 300 mg/kg

dosed group along with reduction of live litter size and decreased fetal body weights. Dose-

dependent significant findings in the offspring were malformations: in the blood vessels,

fused/wavy ribs and verterbral centra, duplicated manubira and skeletal variations: reduced

ossifications were observed at 150 and 300 mg/kg. The NOAEL for maternal toxicity was not

established due to reduced food consumption and reduced body weight gain.

Rabbit study: The NOAEL for maternal toxicity was not established due to reduced food

consumption and reduced body weight gain. Litter endpoints were unaffected by Dapagliflozin

propanediol treatment, malformation and variation were not observed in the offspring.

Prenatal and postnatal development, including maternal function

Table No. 9: Prenatal and postnatal development study in rats

Species Study Clinical findings NOAEL (mg/kg)

Rats F0 Generation Body weight gain was slightly

suppressed during gestation in

high dose group.

NOAEL was not

established, 75 mg/kg was

considered LOAEL for

maternal toxicity.

F1 Generation Incidence and severity of renal

pelvic dilation was increased in

the high dose groups.

15 mg/kg

F1 Generation

Development

toxicity

Reduced weight gain during

lactation at all tested dose levels

< 1 mg/kg

F2 Generation No adverse effect were reported 75 mg/kg

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Healthcare Services (P) Ltd g. Local tolerance studies (4)

In vitro studies with isolated bovine corneas for ocular irritation and in vivo studies with rabbits,

mice, and dogs were conducted to determine the ocular irritation, dermal irritation, sensitization

potential and vascular/perivascular irritation potential of dapagliflozin. In a Bovine Corneal

Opacity and Permeability Assay, dapagliflozin exhibited moderate to severe ocular toxicity.

Dapagliflozin was considered to be a non-sensitizer based on the results of a local lymph node

assay in the mouse. In an acute dermal irritation study in rabbits, dapagliflozin was a non-irritant.

Five days of repeated IV administration of an intravenous formulation of dapagliflozin did not

cause any vascular effects. After subcutaneous injections, there was slight focal necrosis of

subcutaneous muscle at the injection site.

8. IDENTIFICATION OF CRITICAL EFFECTS

The steps deliberated to identify the nature of the adverse effect include its severity and

persistence. If the substance causes multiple types of adverse effects, the critical effect is one that

meets the severity and persistence criteria at the lowest intake.

a. Most Sensitive Indicator of an Adverse Effect Seen in Non-Clinical Toxicity Data.

Kidney, sternum and femur, trachea, heart and vessels, spleen and liver, harderian gland were the

target organs in the rat study. In dogs, increase in absolute and relative adrenal gland weight

(males and females), liver (males) and kidney (males), decreased urine osmolality was seen.

Incidence and severity of renal pelvic dilation was increased in the high dose groups in rat’s

prenatal and postnatal studies. In embryonic fetal development studies in rats 21-22 late gestation

fetal deaths were reported in 150 and 300 mg/kg dosed groups.

b. Clinical Therapeutic and Adverse Effects

Dapagliflozin was studied as monotherapy and in combination with other antidiabetic

medications, including metformin, glimepiride, or insulin. Dapagliflozin was also studied in

patients with type 2 diabetes and cardiovascular disease and in patients with mild to moderate

renal impairment. Treatment with Dapagliflozin as monotherapy and in combination with

metformin, glimepiride, or insulin produced clinically relevant and statistically significant

improvements in mean change from baseline at Week 24 in HbA1c, fasting plasma glucose

(FPG), and 2-hour postprandial glucose (PPG) (where measured), compared to placebo or

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Healthcare Services (P) Ltd control. The estimated, placebo-adjusted, HbA1c reduction across trials and doses ranged from

0.40% to 0.84%. These glycemic effects were sustained in long-term extensions up to 104

weeks. HbA1c reductions were seen across subgroups including gender, age, race, duration of

disease, and baseline BMI. In addition, patients treated with FORXIGA compared to placebo or

control achieved greater HbA1c reductions in patients with a baseline HbA1c ≥9% statistically

significant reductions.

Adverse effect of dapagliflozin propanediol includes female genital mycotic infections,

nasopharyngitis and urinary tract infections. frequent urination, dizziness, or lightheadedness,

UTI and kidney infection may also occur (6). The most commonly reported events leading to

discontinuation and reported in at least three (3).Dapagliflozin 10 mg-treated patients were renal

impairment (0.8%), decrease in creatinine clearance (0.6%), increased blood creatinine (0.3%),

urinary tract infections (0.2%), and vulvovaginal mycotic infection (0.1%).(6)

9. RATIONALE FOR NOAEL VALUES SELECTION

Dapagliflozin caused systemic toxicity in rats and dogs when administered for a period up to 52

weeks. Based on the relevance to clinical use, the NOAEL value of 1 mg/kg is selected from the

prenatal and postnatal development studies in rats.

10. APPLICATION OF ADJUSTMENT FACTORS (RATIONALE FOR

THE ADJUSTMENT FACTORS)

A series of modifying, or safety factors, are used when the NOAEL/ lowest therapeutic dose is

based on studies of differing types and durations in differing species to provide a risk assessment

for human exposure. These factors were generally established according to Appendices 3 of the

ICH Q3C (R5) and VICH GL 18.

a. F1: Interspecies Differences

This factor takes into account the comparative surface area: body weight ratios for the species

concerned and for man. Surface area (S) was calculated as: S= k M0.67 where M is the body mass

and the constant, k, has been taken to be 10 according to the appendices 3 of the ICH guideline.

For a 50 kg person the equation gives a surface area of 64.3 dm2; the surface area: body weight

ratio is thus 2.76.

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Healthcare Services (P) Ltd Applying the same calculation to other species and expressing the results as multiples of the

human surface area: body weight ratio gives factors for the mouse = 12; for the rat = 5; for the

monkey = 3; for the rabbit = 2.5; for the dog = 2. For other species, where the data are not so

well established the factor F1 is taken as 10.

A factor of 5 is considered as rats study is selected.

b. F2: Inter-Individual Differences

A value of F2= 10 is conventionally used to allow for differences between individuals in the

human population.

c. F3: Duration of Exposure

A variable factor up to 10 takes into account the differing durations of exposure in the reported

studies. For reproductive studies, a factor of 1 is used if the whole period of organogenesis is

covered. A factor of 1 has been used for a study last at least one-half lifetime (1 year for rodents

or rabbits; 7 years for cats, dogs and monkeys). A factor of 2 has been used for a 6-month study

in rodents, or a 3.5-year study in non-rodents. A factor of 5 has been used for a 3-month study in

rodents or a 2-year study in non-rodents and a factor of 10 for studies of a shorter duration. In all

cases, the higher factor has been used for study duration between the time points e.g. a factor of

2 for a 9-month rodent study.

A factor 1 is selected for prenatal and postnatal reproductive studies in rats.

d. F4: Nature of Toxicity

A variable factor is applied when the toxicity produced is irreversible in nature i.e.

carcinogenicity, neurotoxicity or teratogenicity. A factor of 10 is used when oncogenic or

neurotoxic responses are present. A variable factor is used for reproductive toxicity effects as

follows: 1 for embryo or foetal toxicity or mortality associated with maternal toxicity; 5 for

embryo or foetal toxicity or mortality without maternal toxicity; 5 for a teratogenic effect with

maternal toxicity and 10 for a teratogenic effect in the absence of accompanying maternal

toxicity.

A factor of 3 is used (1 for embryo fetal toxicity with maternal toxicity and 2 for systemic

toxicity observed in rats).

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Healthcare Services (P) Ltd e. F5: Quality of Data

A variable factor, up to 1, applied to results in which a NOAEL has not been established, the

PDE being derived from a NOAEL.

As NOAEL was selected, so F5 = 1 is used in this report

The PDE calculation:

PDE value = NOAEL X Weight adjustment

F1 x F2 x F3 x F4 x F5

= 1 x 50 for adult population

5 x 10 x 1 x 3 x 1

= 0.333 mg/day

Hence, the PDE of Dapagliflozin propanediol is 0.333 mg/day

Calculation of OEL (Occupational Exposure Limits):

OEL can be calculated by using the following formula (Naumann and Weideman, 1995

and Sargent EV et al 2013)

OEL= NOAEL x BW or Human lowest daily dose

F1 x F2 x F3 x F4 x F5 x α X BLV

NOAEL value of 1 mg/kg/day was derived from the prenatal and postnatal reproductive studies

in rats and will be used for OEL generation.

OEL

= NOAELX BW F1 x F2 x F3 x F4 x F5 x BV x α

= 1x 50 5x 10 x 1 x3x 1 x10 x1.28

= 0.026 mg/m3/day

Hence, the OEL of Dapagliflozin propanediol is 0.026 mg/m3/day

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Healthcare Services (P) Ltd 11. PK CORRECTIONFor PDE calculation, no pharmacokinetic correction was carried out, for OEL calculation a

factor of 1.28 is used.

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Healthcare Services (P) Ltd 12. REFERENCES:

1. Dapagliflozin propanediol, Pubchem, 2019

https://pubchem.ncbi.nlm.nih.gov/compound/Dapagliflozin-propanediol

2. Dapagliflozin propanediol, Drugbank, 2019

https://www.drugbank.ca/salts/DBSALT001101

3. WHO Collaborating Centre for Drug Statistics Methodology

https://www.whocc.no/atc_ddd_index/?code=A10BD15&showdescription=yes

4. Dapagliflozin propanediol, EMA, 2012

https://www.ema.europa.eu/en/documents/assessment-report/forxiga-epar-public-assessment-

report_en.pdf

5. Dapagliflozin propanediol, FDA, 2013

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000PharmR.pdf

6. Dapagliflozin propanediol, WebMD, 2019

https://www.webmd.com/drugs/2/drug-165640/dapagliflozin-oral/details

7. Guideline on setting health based exposure limits for use in risk identification in the

manufacture of different medicinal products in shared facilities EMA/CHMP/ CVMP/

SWP/169430/2012., 2014. url:-https://www.ema.europa.eu/en/documents/scientific-

guideline/guideline-setting-health-based-exposure-limits-use-risk-identification-

manufacture-different_en.pdf

8. Guideline on setting of health-based exposure limits for use in risk identification in the

manufacture of different medicinal products in shared facilities. Date of coming into

effect in June 2015. European Medicines Agency

(EMA/CHMP/CVMP/SWP/169430/2012). URL:http://www.ema.europa.eu

9. ICH guideline Q3C (R6) on impurities: guideline for residual solvents,

EMA/CHMP/ICH/82260/2006, Access via URhttp://www.ema.europa.eu/docs

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Healthcare Services (P) Ltd ANNEXURE I: PHARMACOKINETICS AND METABOLISM

Absorption: Following oral administration of Dapagliflozin propanediol, the maximum plasma

concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC

values increase dose proportionally with increase in Dapagliflozin propanediol dose in the

therapeutic dose range. The absolute oral bioavailability of Dapagliflozin propanediol is 78%. (2)

Distribution: Dapagliflozin propanediol is approximately 91% protein bound. Protein binding is

not altered in patients with renal or hepatic impairment.

Metabolism: The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-

mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively

metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Dapagliflozin 3-Oglucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the

predominant drug-related component in human plasma.

Excretion: Dapagliflozin and related metabolites are primarily eliminated via the renal pathway.

Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is

excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent

drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma

terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose

of 10 mg. (5)

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Healthcare Services (P) Ltd ANNEXURE II: GLOSSARY

ADI: Acceptable daily intake

AUC: Area under the curve

GRAS: Generally regarded as safe

GLP: Good laboratory practice

GMP: Good manufacturing practice

LD: Lethal dose

LED: Lowest-effective dose

TDLo (Toxic Dose Low,): Lowest published toxic dose

LOAEL: Lowest-observed-adverse-effect level

LOEL: Lowest-observed-effect level

MSDS: Material safety data sheet

MTD: Maximum tolerable dose

MPDD: Maximum permissible daily dose

MTEL: Maximum tolerable exposure level

NEL: No-effect level

NOAEL: No-observed-adverse-effect level

NOEL: No-observed-effect level

OEL: Occupational exposure limit

QSAR: Quantitative structure–activity relationship

SDS: Safety data sheet

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Healthcare Services (P) Ltd ADI: Acceptable daily intake. Estimate by JECFA; the amount of a food additive, expressed on a

body weight basis that can be ingested daily over a lifetime without appreciable health risk.

Area under the curve (AUC): Area between a curve and the abscissa (horizontal axis), i.e., the

area underneath the graph of a function; often, the area under the tissue (plasma) concentration

curve of a substance expressed as a function of time.

Bioaccumulation: progressive increase in the amount of a substance in an organism or part of an

organism that occurs because the rate of intake exceeds the organism’s ability to remove the

substance from the body.

Bioavailability: biological and physiological availability. Extent of absorption of a substance by

a living organism compared to a standard system.

Biological half-life: for a substance, the time required for the amount of that substance in a

biological system to be reduced to one-half of its value by biological processes, when the rate of

removal is approximately exponential.

Carcinogen: agent (chemical, physical, or biological) that is capable of increasing the incidence

of malignant neoplasms, thus causing cancer.

Clastogen: agent causing chromosome breakage and (or) consequent gain, loss, or rearrangement

of pieces of chromosomes.

Clearance: volume of blood or plasma or mass of an organ effectively cleared of a substance by

elimination (metabolism and excretion) divided by time of elimination.

Cmax: used in pharmacokinetics refering to the maximum (or peak) serum concentration that a

drug achieves in a specified compartment or test area after the drug has been administrated and

before the administration of a second dose.

Critical dose: dose of a substance at and above which adverse functional changes, reversible or

irreversible, occur in a cell or an organ.

Critical effect: for deterministic effects, the first adverse effect that appears when the threshold

(critical) concentration or dose is reached in the critical organ:

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Healthcare Services (P) Ltd Adverse effects with no defined threshold concentration are regarded as critical. Dose (of a

substance): total amount of a substance administered to, taken up, or absorbed by an organism,

organ, or tissue.

Draize test: evaluation of materials for their potential to cause dermal or ocular irritation and

corrosion following local exposure; generally using the rabbit model (almost exclusively the

New Zealand White) although other animal species have been used.

Elimination (in toxicology): disappearance of a substance from an organism or a part thereof, by

processes of metabolism, secretion, or excretion.

Embryotoxicity: production by a substance of toxic effects in progeny in the first period of

pregnancy between conception and the fetal stage.

Fetotoxicity: production by a substance of toxic effects in progeny in the second period of

pregnancy between fetal stage and delivery.

First-pass effect: biotransformation and, in some cases, elimination of a substance in the liver

after absorption from the intestine and before it reaches the systemic circulation.

Gavage: administration of materials directly into the stomach by esophageal intubation.

Generally regarded as safe (GRAS): phrase used to describe the USFDA philosophy that justifies

approval of food additives that may not meet the usual test criteria for safety but have been used

extensively and have not demonstrated that they cause any harm to consumers.

Genotoxic: capable of causing a change to the structure of the genome.

Good laboratory practice (GLP) principles: fundamental rules incorporated in OECD guidelines

and national regulations concerned with the process of effective organization and the conditions

under which laboratory studies are properly planned, performed, monitored, recorded, and

reported.

Good manufacturing practice (GMP) principles: fundamental rules incorporated in national

regulations concerned with the process of effective organization of production and ensuring

standards of defined quality at all stages of production, distribution, and marketing.

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Healthcare Services (P) Ltd Hazard identification: determination of substances of concern, their adverse effects, target

populations, and conditions of exposure, taking into account toxicity data and knowledge of

effects on human health, other organisms, and their environment.

Hypersensitivity: state in which an individual reacts with allergic effects following exposure to a

certain substance (allergen) after having been exposed previously to the same substance.

In silico: phrase applied to data generated and analyzed using computer modeling and

information technology.

In vitro: in glass, referring to a study in the laboratory usually involving isolated organ, tissue,

cell, or biochemical systems.

In vivo: In the living body, referring to a study performed on a living organism.

Lethal dose (LD): amount of a substance or physical agent (e.g., radiation) that causes death

when taken into the body.

Lowest-effective dose (LED): lowest dose of a chemical inducing a specified effect in a specified

fraction of exposed individuals.

Lowest published toxic dose (Toxic Dose Low, TDLo): the lowest dosage per unit of

bodyweight (typically stated in milligrams per kilogram) of a substance known to have produced

signs of toxicity in a particular animal species.

Lowest-observed-adverse-effect level (LOAEL): lowest concentration or amount of a substance

(dose), found by experiment or observation, that causes an adverse effect on morphology,

functional capacity, growth, development, or life span of a target organism distinguishable from

normal (control) organisms of the same species and strain under defined conditions of exposure.

Lowest-observed-effect level (LOEL): lowest concentration or amount of a substance (dose),

found by experiment or observation, that causes any alteration in morphology, functional

capacity, growth, development, or life span of target organisms distinguishable from normal

(control) organisms of the same species and strain under the same defined conditions of

exposure.

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Healthcare Services (P) Ltd Material safety data sheet (MSDS): compilation of information required under the U.S. OSHA

Hazard Communication Standard on the identity of hazardous substances, health and physical

hazards, exposure limits, and precautions.

Maximum permissible daily dose (MPDD): maximum daily dose of substance whose penetration

into a human body during a lifetime will not cause diseases or health hazards that can be detected

by current investigation methods and will not adversely affect future generations.

Maximum tolerable dose (MTD): highest amount of a substance that, when introduced into the

body, does not kill test animals (denoted by LD0).

Maximum tolerable exposure level (MTEL): maximum amount (dose) or concentration of a

substance to which an organism can be exposed without leading to an adverse effect after

prolonged exposure time. Maximum tolerated dose (MTD): high dose used in chronic toxicity

testing that is expected on the basis of an adequate subchronic study to produce limited toxicity

when administered for the duration of the test period.

Median lethal dose (LD50): statistically derived median dose of a chemical or physical agent

(radiation) expected to kill 50 % of organisms in a given population under a defined set of

conditions.

Mutagenicity: ability of a physical, chemical, or biological agent to induce (or generate) heritable

changes (mutations) in the genotype in a cell as a consequence of alterations or loss of genes or

chromosomes (or parts thereof).

No-effect level (NEL): maximum dose (of a substance) that produces no detectable changes

under defined conditions of exposure.

No-observed-adverse-effect level (NOAEL): greatest concentration or amount of a substance,

found by experiment or observation, which causes no detectable adverse alteration of

morphology, functional capacity, growth, development, or life span of the target organism under

defined conditions of exposure. No-observed-effect level (NOEL): greatest concentration or

amount of a substance, found by experiment or observation, that causes no alterations of

morphology, functional capacity, growth, development, or life span of target organisms

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Healthcare Services (P) Ltd distinguishable from those observed in normal (control) organisms of the same species and strain

under the same defined conditions of exposure.

Quantitative structure–activity relationship (QSAR): quantitative structure–biological activity

model derived using regression analysis and containing as parameters physicochemical

constants, indicator variables, or theoretically calculated values.

Safety data sheet (SDS): single page giving toxicological and other safety advice, usually

associated with a particular preparation, substance, or process.

Target (in biology): any organism, organ, tissue, cell or cell constituent that is subject to the

action of an agent.

Temporary acceptable daily intake: value for the acceptable daily intake proposed for guidance

when data are sufficient to conclude that use of the substance is safe over the relatively short

period of time required to generate and evaluate further safety data, but are insufficient to

conclude that use of the substance is safe over a lifetime. Note: A higher-than-normal safety

factor is used when establishing a temporary ADI and an expiration date is established by which

time appropriate data to resolve the safety issue should be available.

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DAPAGLIFLOZIN PROPANEDIOL (ORAL): DETERMINATION OF ... · [email protected] M: +91 9814133808...

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