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Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
The objective of this study was to evaluate the rate and completeness of metabolism of Propylene Glycol Dibenzoate in human and rat primary cryopreserved hepatocytes via measurement of the parent compound, and quantitation of Benzoic acid in the culture media post-incubation.
GLP compliance:
no
Remarks:
This study was performed under non-GLP conditions. Because the study was conducted in vitro, no human or animal subjects were used. All work was performed with appropriate local health regulations and ethical approval.
Specific details on test material used for the study:
Propylene glycol dibenzoate; Batch no: PR111910A
Form: Liquid
Radiolabelling:
no
Species:
other: human and rat primary cryopreserved hepatocytes
Route of administration:
other: In Vitro test
Vehicle:
unchanged (no vehicle)
Details on exposure:
Experimental Procedure: The test article was incubated in duplicate, for each timepoint, with cryopreserved hepatocytes at 37°C. The cells were thawed; viable cells were counted and equilibrated according to the supplier’s directions. After 30 min equilibration at 37°C with gentle agitation, the test article was added to the cell suspension to achieve desired final concentration of 1 µM. The cell suspension was incubated at 37°C. At the indicated times, samples were removed and mixed with an equal volume of ice-cold acetonitrile (containing the IS internal standard propranolol) to stop the reaction and precipitate proteins. Stopped reactions were kept on ice for at least ten minutes. The samples were centrifuged to remove precipitated protein, and supernatants were analyzed by LC/MS/MS to quantify the % parent compound remaining.

Data analysis was done to calculate % parent remaining by assuming zero minute time point peak area ratio (analyte/IS) as 100% and dividing the remaining time point peak area ratios by the zero minute time point peak area ratio value. Data was subjected to a fit first-order decay model to determine half-life. A graph of log (ln) of peak area ratio against time was plotted to calculate the slope. Subsequently, half-life and intrinsic clearance values were calculated using the equations below:

Elimination rate constant (k) = (- slope)
Half-life (t1/2) min = 0.693/k
Intrinsic Clearance (CLint) (ml/min/million cells) = (Vx0.693)/t1/2
V= incubation volume ml/number of cells
Duration and frequency of treatment / exposure:
Human hepatocytes: 0, 15, 30, 60, 120 minutes
Rat hepatocytes: 0, 15, 30, 60, 120 minutes
Dose / conc.:
10 other: µM
No. of animals per sex per dose / concentration:
Cell count: 0.5 x 10^6 viable cells/mL
Details on study design:
Please see 'Any other information on materials and methods incl. tables'
Metabolites identified:
yes
Details on metabolites:
The parent compound was not detectable at the 15 minute time point, suggesting complete metabolism by that time point. Benzoic acid was detected at 9.7 mM at the 15 minute time point. While complete metabolism of a dibenzoate compound would be expected to yield a 2:1 molar ratio of benzoic acid:parent compound, the fact that only roughly 50% of the expected levels of benzoic acid were detected may be explained by the observation that the remaining benzoic acid is further metabolized after the 15 minute time point. The most likely explanation for this discrepancy is that the initial levels of benzoic acid upon addition of the parent compound were higher, and 50% metabolism of the benzoic acid occurred between T0 and 15 minutes. Propylene Glycol (PG) is the other metabolic by product that was expected but the study authors were unable to develop a LC or GCMS method for derivatized or underivatized PG. Two different derivatization procedures (Boronic Acid and Benzoyl Chloride) were unsuccessful.

Table 2. Data Summary: Hepatocyte Stability

Test Article

Species

Clearance (µl/min/million cells)

Half Life

(mins)

Avg % Remaining at Last Point

Comments

Propylene Glycol Dibenzoate

Humans

NR

NR

0.00%

Highly

metabolized

Rats

NR

NR

0.00%

Highly

metabolized

 

Midazolam

Humans

40.8

33.9

8.39%

Phase I Control

Rats

97.0

14.3

1.15%

 

Verapamil

Humans

46.9

29.6

5.78%

Phase I Control

Rats

65.6

21.1

1.59%

 

7-Hydroxy-4-(trifluoromethyl) coumarin

Humans

107.2

12.9

0.60%

Phase II Control

Rats

109.3

12.7

5.03%

NR: Not reportable due to no measurable compound after T0 time point

Table 3. Quantitation of Benzoic Acid in Human Hepatocytes

Human

Concentration (mM)

Time (minutes)

Replicate 1

Replicate 2

Average

120

1.9

1.65

1.8

60

4.87

4.22

4.5

30

7.52

7.02

7.3

15

11

8.38

9.7

0

BLOQ

BLOQ

NR

 

Table 4. Quantitation of Benzoic Acid in Rat Hepatocytes

Rat

Concentration (mM)

Time (minutes)

Replicate 1

Replicate 2

Average

120

3.76

4.22

4.0

60

4.22

6.01

5.1

30

7.59

6.58

7.1

15

9.48

10

9.7

0

BLOQ

BLOQ

NR

Conclusions:
PGDB was shown to be rapidly metabolized in both in vitro human and rat hepatocytes. Benzoic acid was formed and appeared to undergo metabolism after the 15-minute timepoint. Due to the unsuccessful analytical development of LC or GCMS method for derivatized or underivatized propylene glycol (Boronic Acid and Benzoyl Chloride derivatization procedures), no propylene glycol could be detected.
Executive summary:

The objective of this study was to evaluate the rate and completeness of metabolism of Propylene Glycol Dibenzoate in human and rat primary cryopreserved hepatocytes via measurement of the parent compound, and quantitation of Benzoic acid in the culture media post-incubation.

 

The test article was incubated in duplicate, for each timepoint, with cryopreserved hepatocytes at 37°C. The cells were thawed; viable cells were counted and equilibrated according to the supplier’s directions. After 30 min equilibration at 37°C with gentle agitation, the test article was added to the cell suspension to achieve desired final concentration of 1 µM. The cell suspension was incubated at 37°C. At the indicated times, samples were removed and mixed with an equal volume of ice-cold acetonitrile (containing the IS internal standard propranolol) to stop the reaction and precipitate proteins. Stopped reactions were kept on ice for at least ten minutes. The samples were centrifuged to remove precipitated protein, and supernatants were analyzed by LC/MS/MS to quantify the % parent compound remaining. 

 

Data analysis was done to calculate % parent remaining by assuming zero minute time point peak area ratio (analyte/IS) as 100% and dividing the remaining time point peak area ratios by the zero minute time point peak area ratio value. Data was subjected to a fit first-order decay model to determine half-life. A graph of log (ln) of peak area ratio against time was plotted to calculate the slope. Subsequently, half-life and intrinsic clearance values were calculated.

 

Propylene Glycol Dibenzoate was rapidly metabolized in both human and rat hepatocytes. The parent compound was not detectable at the 15 minute time point, suggesting complete metabolism by that time point. Based on the rapid nature of the disappearance, a half-life could not be calculated. Benzoic acid was detected at 9.7 mM at the 15 minute time point. While complete metabolism of a dibenzoate compound would be expected to yield a 2:1 molar ratio of benzoic acid:parent compound, the fact that only roughly 50% of the expected levels of benzoic acid were detected may be explained by the observation that the remaining benzoic acid is further metabolized after the 15 minute time point. The most likely explanation for this discrepancy is that the initial levels of benzoic acid upon addition of the parent compound were higher, and 50% metabolism of the benzoic acid occurred between T0 and 15 minutes. Propylene Glycol(PG) was the other metabolic by product that was expected but the laboratory was unable to develop a LC or GCMS method for derivatized or underivatized PG. Two different derivatization procedures (Boronic Acid and Benzoyl Chloride) were unsuccessful.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 1978 to December 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pre-Guidline study
GLP compliance:
no
Remarks:
Pre-Guidline; pre-GLP study
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Midwest Research Institute; Kansas City, Missouri
- Expiration date of the lot/batch: Not specified
- Purity test date: Not specified

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: >97%
- Specific activity: 12.78 mCi/mM
- Locations of the label: Not specified
- Expiration date of radiochemical substance: Not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
Not specified

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
31.5 mg of analytical reference standard Benzoflex 9-88 was weighed in a 10 mL volumetric flask and the flask filled to mark with 50% ethanol/distilled H2O and shaken. An aliquot of 0.450 mL of the above stock solution was individually pipetted into several vials and 100 µg of 14C-Benzoflex 9-88 in ethanol was added to each vial. Thus, each vial contained 1.495 mg of Benzoflex 9-88 having a specific activity of 0.85 mCi/mM. Each vial contained the dose for a single rat.

OTHER SPECIFICS:
Purity: >97%
Radiolabelling:
yes
Species:
rat
Strain:
other: Holzman's albino rats
Details on species / strain selection:
Not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not specified
- Age at study initiation: Not specified
- Weight at study initiation: 200 - 265 grams
- Housing: Individual metabolism cages (Scientific Products; Cat. no. 4565)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): Not specified

IN-LIFE DATES: Not specified
Route of administration:
oral: gavage
Vehicle:
other: ethanol/water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
31.5 mg of analytical reference standard Benzoflex 9-88 was weighed in a 10 mL volumetric flask and the flask filled to mark with 50% ethanol/distilled H2O and shaken. An aliquot of 0.450 mL of the above stock solution was individually pipetted into several vials and 100 µg of 14C-Benzoflex 9-88 in ethanol was added to each vial. Thus, each vial contained 1.495 mg of Benzoflex 9-88 having a specific activity of 0.85 mCi/mM. Each vial contained the dose for a single rat.

Rats, lightly anesthesized with ethyl ether, were administered a single dose of Benzoflex 9-88 dissolved in ethanol/water (3.7 to 6.3 mg/Kg) by oral intubation. Each rat received a know dose of between 0.8 and 1.3 mg of Benzoflex 9-88, depending on body weight. One male rat was given a sham dose.
Duration and frequency of treatment / exposure:
single dose of Benzoflex 9-88 dissolved in ethanol/water (3.7 to 6.3 mg/Kg) by oral intubation. Each rat received a know dose of between 0.8 and 1.3 mg of Benzoflex 9-88, depending on body weight.
Dose / conc.:
0 mg/kg bw (total dose)
Remarks:
Sham dose
Dose / conc.:
3.7 mg/kg bw (total dose)
Remarks:
Single dose of Benzoflex 9-88 dissolved in ethanol/water (3.7 mg/Kg) by oral intubation
(0.8 mg of Benzoflex 9-88, depending on body weight)
Dose / conc.:
6.3 mg/kg bw (total dose)
Remarks:
Single dose of Benzoflex 9-88 dissolved in ethanol/water (6.3 mg/Kg) by oral intubation
(1.3 mg of Benzoflex 9-88, depending on body weight)
No. of animals per sex per dose / concentration:
10 females and 4 males
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Not specified
- Rationale for animal assignment (if not random): Not specified
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood; heart; lungs; muscle; fat; gonads, uterus, spleen, kidneys, liver, brain
- Time and frequency of sampling: Urine and faeces collected daily; Blood collected from each rat at 1, 4, 8, 17, 24, and 48 hours post dosing. Tissues - At sacrifice, tissues were excised and frozen until further analysis.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, tissues
- Time and frequency of sampling: See above
- From how many animals: (samples pooled or not) : not pooled
- Method type(s) for identification: Liquid scintillation counting used to determine radioactivity
Statistics:
A computerized program was developed for data analysis. This program was designed to compute values for several pharmacokinetics parameters in the whole animal or its components. These parameters were:

1. Regression – the concentration of the chemical in urine, faeces, and blood as a function of time checked for 6 mathematical model curves to determine the curve of best fit.
2. Analysis of Variance – the best fit curve subjected to analysis of variance to quantify the goodness of fit.
3. ke – the rate constant multiplier which describes the rate of change as a function of time.
4. t1/2 – the time required to reduce the concentration by 50%. It is related to ke by t1/2 = (ln 0.5 / ke)
5. t0.95 - the time required to reduce the concentration by 95%.
6. Co - the calculated theoretical concentration at the instant of administration (time = 0). It is an extrapolation of the decay curve.
7. C (max) – the extrapolated maximum concentration attained from repeated regular administration of the chemical. It is the asymptomatic value of plateau.
8. N98 – the number of doses until 98% of C(max) is reached. Since doses were given at 24 hour intervals, N98 is the number of days to reach plateau.
Type:
absorption
Results:
Rapidly absorbed in the gut
Type:
distribution
Results:
Total amount of radiocarbon in the body was 0.644% of administered dose at 17 hours which decreased to 0.051% at 48 hours.
Type:
metabolism
Results:
Benzoic acid was the major 14C-compound present in the urine
Type:
excretion
Results:
70% eliminated in the urine and 10% in faecs within 48 hours
Details on absorption:
The test material was rapidly absorbed in the rat gut.
Details on distribution in tissues:
Total amount of radiocarbon in the body was 0.644% of administered dose at 17 hours which decreased to 0.051% at 48 hours. Liver and fat had 0.015 and 0.014 ppm , Benzoflex 9-88 equivalents, 48 hours post dosing. All other tissues contained residues less than 0.010 ppm, Benzoflex 9-88 equivalents. The rate of radiocarbon elimination from any tissue was rapid, showing a maxiumum half-life of less than 16 hours. There was no difference between the sexes in the body distribution of radiocarbon.

The Benzoflex 9-88 equivalents in blood peaked at 0.310 ppm after 2 hours and rapidly decreased to 0.011 ppm after 24 hours. The half-life of the radiolabelled material in blood is 3 hours and the rate constant of elimination (ke) is 0.231 per hour. The disspiation of the test material from the blood followed a hypebolic curve with a correlation co-efficient of 0.98.
Details on excretion:
About 70% of the administered dose was eliminated in the urine within 48 hours. During the same period about 10% of the administered dose was eliminated in the faeces. Radiocarbon content in the urine of males was slightly higher than that of females. The rate constant of elimination for all tissues was from 0.046 to 0.176 / hr. The t1/2 in tissues was 6.76, 8.09, 10.78, 15.20, 6.32, 6.45, 5.47, 3.94, 11.78, and 13.35 hours for heart, lungs, muscle, fat, gonads, uterus, spleen, kidneys, liver, and brain, respectively. The t0.95 was about 2 days for most tissues.
Metabolites identified:
yes
Details on metabolites:
Benzoic acid was the major 14C-compound present in the urine. However, when a saturated solution of mercuric chloride (to prevent bacterial decomposition) was added to the urine container in the metabolism cage, the only metabolite detected was hippuric acid. Therefore, hippuric acid will degrade to benzoic acid during urine collection, if a preservative is not added. This is in agreement with the findings of Bridges et al. (1979). The unabsorbed portion of the compound in the faeces consisted mainly of unchanged Benzoflex 9-88.

All C(max) values for tissues were less than 0.50 ppm except for kidney (23.84 ppm). The C(max) values were almost identical to the C0 values. The time required to reach C(max), which is extrapolated body burden after repeated regualr administration of the chemical at 24 hour intervals, ranged between 1 to 4 days with an average of 3 days.

Table 2. Excretion of Radiocarbon from Rats administered a Single Oral Dose of14C-Benzoflex 9-88 (3.7 – 6.3 mg/Kg) – Cumulative Percent of Administered Dose1

 

Group I

(17 hours)

Group II

(24 hours)

Group III

(48 hours)

Group IV

(48 hours)

Urine

 

24 hours

59.32

64.82

78.66

89.39

48 hours

 

 

81.41

101.27

 

Faeces

 

24 hours

8.08

2.92

6.21

0.84

48 hours

 

 

7.87

0.98

 

Total excretion

67.40

67.74

89.27

102.25

1 – Values represent mean of separate analyses of excreta which were collected from 2-4 rats.

Table 3. Retention of Radiocarbon in Rats Administered a Single Oral Dose of Benzoflex 9-88 (3.7 – 6.3 mg/Kg)

- % of Administered Dose (ppm)1

Tissue

Group I

(17 hours)

Group II

(24 hours)

Group III

(48 hours)

Group IV

(48 hours)

%

ppm

%

ppm

%

ppm

%

ppm

Blood

0.134

0.114

0.015

0.012

0.003

0.003

0.006

0.004

 

Heart

0.003

0.048

0.001

0.016

1.3 x 10-4

0.002

<0.001

<0.001

 

Lungs

0.008

0.057

0.002

0.016

0.001

0.004

0.7 x 10-4

0.001

 

Muscle

0.170

0.022

0.079

0.009

0.024

0.003

<0.001

<0.001

 

Fat

0.064

0.037

0.030

0.016

0.018

0.009

0.031

0.014

 

Gonads

0.001

0.060

2 x 10-4

0.018

0.2 x 10-4

0.002

<0.001

<0.001

 

Uterus

0.002

0.056

4.4 x 10-4

0.011

0.4 x 10-4

0.002

-

-

 

Spleen

0.003

0.051

0.6 x 10-4

0.002

0.4 x 10‑4

0.001

<0.001

<0.001

 

Kidneys

0.182

1.176

0.009

0.065

6.4 x 10-4

0.005

8 x 10-4

0.004

 

Liver

0.075

0.093

0.016

0.018

0.004

0.015

0.003

0.003

 

Brain

0.002

0.010

0.001

0.008

2.5 x 10-4

0.002

<0.001

<0.001

 

Total

(% Only)

0.644

-

0.154

-

0.051

-

0.040

-

1 – Values represent mean of two separate analyses conducted on each tissue taken from 2-4 rats.

Table 4. Radiocarbon Levels in Rats Administered a Single Oral Dose of 14C-Benzoflex 9-88 (5.0 mg/Kg)1

Interval (Time in Hours)

ppm Equivalent of Benzoflex 9-882

1

0.286

2

0.310

4

0.167

8

0.016

17

0.005

24

0.011

1 – Group II female rats were used to monitor residue levels in the blood.

2 – Values represent the means from duplicate analyses of samples taken separately from 2 to 4 rats.

Conclusions:
The pharmacokinetics of Benzoflex 9-88 appears to follow a one compartment open model system. The chemical is rapidly absorbed from the digestive system and the maximum concentration appeared in blood within 2 hours of treatment. The elimination of the chemical in the urine is proportional to its concentration in the blood. Based on the results of this study, Benzoflex 9-88 should neither be persistent not accumulative in mammalian systems.
Executive summary:

No data is available for propylene glycol dibenzoate (PGDB). Relevant toxicokinetics information is available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

 

Male and female rats were administered a single oral dose of Benzoflex 9-88. The compound was rapidly absorbed in the rat gut. About 70% of the administered dose was readily eliminated in the urine within 48 hours. During the same period, about 10% of the dose was excerted in the faeces. Almost all the radiocarbon present in the urine was hippuric acid. The maximum half-life Benzoflex 9-88 residue in any tissue was less than 16 hours. The time required to reach equilibirum (N98) after repeated regular administration of the chemical at 24 hour intervals was 1-4 days with an average of 3 days. The half-life of Benzoflex 9-88 in the blood was 3 hours.

 

The pharmacokinetics of Benzoflex 9-88 appears to follow a one compartment open model system. The chemical is rapidly absorbed from the digestive system and the maximum concentration appeared in blood within 2 hours of treatment. The elimination of the chemical in the urine is proportional to its concentration in the blood. Based on the results of this study, Benzoflex 9-88 should neither be persistent not accumulative in mammalian systems.

Description of key information

In Vitro metabolism data is available for propylene glycol dibenzoate (PGDB). This is supported by relevant toxicokinetic information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

The pharmacokinetics of DPGDB appears to follow a one compartment open model system. The chemical is rapidly absorbed from the digestive system and the maximum concentration appeared in blood within 2 hours of treatment. The elimination of the chemical in the urine is proportional to its concentration in the blood. Based on the results of this study, DPGDB should neither be persistent not accumulative in mammalian systems. This data is read across to PGDB.

PGDB was shown to be rapidly metabolized in vitro, in both human and rat hepatocytes. The parent compound was not detectable at the 15 minute time point, suggesting complete metabolism by that time point. Benzoic acid was formed and appeared to undergo metabolism after the 15-minute timepoint.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In Vitro metabolism data is available for propylene glycol dibenzoate (PGDB). This is supported by relevant toxicokinetic information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

PGDB consists of two moieties of propyl glycol (PG) and benzoic acid (BA) joined by an ester linkage. Similarly, DPGDB is a diester of dipropylene glycol (DPG) and BA. Any difference in toxicity of PGDB and DPGDB would be expected to be caused by the differences in alcohol type for both target (PGDB) and source (DPGDB) substances, as the metabolism of the ester would be equivalent in both cases. 

 

Both DPGDB and PGDB would be expected to be ideal candidates for ester hydrolysis within the gut, resulting in DPG/PG and BA being available for absorption across the small intestine into the portal blood circulation.

The esterification hydrolysis of DPGDB to DPG and BA has been demonstrated in a key study, where male and female rats were administered a single oral dose of DPGDB (Diaz and Atallah., 1979; Klimisch score = 2). The compound was rapidly absorbed in the rat gut. About 70% of the administered dose was readily eliminated in the urine within 48 hours. During the same period, about 10% of the dose was excerted in the faeces. Almost all the radiocarbon present in the urine was hippuric acid. The maximum half-life DPGDB residue in any tissue was less than 16 hours. The time required to reach equilibirum (N98) after repeated regular administration of the chemical at 24 hour intervals was 1-4 days with an average of 3 days. The half-life of DPGDB in the blood was 3 hours.

 

The pharmacokinetics of DPGDB appears to follow a one compartment open model system. The chemical is rapidly absorbed from the digestive system and the maximum concentration appeared in blood within 2 hours of treatment. The elimination of the chemical in the urine is proportional to its concentration in the blood. Based on the results of this study, DPGDB should neither be persistent not accumulative in mammalian systems.

In another key in vitro toxicokinetic study (Cyprotex, 2018; Klimisch score = 2), PGDB was shown to be rapidly metabolized in both in vitro human and rat hepatocytes. BA was formed and appeared to undergo metabolism after the 15-minute timepoint. Due to the unsuccessful analytical development of LC or GCMS method for derivatized or underivatized PG (Boronic Acid and Benzoyl Chloride derivatization procedures), no PG could be detected. It is however well demonstrated in vivo, that PG is rapidly absorbed after oral administration. Once absorbed into the body, about 45% of an absorbed PG dose is excreted by the kidneys unchanged or as the glucuronide conjugate. Approximately 40% to 50% of administered propylene glycol is also metabolized in the liver by alcohol dehydrogenase to lactic acid, and then pyruvic acid. Both of these metabolites are normal constituents of the citric acid cycle and are further metabolized to carbon dioxide and water (Szerlip, 2014 - attached to Section 13 of the IUCLID dossier).