Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.
Justification for type of information:
The Glycol ester category covers esters of an aliphatic diol (ethylene glycol (EG), propylene glycol (PG) or 1,3-butyleneglycol (1,3-BG)) and one or two carboxylic fatty acid chains. The fatty acid chains comprise carbon chain lengths ranging from C6 to C18, mainly saturated but also mono unsaturated C16 and C18, branched C18 and epoxidized C18.Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. ethylene glycol) with an organic acid (e.g. stearic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by a transfer of a proton from the acid catalyst to the alcohol to form an alkyloxonium ion. The acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to a carbonyl carbon of acid. An intermediate product is formed. This intermediate product loses a water molecule and a proton to give an ester (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Di- and/or monoesters are the final products of esterification of an aliphatic diol and fatty acids.
 
In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests", which includes the use of information from structurally related substances (grouping or read-across).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1958

Materials and methods

Objective of study:
absorption
distribution
excretion
Principles of method if other than guideline:
In vivo catabolism study of 14C-labelled propylene glycol distearate in rats.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Weight at study initiation: 192 ± 20 g
- Individual metabolism cages: yes
- Diet: commercial dog meal, ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: casein-sugar-water emulsion
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The radioactive test compounds were prepared as components in a casein-sugar-water emulsion wherein the “fat” globules were dispersed by use of a Virtis high-speed homogenizer to an average diameter of 4 µm. All emulsions were prepared fresh immediately preceding gastric intubation.

VEHICLE
- Amount of vehicle: 1.0-1.5 mL
Duration and frequency of treatment / exposure:
72 h
Doses / concentrations
Remarks:
Doses / Concentrations:
150 mg/100 g
No. of animals per sex per dose:
2 animals (PGDS*)
1 animal (PG*DS)
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, gastrointestinal content and carcassess (total animal less specific organs)
- Time and frequency of sampling: animals were placed in a closed metabolism glass chamber, and continuous CO2 measurements were recorded for 72h. 72h urine and faeces collections were made, as well. At the conclusion of the 72 h-period, animals were sacrificed with chloroform and autopsied. The dried organ weights were obtained. A continuous record of the respires radioactive CO2 was accomplished by a method similar to that reported by Tolbert et al. (Tolbert, B.M., Lawrence, J.H. and Calvin, M. A-Conf. 8/12/56, Intern, Conf. Peaceful Uses Atomic Energy, July 1, 1955.)

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, CO2
- Time and frequency of sampling: 72 h
- Method type for identification: GC

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
PGDS*: 34.2% total dose in 72 h
Type:
absorption
Results:
PG*DS: 99.8% total dose in 72 h
Type:
absorption
Results:
Glyceryl stearate* mixture: 98.3% total dose in 72 h
Type:
absorption
Results:
PG + S*: 48.2% total dose in 72 h
Type:
absorption
Results:
PG* + S: 99.5% total dose in 72 h
Type:
distribution
Results:
PGDS*: (65.8, 17.5, 6.4, 6.2, 10,8% in faeces, CO2, urine, organs and carcass, respectively)
Type:
distribution
Results:
PG*DS: (0.2, 94.0, 0.4, 2.7 and 2.3% in faeces, CO2, urine, organs and carcass, respectively)
Type:
distribution
Results:
Glyceryl stearate* mixture: (40.6, 43.2, 0.0, 6.4, 8.1 in faeces, CO2, urine, organs and carcass, respectively)
Type:
distribution
Results:
PG + S*: (51.8, 42.6, 1.6, 3.2 and 4.8% in faeces, CO2, urine, organs and carcass, respectively)
Type:
distribution
Results:
PG* + S:(0.5, 76.4, 2.3, 3.3 and 16.5% in faeces, CO2, urine, organs and carcass, respectively)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The rate of absorption of PGDS* was determined by the residual radioactivity of the gastrointestinal tract extracts (see Table 1 under “Any other information on results incl. tables). The total extent of absorption of PGDS* in the rat was found to be 33% of the administered dose in 8h. Comparative studies using 14C-labeled stearic acid have demonstrated a greater absorption than that determined for PGDS*. The authors concluded that, that the initial limiting factor governing PGDS* absorption is the hydrolysis rate of the ester. The low rate for PGDS* absorption was linked to the hydrolysis of the ester molecule as shown by comparative absorption studies undertaken at the 3h digestion level using PG*DS. For PG*DS an absorption of 25% of the radioactivity within 3 h was demonstrated. After the 3 h period, the governing factor for absorption was that of the stearic acid moiety. This was evident from the results in which PG*DS and PG* plus S was 100% absorbed after 72 h as compared to 34% for PGDS* ad 48% for PG plus S*. Thus, extensive hydrolysis and more rapid absorption of the PG moiety, leaving behind a slowly absorbed stearate was considered.
In addition, the absorption study showed 100% of the activity from a dose of PG* plus S and also PG*DS is absorbed within 72 h. PG plus S* activity was absorbed only to the extent of 48% in 72 h, generally resembling PGDS* and stearate in the extent of uptake.
Details on excretion:
The greatest extent of faecal excretion occurred with stearate-labelled PGDS*, PG plus S* and glyceryl stearate* mixtures. Approximately 6% of the total dose or 19% of the absorbed dose of PGDS* is excreted in the urine in 72h. Only 0.4% was excreted form PG*DS, indicating the origin of urinary excretory products to be derived largely from the stearate portion of the molecule. The glyceryl stearate* mixture gave rise to negligible radioactivity in the urine. Similar findings were obtained with PG* plus S and PG plus S*. Metabolic products of PGDS* appear to partition more toward urinary excretion than do the other compounds studied. No explanation was given for this relatively large output of urine activity. The authors concluded that the metabolism of the stearic acid portion of PGDS was different form free stearic acid given in the presence of PG. 94% of the absorbed radioactivity in PG*DS was utilized, as evident by the 14CO2 excretion within 72 h. 51% of the absorbed activity of PGDS* was metabolized to CO2 and 73% of absorbed activity of the glyceryl stearate* mixture was metabolized to CO2. Up to 6 h the percent of total absorbed 14C dose expired was the same for PGDS* and PG*DS and the measured absorption at 3 h was similar for these two compounds. After 6 h, an increase in the 14CO2 excretion from PG*DS which may be due to the more rapid absorption and turnover of free PG as compared to stearic acid was observed. The per cent of the absorbed radioactivity expired at the end of 72 h was 94% for PG*DS, 76% for PG* plus S, 72% for the glycerol stearate* mixture, and 89% for S* plus PG. A marked difference in 14CO2 output between the free stearic acid and the glyceride mixture was observed. The authors concluded that this difference might be due to the time required for esterification of the stearic acid to the corresponding glyceride, as well as the probable absorption rate lag of the stearic acid.

Any other information on results incl. tables

Table 1. Intestinal absorption of radioactive compounds.

Component

No of rats

Absorption time [h]

Average fasted body weights [g]

Average administered dose [mg]

Average recovered dose [mg]

Average per cent total dose absorbed

PGDS*

2

0

182

319

313

2.0

 

3

1

190

342

304

11.1

 

4

3

190

301

233

22.9

 

5

5

193

354

312

19.0

 

4

8

188

153

102

33.3

PG*DS

3

3

181

367

275

25.0

S* + PG

4

3

202

198

133

33.0

Table 2. Recovery of radioactivity from 14C-labelled PGDS and related compunds in 72 h.

 

Total per cent of dose in 72 h

 

PGDS*

PG*DS

Glyceryl stearate* mixture

PG + S*

PG* + S

Faeces

65.8

0.2

40.6

51.8

0.5

CO2

17.5

94.0

43.2

42.6

76.4

Urine

6.4

0.4

0.0

1.6

2.3

Organs

6.2

2.7

6.4

3.2

3.3

Carcass

10.8

2.3

8.1

4.8

16.5

Recovery

106.8

99.6

98.3

104.0

99.0

 

Per cent alimentary absorption

 

34.2

99.8

59.4

48.2

99.5

 

Per cent recovery of absorbed dose

CO2

51.3

94.8

72.8

89.0

76.4

Urine

18.9

0.4

0.0

3.4

2.3

Organs

18.5

0.9

10.7

4.2

4.5

Carcass

31.6

2.3

13.7

10.1

16.5

Recovery#

120.3

98.4

97.2

106.7

99.7

#: The difference in recovery between the total dose and absorbed dose is due to the apparent per cent error in the total recovery which was compounded by assuming no error in the absorbed dose.

Applicant's summary and conclusion

Conclusions:
The extent of absorption of PG*DS, PGDS*, PG plus S* were all similar to a 14C carboxyl-labeled stearic acid mixture of glyceride esters. Continuous CO2 measurements for 72 h were made for the above compounds and for PG* plus S. Results show that the propylene glycol stearate esters are hydrolysed and absorbed in a manner similar to glyceride esters of stearic acid.