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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Justification of read-across: Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Justification of reliability of 2: scientifically well-performed study

Data source

Reference
Reference Type:
publication
Title:
The metabolism of sorbitan monostearate
Author:
Wick, A.N. and Joseph, L.
Year:
1953
Bibliographic source:
Food research, 1953, 18:79-84
Report Date:
1952

Materials and methods

Objective of study:
distribution
excretion
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
analytical purity of test substance not given
Principles of method if other than guideline:
Rats were fed with C14 radiolabelled sorbitan monostearate and samples from the animals were collected for 48h and analysed.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Sorbitan monostearate
- Locations of the label (if radiolabelling): polyol residue or stearic acid fraction
Radiolabelling:
yes
Remarks:
C14

Test animals

Species:
rat
Strain:
other: Albino
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Purina Laboratory Chow
- Weight at study initiation: 90-210 g
- Fasting period before study: no fasting

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water emulsion or corn oil because of different absorption properties
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): absorption from the intestinal tract by itself is not necessarily identical with its route when dissolved in oil or in water
- Concentration in vehicle: dose dependent
- Amount of vehicle (if gavage): 4 mL corn oil or 8 mL water
Duration and frequency of treatment / exposure:
single exposure, 48h observation time
Doses / concentrations
Remarks:
Doses / Concentrations:
dependent on the experiment: 100, 240, 258, 263, 303, 307, 400 or 1293 mg in 4 or 8 mL vehicle
No. of animals per sex per dose:
no data
Control animals:
no
Details on study design:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum or other tissues, cage washes, bile

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, liver, kidneys, intestinal tract, hind lend muscle or entire carcas for fat, CO2
- Time and frequency of sampling: CO2 for 48h in 6h intervals, others after 48h
- From how many animals: (samples pooled or not) single samples
- Method type(s) for identification: by BaCO3 obtained directly or by dry combustion, or by direct counting
Details on dosing and sampling:
See "any other information on materials and methods incl. talbles"

Results and discussion

Preliminary studies:
no

Toxicokinetic / pharmacokinetic studies

Details on absorption:
90% of the sorbitan monostearate when administerd in corn oil is hydrolyzed in the intestinal tract and after its absorption. The resulting anhydrid is poorly absorbed. When administered in water only 50% are hydrolyzed. The anhydrids of sorbitol were largly excreted into the urine before they could be completely oxidized to CO2.
Details on distribution in tissues:
Distribution of the radioactivity 48 hours after the oral administration of sorbitan monostearate is shown in the Tables in the following ("any other information on results incl.tables".
A small amount (3-7%) of the ingested radioactivity was recovered in the tissues 48 hours after the feeding of the polyol labeled compound. Under similaconditions a 4- to 6-fold increase in C14 deposition occurred by feeding the stearate labeled compound when dissolved in oil.
The distribution of the C14 in the crude fat obtained from animal given 100 mg of sorbitan monostearate dissolved in 4 ml of corn oil is shown in the Table in the following. Three animals were sacrifieced after 2 and 7 days, respectively. In these experiments the carcasses included the kidneys and the liver, Although the crude fat obtained from each animal was saponified separately for the isolation of the fatty acids, the water soluble fractions were combined for the 2- and 7-day animals, respectively. by averaging the results from the 3 animals in each of the 2- and 7-day groups, the percentage of the injected C14 in the crude fat (excluding the intestinal tract) was 0.76 and 0.46%.
Details on excretion:
Expired CO2:
In all experiments a significant fraction of theadministered C14 was found in the expired CO2. The feeding of the polyol labeled ester resulted in recoveries of 14 to 24% of the administered radioactivity.

Urine:
When the polyol labeled substance was administered in water 25 and 16% of the C14 was recovered in the urine. when administered in oil 44 to 66% of the radioactivity was recovered. On the other hand, the feeding of the stearate labeled compound resulted, as expected from the stool analyses, in only a trace of C14 excretion.

Stool:
The feeding of the stearate labeled substance as a water emulsion resulted in an excrection of 69 to 76 of the fed C14 as CHCl3 soluble which is in line with results obtained by absorption studies on stearic acid. When the stearate labeled compound was fed in oil, lower values (33 to 37%) were obtained. Considerably lower results were obtained when feeding the polyol labeled compound. Hence the administration of the esters in oil in all experiments increased their intestinal absorption as indicated by the diminished C14 content of the stools.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Stearic acid and anhydrids of sorbitol

Any other information on results incl. tables

The analogue approach using sorbitan stearate as source chemical is justified:

Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Compared to the source chemical, the target chemical has a shorter alkyl chains that affect its physicochemical properties. But based on the kinetic / metabolic investigations on both chemicals, the length of the alkyl chain is not considered to have significant impact on the metabolic pathway or toxicological mode of action. Oral gavage studies in rats administered C14 labeled sorbitan stearate in oil solutions have demonstrated that about 90% of the substance was absorbed and hydrolyzed to stearic acid and sorbitan. The metabolic fate of sorbitan caprylate was investigated using a lipase assay. The hydrolysis mediated by porcine pancreas lipase was quantitatively determined. The target chemical sorbitan caprylate is proved to be hydrolyzed and caprylic acid was formed . These findings suggest that metabolism of the sorbitan occur initially via enzymatic hydrolysis, leading to sorbitan and the corresponding natural acids.

Based on the above mentioned information, it is reasonable to consider that these two substances are comparable in their metabolic fate and thereby toxicological profiles. Hence, the source chemical is considered as “suitable with interpretation” analog.

According to the available toxicity studies, the findings are also comparable for target and source chemicals:

·        The findings in acute toxicity studies are comparable. Both chemicals are of no acute toxicity.

·        The findings in subacute dose toxicity studies are comparable. No treatment effects were observed in 28-day repeated toxicity studies in Wistar rats. The same NOEL of 1000 mg/kg bw/d was derived for both chemicals.

·        The findings in genetic toxicity are comparable. Both chemicals did not induce gene mutations in Ames tests, but induced structural chromosomal aberrations in cell lines of Chinese Hamster.

·        The findings in reproduction / developmental toxicity studies are comparable.

Percent distribution of radioactivity 48 hours after oral administration of carbon 14 labeled sorbitan stearate

                Polyol labled              Stearate labeled
 Experiment No.  1 10  11 
 Expired CO2  15 14  18  19  24  20  18  12  33  21 
 Urine  25 16  66  66  50  44 
 Stool CHCl3 soluble  31 54  75  76  69  37  33 
 Stool CHCl3 insoluble  17 12  12 10  12 
 Combined tissues  - 10  15  32  41 
 Total recovery  88 99  109  106  96  91  97  99  101  105  98 
In experiments 1, 2,7,8 and 9 the sorbit.an monost.earate was emulsified with 8 ml of water before daministration. In Runs 3, 4, 5, 6, 10 and 11 it was dissolved in 4 ml. of corn oil. Amounts of sorbitan monostrarate administered in experiments 1 to 11 were 240, 1293, 100, 100, 100, 100, 268, 303, 307, 400, and 258 mg, respectively. The total counts administered in experiments 1 to 11 were 1.04, 5.6, 2.35, 2.35, 2.35, 2.35, 0.43, 0.49, 0.50, 2.1 and 0.42 million, respectively. Lot No. 1(polyol labeled sorbitan monostearate) was used in experiments 1 and 2, and Lot No. 2 in experiments 3, 4, 5 and 6. Stearate labeled (Lot No.1) was used in experiments 7, 8, 9 and 11, and Lot No.2 in experiment 10.

Percent distribution of radioactivity in tissues 48 hours after oral administration of carbon 14 labeled sorbitan stearate

                  Polyol labeled           Stearate labeled
    Experiment No.  2 8 9 10 11
    Liver CH3Cl3 soluble  0.06 0.08  0.09  0.10  0.11  1.28  1.45  4.30   4.70
CH3Cl3 insoluble  0.23 0.52  0.55  0.57  0.50  0.35  0.62  0.92  1.82 
    Kidney CH3Cl3 soluble 0.01  0.01  0.02  0.08  0.03  0.18  0.05  0.14  0.18 
CH3Cl3 insoluble  0.02 0.05  0.05  0.05  0.05  0.05  0.14  0.09  0.49 
    Intestines CH3Cl3 soluble  0.07 0.29  1.18  0.12  0.76  0.61  0.62  2.53  2.54 
CH3Cl3 insoluble   0.18 0.98  0.77  0.59  1.64  0.18  0.23  0.73  0.85 
    Carcasse CH3Cl3 soluble  0.53 1.13  1.39  0.68  0.91  6.20  11.30  17.95  26.40 
CH3Cl3 insoluble  1.44 2.58  2.58  2.84  2.80  1.45  1.07  5.65  3.90 
    Total recovery  2.54 5.64  6.90  5.03  6.80  10.40  15.48  32.31  40.88 

Rate of C14 excretion in expired CO2 after administration of polyol labeled sorbitan monostearate

    Period (hours) Experiment number          
 3
 1 -6 3.2  2.1  3.2  1.8 
 7 -12 4.9  4.2  4.9  2.3 
 13 -18 4.8  3.8  4.1  2.6 
 19 -24 2.7  4.6  4.2  1.8 
 25 -30 1.1  2.5  2.5  4.5 
 31 -36 0.7  1.0  1.9  4.2 
 37 -42 0.6  0.7  2.1  1.4 
 43 -48 0.3  0.4  1.0  1.4 
 Total 18  19  24  20 

Vales expressed as % of fed ester

Percent distribution of radioactivity 48 hours after administration of urine and stool extracts

   Stool from No.2 Urine frome No.2   Urine from No.12
 Experiment No.  12 13 14
 Expired CO2 28 23  24 
 Urine  27 64  34 
 Stool CHCl3 soluble 32 
Stool CHCl3 insoluble 17  24  31 
 Total 104  116  94 

Distribution of C14 in crude carcass fat

 Time of sacrifice after feeding 2 -day  7 -day 
 1. Fatty acids 38  42 
 2. Glycerol 27  43 
 3. Residue 14  12 
 Total 79  97 

Values expressed as precent of the crude fat

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other:
The target chemical sorbitan caprylate is considered to be hydrolyzed to caprylic acid and the anhydrides of sorbitol.
Executive summary:

The metabolism and toxicokinetics of sorbitan caprylate was assessed based on the analogue approach using sorbitan stearate as a read-across supporting substance.

Radioactive sorbitan monostearate has been fed to rats and the fate of the C14 has been studied. The distribution of the C14 shows that at least 90% of the polyol labeled emulsifier, when fed in oil solution, was hydrolyzed to stearic acid and the anhydrides of sorbitol. When fed as a water emulsion, about 50% of the ester is hydrolyzed.

The anhydrides of sorbitol which were liberated by the hydrolysis were largely excreted into the urine before they could be completely oxidized to CO2.

The amount of C14 found in the tissues 48 hours after feeding of polyol labeled sorbitan monostearate in oil was 5 to 7% of the administered C14. Fractionation of the crude fat extract of the tissues (excluding the intestinal tract) indicated that less than 0.1% of the fed C14 may represent sorbitans derived from fed sorbitan monostearate or sorbitan esters synthesized from circulating sorbitan.

Based on the results from the study of sorbitan monostearate, the target chemical sorbitan caprylate is considered to be hydrolyzed to caprylic acid and the anhydrides of sorbitol.