Diutan gum

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well reported in vivo absorption, distribution and excretion study of a close chemical analogue.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

3-stage investigation, a single oral dose of radiolabelled test substance being given to rats for each stage:
[1] respired 14CO2 levels determined over 24 hours post-dose
[2] urine and faeces collected and checked for radioactivity over 7 days post-dose, then organs/tissues collected at termination and checked for radioactivity
[3] blood samples collected over 168 hours post-dose and analysed for radioactivity.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Gellan gum

EC Number:

275-117-5

EC Name:

Gellan gum

IUPAC Name:

Gellan gum

Details on test material:

Gellan gum, sample ID EX 4949 radiolabelled as indicated.

Radiolabelling:

yes

Remarks:

14C and 3H

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were age 42-49 days on arrival in test laboratory (7 days prior to study start). Individually housed in metal cages, with free access to food and water (except where restricted in test phase). 12-hour light/dark cycle in animal room, temperature 72 +/-2 degrees F.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Test substance mixed with corn oil and homogeneity checked by sampling and radiocounting. Specific activity of formulated dose checked by sample combustion and scintillation counting.

Duration and frequency of treatment / exposure:

Single administration, following 18 hours of fasting..

Doses / concentrations

Remarks:

Doses / Concentrations:
Stage 1: males 950 mg/kg, 4.5 microCuries 14C. Females 980 mg/kg, 3.3 microCuries 14C.
Stage 2: males 848 +/- 33.9 mg/kg, 4.08 +/- 0.35 microCuries 14C, 0.09 +/-0.07 microCuries 3H. Females 896.7 +/- 7.9 mg/kg, 2.9 +/- 0.08 microCuries 14C, 0.67 +/-0.07 microCuries 3H.
Stage 3: males 862.8 +/- 17.2 mg/kg, 4.1 +/- 0.07 microCuries 14C, 0.9 microCuries 3H. Females 902.8 +/- 30.3 mg/kg, 2.9 +/- 0.1 microCuries 14C, 0.63 +/-0.04 microCuries 3H.

No. of animals per sex per dose / concentration:

Stage 1 (CO2 collection): 1 male, 1 female.
Stage 2 (during faeces collection, tissue distribution): 4 males, 4 females but one female excluded from study (abnormal findings at necropsy - suggestive of maldosing).
Stage 3 (blood levels): 4 males, 4 females.

Control animals:

no

Positive control reference chemical:

No

Details on dosing and sampling:

Stage 1: dosed rats placed in Roth metabolism chambers with scrubbed air supply (CO2, moisture removed). Expired air absorbed in ethanolamine/cellosolve trap, sampled 4, 12 and 24 hours post-dose.

Stage 2: dosed rats placed in open metabolism chambers (fed from 6 hours post-dose). Urine freeze-trapped, faeces collected separately: samples taken at 4,12,24,48,72,96,120,144 and 168 hours post-dose. After this 7 day period, rats anaesthetised and exsanguinated. Blood, brain, liver, kidneys, lung, muscle, skin, heart, testes, prostate, ovaries, uterus removed for radioanalysis.

Stage 3: dosed rats placed in restrainers for blood sampling at 0.25,0.5,1,2,3,4 and 6 hours post-dose, Then transferred to cages and fed. Restrained again for blood collection at 8,24,48,72,96,120,144 and 168 hours post-dose.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

results indicate very little absorption from GI tract

Main ADME results 2

Type:

distribution

Results:

levels in tissues/organs generally low

Main ADME results 3

Type:

excretion

Results:

most (85% or more) of administered radioactivity excreted in faeces

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

See tables: in all cases, a total of <5% of the administered 14C radioactivity was found in all examined tissues/organs plus the animal carcase. Residual 3H levels in tissues/organs were so low (close to twice background count) they could not be accurately quantified.

Details on excretion:

Stage 1: less than 0.55% of dosed radioactivity was expired in the form of 14CO2.
Stage 2: females excreted 1.85 +/-0.55% of dosed 14C in urine, 86.79 +/-3.08% in faeces.

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Urinary and faecal excretion results (Stage 2 experiment).

Sex	% dosed^14C excreted			% dosed^3H excreted
	In urine	In faeces	7-day total	In urine	In faeces	7-day total
Males	3.29+/-0.8	85.16+/-1.11	92.18+/-0.59	5.04+/-0.88	98.40+/-1.34	103.44+/-1.39
Females	1.85+/-0.55	86.79+/-3.08	91.6+/-2.5	4.06+/-1.04	100.86+/-3.21	104.92+/-2.19

Tissue distribution results (Stage 2 experiment).

Organ/tissue	% of administered^14C radioactivity recovered in sample
	Male 1	Male 2	Male 3	Male 4	Female 1	Female 2	Female 3
Brain	0.015	0.012	0.016	0.016	0.023	0.024	0.021
Liver	0.420	0.309	0.295	0.327	0.347	0.302	0.328
Kidney	0.050	0.040	0.038	0.042	0.040	0.043	0.048
Heart	0.015	0.013	0.012	0.013	0.015	0.014	0.012
Lung	0.021	0.019	0.017	0.018	0.022	0.0224	0.025
Prostate	0.007	0.008	0.012	0.013	-	-	-
Testes	0.032	0.023	0.021	0.028	-	-	-
Ovaries	-	-	-	-	0.002	0.002	0.001
Uterus	-	-	-	-	0.005	0.006	0.003
Carcase	2.794	2.765	4.551	3.096	2.502	2.426	2.647
Total	3.354	3.189	4.962	3.553	2.956	2.841	3.085

Muscle, skin and blood values not reported.

In the Stage 3 experiment, recorded levels of radioactivity in the blood were low: mean peak blood radioactivity in both sexes was close to 3000 DPM/ml blood, occurring around 5.5 hours post-dosing in males, 5.25 hours post-dosing in females.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The low levels of radioactivity recorded in tissues and blood samples and the high levels of radioactivity excretion in faeces suggest very little absorption from the gastrointestinal tract occurred following oral dosing. No potential for bioaccumulation was indicated by the study findings. Based on the close chemical similarity between gellan gum and Diutan, it is reasonable to predict that a comparable pattern of non-absorption would be seen if Diutan were to be similarly tested.