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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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, GLP-compliant study of close chemical analogue, using methods similar to those of the relevant OECD guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Twice daily observation and opthalmoscopy during treatment period, but no functional observation battery.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Polysaccharide gum K9A50
IUPAC Name:
Polysaccharide gum K9A50
Details on test material:
K9A50: gellan gum (EC 275-117-5): high polysaccharide content.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Individually housed in stainless steel, wire mesh cages. Tapwater and powdered diet freely available, 12 hour/12 hour dark cycle (temperature and humidity controlled). Bodyweights 121-141g (males) 100-118g (females) 7 days prior to treatment.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: powdered basal diet
Details on oral exposure:
Test diets mixed weekly in blender.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability of test substance in diet confirmed in pilot study prior to this 13-week toxicity study. Samples taken during treatment weeks 1,6,10,13 and achieved concentrations confirmed by analysis.
Duration of treatment / exposure:
Continuous exposure via diet for 13 weeks.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
3.0%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
4.5%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
6.0%
Basis:
nominal in diet
No. of animals per sex per dose:
20 males, 20 females.
Control animals:
yes, plain diet
Details on study design:
2-week acclimation pre-treatment; satellite group (health screen, 10 males + 10 females) terminated pre-treatment.
Positive control:
No.

Examinations

Observations and examinations performed and frequency:
Mortality checked twice daily; clinical signs recorded once daily.
Bodyweights and food consumption recorded pre-treatment and weekly during treatment.
Opthalmoscopy checks (control and high-dose groups) pre-treatment and prior to termination.
Haematology, blood chemistry, urinalysis checked pre-treatment (health screen satellite group) and (together with faecal moisture content) in weeks 6 and 12 of treatment period (10 or 12 rats/sex/group).
Sacrifice and pathology:
Termination was by CO2 asphyxiation followed by exsanguination. Full postmortem at necropsy with organ weights (adrenals, brain, heart, kidneys, liver, ovaries, pituitary, spleen, tested, thyroid and parathyroid).
Full tissue list taken and fixed, femoral bone marrow smears prepared and stained.
Histopathology examinations on all tissue taken from control and high group rats.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
Small increases in neutrophil counts in treated males achieved statistical significance compared to controls but were considered not to be of toxicological significance.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No toxicologically significant differences from controls were recorded in test groups.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No toxicologically significant differences from controls were recorded in test groups.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Some cases of reddened stomach mucosa were noted (maximum 4 males, 1 female at 6%) but histopathological examination found no abnormalities.
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
For about 1 week mid-study, most animals showed symptoms of viral infection (syalodacryoadenitis) but all recovered, showing no residual effects.
No adverse reactions top treatment were seen.

Effect levels

Dose descriptor:
NOAEL
Effect level:
6 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No evidence of toxicity seen in any test group. Achieved intake at 6% in diet was 2.95-7.26 g/kg/day (according to sex and week of the test period).

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Achieved intake of test substance by rats given 6% in diet was calculated to be:

- in males, 6.99 g/kg/day in week 1, 2.95 g/kg/day in week 13

- in females, 7.26 g/kg/day in week 1, 3.76 g/kg/day in week 13.

Applicant's summary and conclusion

Conclusions:
Rats fed 6% gellan gum in diet for 13 weeks (corresponding to daily intakes ranging from 2.95 to 7.26 g/kg/day) showed no evidence of treatment related toxicity. It is reasonable to predict that a similar pattern of low subchronic toxicity would be seen if Diutan were to be tested in the same way.