Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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
Study period:
1998-10-14 till 1999-02-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 408)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Undecylenic Acid Sodium Salt, Undecylenate de Sodium
- Substance type: salt
- Physical state: translucent yellow liquid (33% aqueous solution w/w)
- Composition of test material, percentage of components: 33% aqueous solution w/w
- Expiration date of the lot/batch: Jan. 1999
- Storage condition of test material: at RT
- Analytical purity: 98.5%
- Lot No. 2202K

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
-Cesarian obtained, barrier-sustained, virus antibody free
- Source: Charles River, Ste-Aubain-les-Elbeuf, France
- Age at study initiation: 6 weeks
- Weight at study initiation: 188-217g (males) 160-193g (females)
- Housing: suspended wire mesh cages, 2/cage (same sex)
- Diet (e.g. ad libitum): ad lib., pelleted
- Water (e.g. ad libitum): ad lib. 0.22 um-filtered tap water
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-2
- Humidity (%): 50+/-20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1998-10-14 To: 1999-02-11

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
weekly, used up to 9 days; stored light protected at RT
stirred continously under light protection during administration

VEHICLE
- Concentration in vehicle: 1.67, 5, 15 and 30 mg/ml
- Amount of vehicle (if gavage): 6 ml/kg BW/day
- Purity: 98.5
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by GC-FID; weeks 1,4,8, and 13
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily; half of the dose twice a day (3-4 h interval between)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
20 mg/kg BW
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg BW
Basis:
actual ingested
Remarks:
Doses / Concentrations:
180/360 mg/kg BW (180 mg/kg BW up to day 50, afterwards 360 mg/kg)
Basis:
actual ingested
No. of animals per sex per dose:
10 (plus additional 10 animals per sex added to control and high dose group for recovery period)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose-finding study (14 d)
- Rationale for animal assignment (if not random): random by body weight
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION : Yes
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: Yes
URINALYSIS: no
NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table2)
HISTOPATHOLOGY: Yes (see table2)
Statistics:
Yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
dose-dependent observation of ptyalism, loud breathing/respiratory difficulties and poor clinical condition

BODY WEIGHT AND WEIGHT GAIN
reduced body weight gain in males of the high dose group, especially after dose increase starting day 50

FOOD CONSUMPTION
slightly reduced in males of the high dose group after dose increase starting day 50

FOOD EFFICIENCY
no effects

WATER CONSUMPTION
no effects (minor, not dose-related)

OPHTHALMOSCOPIC EXAMINATION
no effects (minor, within historical control)

HAEMATOLOGY
no effects (slight, within historical control)

CLINICAL CHEMISTRY
high dose group:
reduced glucose plasma levels in females, reversible in treatment-free period
reduced triglyceride-levels in females, not reversible in the treatment-free period

URINALYSIS
no effects

ORGAN WEIGHTS
no effects

GROSS PATHOLOGY
no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
cardiomyopathie in the highest dose group exclusively (control: 2/20, low dose: 3/20, inter dose: 3/20, high dose: 11/23), myocardial degeneration/monocellular aggregation which was reversible during treatment free period in the highest dose group; minimal liver steatosis, not considered treatment related; one animal in high dose group cerebrellar changes, not considered of relevance; two animals of the high dose group forestomach oedema/inflammatory cell infiltration;

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
urinalysis
behaviour (functional findings)
immunology
organ weights and organ / body weight ratios
gross pathology
neuropathology
histopathology: non-neoplastic
histopathology: neoplastic
other: non adverse effect
Remarks on result:
other:
Key result
Dose descriptor:
LOAEL
Effect level:
180 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other:

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the experimental conditions, the 13 week oral toxicity study derived LOAEL for the sodium salt of undecylenic acid was 180 mg/kg BW. Therefore, there is no classification of the substance as to its repeated dose toxicity properties.
Executive summary:

The potential of the test substance, sodium salt of undecylenic acid, to induce toxicity under subchronic repeated oral treatment conditions was investigated in rats according to OECD guideline 408. Male and female Sprague-Dawley rats were treated with the test substance by oral gavage on a daily basis over a period of 90 days. In addition, a satellite group was included that was allowed to recover during a 4 week treatment-free period.

Animals were examined for mortality, clinical signs, food/water consumption, food efficiency and body weight gain throughout the study. At the end of the study, the animals were sacrificed and haematology/clinical chemistry was performed from blood and/or urine. Furthermore, animals were subjected to detailed macroscopic and microscopic pathological investigation.

Treatment with the test substance did not result in mortality, but in dose-dependent observation of clinical signs. The observed signs included ptyalism, loud breathing/respiratory difficulties and poor clinical condition. Body weight gain and food consumption were reduced in males of the high dose group, especially after dose increase starting day 50 of the study. Reduced glucose plasma levels and reduced triglyceride-levels were found in females of the high dose group, the first being reversible and the latter not reversible in the treatment-free period. Histopathology revealed cardiomyopathy in some animals of the highest dose group (myocardial degeneration/monocellular aggregation) which was reversible during treatment free period. Forestomach oedema/inflammatory cell infiltration was observed in the high dose group. There were no treatment related effects in the low and intermediate dose-groups.

Under the experimental conditions, the 13 week oral toxicity study derived LOAEL for the sodium salt of undecylenic acid was 180 mg/kg BW. Therefore, there is no classification of the substance as to its repeated dose toxicity properties.