Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1993

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of 25 weanling Sprague-Dawley rats of each sex were fed diets containing caprenin at dietary concentrations of 0, 5.23, 10.23 or 15.00% (w/w) for 91 d. Survival, clinical signs, body weight, feed consumption, feed efficiency, organ weights, organ-to-bodyweight ratios, organ-to-brain-weight ratios, haematological values and clinical chemistry parameters were evaluated in all groups. Histopathology of a full complement of tissues was evaluated in the corn oil and MCT oil control groups as well as the high-dose caprenin group.


GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
138184-95-9
Cas Number:
138184-95-9
IUPAC Name:
138184-95-9
Constituent 2
Reference substance name:
Caprenin
IUPAC Name:
Caprenin
Details on test material:
- Name of test material (as cited in study report): Caprenin
- Composition of test material, percentage of components: Fatty acid composition of caprenin:- C8:0-23.2; C10:0-26.6; C12:0-0.3; C18:0-0.9, C20:0-2.7; C22:0-45, C24:0-1.1

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC, USA
- Age at study initiation: 4 wk
- Weight at study initiation: 71 to 98 g (male) and from 68 to 88 g (female)
- Housing: Housed individually in suspended wire-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23.8°C
- Humidity (%): 50 + 20%
- Photoperiod: 12 h light/12 h dark

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): All diets were prepared to provide about 4000 kcal/kg, based on the assumption that the
caloric densities (or physiological fuel values) of corn oil, MCT oil and caprenin were 9, 7 and 5 kcal/g, respectively


Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
91 d
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0, 5.23, 10.23 and 15.00 % (w/w of the diet) caprenin
Basis:
nominal in diet
No. of animals per sex per dose:
25 rats/dose
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before initiation of the study and at week 13

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the study (Day 91)
- Anaesthetic used for blood collection: Yes (CO2/02 mix)
- Animals fasted: Yes
- How many animals: 20

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the study (Day 91)
- Animals fasted: Yes
- How many animals: 20


Sacrifice and pathology:
At terminal necropsy, organ weights were determined for brain, spleen, liver, kidneys, heart, gonads, adrenals, caecum (after rinsing with saline) and colon (after rinsing with saline) were determined and expressed as absolute and relative (organ-to-body weight and organ-to-brain weight)
values, and a histopathological examination was performed.
Other examinations:
Additional sections from the liver and heart were stained with Oil Red O and graded under microscopic evaluation for fat content.
Extra sections of kidney were stained with alizarin red and graded for incidence and severity of nephrocalcinosis.
Statistics:
- ANOVA
- Bartlett's test of homogeneity
- t-test
- Wilcoxon's rank sum test
- Fisher-Irwin exact test

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:
no effects observed
Description (incidence and severity):
Lower feed efficiency in the high-dose group females in comparison with rats fed the MCT oil diet
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):
No significant treatment related effects were observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No significant treatment related effects were observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant treatment related effects were observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant treatment related effects were observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant treatment related effects were observed
Histopathological findings: neoplastic:
not specified
Details on results:
No treatment-related effects on growth, mortality, haematology and serum chemistry values, or in anatomical or microscopical pathology

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
13 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Absence of treatment-related effects in growth, mortality, haematology and serum chemistry values, or in anatomical or microscopical pathology
Key result
Dose descriptor:
NOAEL
Effect level:
14 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Absence of treatment-related effects in growth, mortality, haematology and serum chemistry values, or in anatomical or microscopical pathology

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOAEL of the substance was determined to be 13,200 and 14,600 mg/kg bw/day (the highest tested dose) for males and females, respectively.
Executive summary:

A study was conducted to evaluate the sub-chronic repeated dose toxicity of the constituent caprenin (a randomized triglyceride primarily comprising caprylic (C8:0), capric (C 10:0), and behenic (C22:0) acids) in rats. Groups of 25 rats of each sex were fed diets containing 5.23, 10.23 or 15.00% (w/w) of the substance for 91 d. Corn oil was added at 8.96, 5.91 and 3.00%, respectively, to provide essential fatty acids and digestible fat calories. Corn oil alone (12.14%) and a blend of medium-chain triglyceride (MCT) oil plus corn oil (11.21 and 3.13%, respectively) served as controls. All diets were formulated to provide about 4000 kcal/kg of diet and 26.8% of digestible calories from fat by assuming that corn oil, MCT oil, and caprenin provided 9, 7 and 5 kcal/g respectively. Survival, clinical signs, body weight, feed consumption, feed efficiency, organ weights, organ-to-bodyweight ratios, organ-to-brain-weight ratios, haematological values and clinical chemistry parameters were evaluated in all groups. Histopathology of a full complement of tissues was evaluated in the corn oil and MCT oil control groups as well as the high-dose caprenin group. Additional rats (5/sex/group) were included in the study to determine the levels of C22:0 in heart, liver or perirenal fat at the end of the 91 d feeding period. No significant differences in body weight gain were measured with the balanced caloric diets, although feed conversion efficiency was reduced in the high-dose group. No adverse effects from the ingestion of the substance were detected, nor were significant amounts of C22: 0 present in the fat extracted from the selected fat depot sites. Under the test conditions, the NOAEL of the substance was determined to be >15% (w/w) in the diet (or more than 83% of total dietary fat), which is equal to a mean exposure level of > 13,200 and 14,600 mg/kg/day for male female rats, respectively (Webb, 1993).