Glycerides, C12-18 mono- and di-

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1968

Materials and methods

Principles of method if other than guideline:

Long-term growth study in rats

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

medium chain triglycerides

IUPAC Name:

medium chain triglycerides

Details on test material:

- Name of test material (as cited in study report): MCT (medium-chain triglycerides)
- Composition of test material, percentage of components: MCT preparation containing 75% octanoic acid and 25% decanoic acid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: individually in screen-bottom cages
- Diet: ad libitum

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): fully air-conditioned room

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

47 weeks

Frequency of treatment:

daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
19.6%
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
9800 mg/kg bw/day
Basis:
other: assuming a daily food consumption of 50 g/kg/bw /day according to OECD ENV/JM/MONO(2000)18

No. of animals per sex per dose:

15

Control animals:

other: 21% safflower oil as dietary fat... (see attached file)

Positive control:

Diets (see Table 1 under "Any other information on materials and methods incl. tables") with conventional dietary fats (18.5% oleo oil, butter fat or coconut oil)

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: body weight gains were determined after 4, 8 and 47 weeks.

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

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 7, 14, 21, 35 and 47 weeks
- Animals fasted: Yes, but only for blood collection at necropsy
- How many animals: all surviving
- Parameters checked: plasma cholesterol (total: after 7, 14, 21 and 35 weeks; total, free, esterfied: after 47 weeks)

OTHER:

CALORIC EFFICIENCY:
- Body weight gain in g/1000 calories calculated from the body weight gain data: Yes (after 4 weeks)

NET ABSORPTION OF DIETARY FAT, PROTEIN AND CALCIUM (percentage calculated from dietary intakes and faecal excretion):
- Time schedule for collection of faeces: daily during the study period
- Time schedule for determination of fat absorption: after 35 weeks
- Time schedule for determination of protein absorption: after 35 weeks
- Time schedule for determination of calcium absorption: after 3 and 10 weeks, and after 21, 35 and 47 weeks (average of all three time points)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (liver, kidney, spleen, heart, adrenals, femurs and testes)
HISTOPATHOLOGY: Yes (liver and intestine)
At necropsy, absolute weights of liver, kidney, spleen, heart, adrenals, femurs, testes and epididymal fat pads were determined.

Other examinations:

LIVER LIPID COMPOSITION
- Parameters checked: total lipid, phospholipids, cholesterol

CARCASS COMPOSITION:
- Parameters determined: percentage of fat, protein and ash calculated from the carcass weight (excluding liver, heart, epididymal fad pads and gastrointestinasl tract)

DIETARY AND EPIDIDYMAL FAT COMPOSITION:
- Fatty acids determined: C8, C10, C12, C14, C16, C16:1, C18, C18:1, C18:2, C18:6, C20:4

Statistics:

Mean values and standard deviations of all analysed parameters were calculated, except for the net absorption of dietary fat, protein and calcium. Statistical analysis was performed between the different dietary fat groups (oleo oil, butter fat, coconut oil, corn oil, safflower oil) and the MCT group. Statistical significance was indicated at p < 0.05.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

MCT group: 3 males and 2 females died during the study period

Mortality:

mortality observed, treatment-related

Description (incidence):

MCT group: 3 males and 2 females died during the study period

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

after 4, 8 and 47 weeks: slightly decreased body weight gain compared to other fat diets; at necropsy: carcass weight was significantly higher in coconut oil group compared to MCT group

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

after 7, 14, 21, 35: significantly lower total cholesterol levels in males of MCT group compared to other dietary fat groups; after 47 weeks: significantly increased plasma cholesterol (total, free, esterified) compared to corn oil or safflower oil group

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

epididymal fat pads: lower absolute and relative weights compared to groups receiving the other dietary fats (statistically significant difference between MCT and coconut oil group)

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No marked differences in mortality were observed between the MCT group and the other dietary fat groups: During the study period, an average of 2.5 rats died per group of 15 males and 1.7 per group of 15 females. Three males and two females died in the group receiving the diet containing MCT.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain of the MCT group was only slightly less compared to the other dietary fat groups (see Table 2 under "Any other information on results incl. tables". At the study termination, body weight gain in animals of the MCT group was moderately lower compared to the groups receiving other dietary fats. A significant difference was only observed between the body weight gain of males from the MCT group and males of the coconut oil group.

CLINICAL CHEMISTRY
Total plasma cholesterol levels after 7, 14, 21 and 35 weeks were lower in male rats receiving the MCT diet compared to the rats fed with other dietary fats. In females, no effects on total plasma cholesterol were observed during these measurement intervals. At study termination, MCT values were similar or higher compared to the other groups. The differences in finding between earlier values and terminal values may have been attributable in part to differences in conditions under which the blood samples were obtained or may reflect changes in animal’s age or length of time on the diets.

ORGAN WEIGHTS
Organ weights of liver, kidney, spleen, heart, adrenals, femurs, and testes were similar between all tested groups.

GROSS PATHOLOGY
No effects on liver, kidney, spleen, heart, adrenals, femurs, and testes were observed at necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
No effects on histopathology were observed after test substance administration. No differences were observed compared to the groups receiving the other dietary fats.

OTHER FINDINGS:
- Caloric efficiency: 4-week caloric efficiency (115 g body weight gain/1000 calories) in the MCT group was similar compared to the other groups of dietary fats (118-122 g body weight gain/1000 calories).
- Weight of epididymal fat pads: lower absolute and relative weights were found compared to groups receiving the other dietary fats (statistically significant difference between MCT and coconut oil group). These data correlated well with the lower level of carcass fat compared to all other groups.
- Liver lipid composition: levels of total lipids, cholesterol and the fraction of triglycerides were lower in animals on the MCT diet compared to those receiving the other dietary fats. Phospholipid levels were not affected by the type of dietary fat administered to the animals.
- Dietary and epididymal fat composition: although the MCT diet comprised 51 and 35% C8 and C10 fatty acid, respectively, only 0.4% C8 and 4.9% C10 were found in the epididymal fat pads of rats. In contrast, high levels of the fatty acids C16 and C18:1 were found in the epididymal fat pad of the MCT group. However, only traces of these fatty acids were found in the MCT diet, suggesting a rapid metabolism of C8 and C10 to smaller units, which are used for the synthesis of C16 and C18:1 fatty acids.
- Net absorption of dietary fat, protein and calcium: the net absorption of MCT after 35 weeks was higher than that of the other dietary fats. No differences in values for protein and calcium absorption between the MCT group and all other test groups were observed after 3, 10 or 21, 35 and 47 weeks.

Effect levels

Dose descriptor:

NOAEL

Effect level:

9 800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 2. Body weights of male and female Wistar rats fed different dietary fats

Dietary fat	Body weight [g] after
	4 weeks	8 weeks	47 weeks
Males
MCT	181 ± 21	332 ± 44	637 ± 94
Oleo oil	200 ± 22*	354 ± 39	668 ± 115
Butterfat	201 ± 15*	356 ± 32	669 ± 97
Coconut oil	197 ± 14*	353 ± 25	715 ± 102*
Corn oil	196 ± 19*	353 ± 38	630 ± 62
Safflower oil	188 ± 17	345 ± 37	674 ± 71
Females
MCT	139 ± 12	209 ± 21	375 ± 83
Oleo oil	137 ± 10	208 ± 20	403 ± 76
Butterfat	146 ± 16	223 ± 29	417 ± 81
Coconut oil	142 ± 13	215 ± 18	432 ± 76
Corn oil	140 ± 11	220 ± 19	414 ± 39
Safflower oil	139 ± 15	212 ± 21	400 ± 64

*significantly different from MCT group (p < 0.05)

Dietary fat	Epididymal fat pads
	Absolut weight [g]	Relative weight [% body weight]
MCT	14.6	2.2
Oleo oil	18.7	2.6
Butterfat	19.1	2.7
Coconut oil	23.2*	3.1*
Corn oil	16.7	2.5
Safflower oil	17.9	2.5

*significantly different from MCT group (p < 0.05)