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EC number: 210-647-2 | CAS number: 620-67-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well documented study report which meets basic scientific principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
Materials and methods
- Principles of method if other than guideline:
- Male rats were exposed to corn oil, safflower oil and tricaprylin via gavage. After 15 months (interim evaluation) and 2 years, animals were sacrificed for gross and histopathological examinations to evaluate the treatment-related effects on neoplasm incidence.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Glycerol trioctanoate
- EC Number:
- 208-686-5
- EC Name:
- Glycerol trioctanoate
- Cas Number:
- 538-23-8
- IUPAC Name:
- propane-1,2,3-triyl trioctanoate
- Details on test material:
- - Name of test material (as cited in study report): tricaprylin
- Molecular formula (if other than submission substance): C27H50O6
- Molecular weight: 470.69
- Analytical purity: 94% (A15), 97% (A11), 91% (8812-806876)
- Lot/batch No.: A15, A11, 8812-806876
- Physical state: clear, colorless to amber liquid
- Stability under test conditions: in amber glass containers at 4°C under an argon headspace
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Fischer 344/N
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 7 weeks
- Weight at study initiation: 126 - 159 g
- Housing: groups of 5 animals in polycarbonate cages with hardwood chips
- Diet: NIH-07 open-stock mash diet (Zeigler Bros., Inc., Gardners, PA), ad libitum
- Water: Worcester public water, ad libitum
- Acclimation period: 14 to 22 days; prior to study start, five rats from each study were randomly selected and killed for parasite evaluation and gross observation of disease.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 22
- Humidity (%): 47.1 ± 4.9
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Tricaprylin was dispensed into vials for gavage dosing on a weekly basis. After dispensing, the test item was stored at 4°C for no more than 3 weeks. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Accelerated bulk chemical stability studies were performed using gas chromatography. The test substance was found to be stable as a bulk chemical for 2 weeks when stored protected from light at temperatures up to 60°C. The stability of tricaprylin was monitored periodically by ultraviolet spectroscopy and gas chromatography. In addition, the peroxide concentration was determined prior to use. The acceptable peroxide concentration was set at 2 mEq/L. A bottle was discareded if it exceeded this specification. No significant degradation of the bulk chemical was observed throughout the study.
- Duration of treatment / exposure:
- 104 weeks
- Frequency of treatment:
- daily, 5 days/week
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
2.5, 5, 10 mL/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
2390, 4770, 9540 mg/kg bw/day
Basis:
other: actual ingested; based on a density of 0.9540 g/cm3 (Final Report on the Safety Assessment of Trilaurin, Triarachidin, Tribehenin, Tricaprin, Tricaprylin; International Journal of Toxicology, 2011)
- No. of animals per sex per dose:
- 60 males/group; 10 from each group were sacrificed after 15 months
- Control animals:
- yes, concurrent no treatment
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, findings were recorded at least monthly
BODY WEIGHT: Yes
- Time schedule for examinations: at study initiation, than weekly for 13 weeks, and monthly thereafter
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 15 months. Blood was collected from the posterior vena cava.
- How many animals: 10
- Parameters checked: haematocrit, haemoglobin, erythrocyte count, mean erythrocyte haemoglobin, mean erythrocyte haemoglobin concentration, mean erythrocyte haemoglobin volume, reticulocyte count, total and differential leukocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 15 months from the posterior vena cava
- How many animals: 10
- Parameters checked: potassium, total protein, albumin, cholesterol, alanine aminotransferase, creatine kinase, sorbitol dehydrogenase, bile acids - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, on all animals. Animals found in a moribund state, selected for the 15-month interim evaluations, or surviving to the end of the 2-year study were killed by the use of "Biotol", an ultra fast-acting barbiturate. All organs and tissues were examined for gross lesions.
HISTOPATHOLOGY: Yes, on all animals. All of the following tissues were preserved in 10% neutral puffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination: adrenal gland, bone and marrow, brain, esophagus, gross lesions, heart, kidney, large intestine (cecum, colon, rectum), liver, lung, mammary gland, lymph nodes (mandibular and mesenteric), pancreas, parathyroid gland, pituitary gland, preputial gland, salivary gland, skin, small intestine (duodenum, jejunum, ileum), spleen, stomach, testis with epididymis and seminal vesicle, thymus, thyroid gland, tissue masses, trachea, and urinary bladder. - Other examinations:
- Brain, kidney (right) and liver of each animal were weighed at the 15 month interim evaluation.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 9540 mg/kg bw/day: 30 animals died
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 9540 mg/kg bw/day: 30 animals died
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 9540 mg/kg bw/day: decreased body weights
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 9540 mg/kg bw/day: decreased food consumption (non-adverse)
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 9540 mg/kg bw/day: increase in the haematocrit, haemoglobin and erythrocyte levels
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 4770 mg/kg bw/day: significant decrease in the absolute kidney weight (non-adverse)
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 9540 mg/kg bw/day: decreased incidence in nephropathy and severity
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- dose-related increase in the incidences of pancreatic exocrine hyperplasia and adenoma; proliferative lesions of the forestomach
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Clinical findings including dyspnea, ataxia and lethargy were observed in 50 out of 60 animals in the high-dose group. However, most of the animals generally recovered prior to the next daily dosing and the incidence of clinical findings declined during the second half of the study.
The two-year survival rate was lower in test animals compared to the respective controls with statistical significance for the high-dose group (31/50, 30/50, 31/50, 23/53 for control, 2390, 4770, 9540 mg/kg bw/day, respectively (Table 1)). 23 rats of the high-dose group died or were killed between weeks 33 - 85 including 10 animals found dead and 13 animals killed moribund. In 20 of these animals, the cause of death or moribund condition could not be determined. 8 rats died between weeks 45 - 49 when the incidence of clinical findings (dyspnea, ataxia and lethargy) was highest. In addition, these animals revealed a significantly lower body weight than the mean group body weight (316 g vs 360 g) at 11 months. Only one of the moribund animals had a pulmonary mass that may explain the dyspnea. Up to 4 animals died or were killed in each subsequent month.
BODY WEIGHT AND WEIGHT GAIN
9540 mg/kg bw/day: Mean body weights were decreased in test animals compared to controls throughout the study. However, the difference was less than 5% after week 61.
No effects were observed in the low- and mid-dose group (Table 2).
FOOD CONSUMPTION
A dose-dependent decrease in food consumption was determined in test animals (Table 3) which resulted in a decreased protein consumption per day (protein consumption (g/rat/day): 3.88, 3.45, 3.09 and 2.70, for control, low-, mid- and high-dose animals, respectively). This effect is most probably due to the fact that rats exposed to tricaprylin received more than 10% of their caloric intake from the test item (10.4%, 19.8% and 35.4% for the low-, mid- and high-dose animals, respectively). Thus, the effect on food consumption is considered as non-adverse.
HAEMATOLOGY
Significant increases in the haematocrit, haemoglobin and erythocyte counts were determined for the high-dose group. No effects were observed in the low- and mid-dose group (Table 4).
ORGAN WEIGHTS
Test animals of the mid-dose group revealed a statistically significant lower absolute kidney weight. As the relative organ weight is not different from the control and the effect is not observed in the low- and high-dose group (Table 5), the effect is considered as incidental and not treatment-related.
HISTOPATHOLOGY: NON-NEOPLASTIC
A significant decrease in the incidence of nephropathy was determined in the high-dose group (control: 46/50, 2390 mg/kg bw/day: 42/50, 4770 mg/kg bw/day: 45/50, 9540 mg/kg bw/day: 27/49) with a dose-related decrease in severity (control: 2.0, 2390 mg/kg bw/day: 1.5, 4770 mg/kg bw/day: 1.7, 9540 mg/kg bw/day: 0.9, Table 6)). As the severity of nephropathy is normally related to the amount of protein in the diet, the decrease in severity induced by tricaprylin might be due to the lower food consumption in test animals (Table 3).
No further findings have been determined in control vs test animals.
HISTOPATHOLOGY: NEOPLASTIC
Tricaprylin induced dose-related increases in the tumor incidences of pancreatic exocrine hyperplasia reaching statistically significance for the mid-and high-dose group (control: 8/49, 2390 mg/kg bw/day: 9/49, 4770 mg/kg bw/day: 18/49, 9540 mg/kg bw day: 28/50), adenoma (control: 2/49, 2390 mg/kg bw/day: 6/49, 4770 mg/kg bw/day: 13/49, 9540 mg/kg bw/day: 18/50) and proliferative lesions in the forestomach (basal cell hyperplasia: control: 4/50, 2390 mg/kg bw/day: 7/50, 4770 mg/kg bw/day: 12/49, 9540 mg/kg bw/day: 21/52; squamous cell papilloma: control: 0/50, 2390 mg/kg bw/day: 0/50, 4770 mg/kg bw/day: 3/50, 9540 mg/kg bw/day: 10/53) reaching statistically significance for squamous cell papilloma in the high-dose group. In contrast, a decrease in the incidence of mononuclear cell leukemia was observed in high-dose animals (control: 23/50, 2390 mg/kg bw/day: 28/50, 4770 mg/kg bw/day: 22/50, 9540 mg/kg bw/day: 9/53). The incidence of pancreatic islet hyperplasia and adenoma or carcinoma decreased in a dose-dependent, but not significant manner (hyperplasia: control: 6/49, 2390 mg/kg bw/day: 5/48, 4770 mg/kg bw/day: 3/49, 9540 mg/kg bw/day: 1/49; adenoma/carcinoma: control: 5/49, 2390 mg/kg bw/day: 2/48, 4770 mg/kg bw/day: 3/49, 9540 mg/kg bw/day: 1/49) (Table 6).
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 9 540 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: systemic toxicity (clinical signs, mortality, body weight ); corresponding to 10 mL/kg bw /day (calculation based on a density of 0.9540 g/cm³)
- Dose descriptor:
- NOAEL
- Effect level:
- 4 770 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: systemic toxicity (clinical signs, mortality, body weight ); corresponding to 5 mL/kg bw /day (calculation based on a density of 0.9540 g/cm³)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Mortality data after tricaprylin exposure
|
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
number of animals included in the study |
60 |
60 |
60 |
60 |
sacrificed for 15-month interim evaluationa |
10 |
10 |
10 |
7 |
natural deaths |
4 |
7 |
4 |
13 |
moribund kills |
15 |
13 |
15 |
17 |
animals surviving until study termination |
31d |
30 |
31d |
23d |
mean survival (days)b |
651 |
639 |
642 |
553 |
survival analysisc |
P = 0.004 |
P = 0.944 |
P = 0.969 |
P = 0.014 |
a: censored from survival analyses
b: mean of all death including uncensored, censored and terminal sacrifice
c: The result of the life table trend test is shown in the control column whereas the results of life table pairwise comparisons with the controls are listed in the dosage columns.
d: Includes 2 rats for the control and 1 rat for the mid- and high-dose groups that died during the last week of the study.
Table 2: Effects on body weight after tricaprylin exposure
|
body weight (g) |
|||
weeks on study |
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
1 |
146 |
144 |
145 |
145 |
2 |
172 |
171 |
169 |
168 |
3 |
199 |
198 |
193 |
190 |
4 |
219 |
215 |
215 |
207 |
5 |
243 |
241 |
239 |
231 |
7 |
263 |
259 |
255 |
247 |
8 |
266 |
265 |
257 |
254 |
9 |
283 |
282 |
277 |
266 |
10 |
300 |
295 |
285 |
278 |
12 |
306 |
301 |
294 |
283 |
13 |
306 |
301 |
296 |
284 |
14 |
317 |
311 |
303 |
289 |
17 |
332 |
329 |
319 |
303 |
21 |
351 |
350 |
339 |
319 |
25 |
363 |
367 |
354 |
330 |
29 |
376 |
372 |
357 |
335 |
33 |
381 |
379 |
371 |
345 |
37 |
386 |
387 |
376 |
353 |
41 |
388 |
389 |
377 |
347 |
45 |
389 |
389 |
382 |
358 |
49 |
388 |
395 |
388 |
368 |
53 |
401 |
408 |
396 |
380 |
57 |
404 |
411 |
394 |
380 |
61 |
403 |
416 |
400 |
390 |
65 |
408 |
419 |
399 |
392 |
69a |
406 |
421 |
400 |
392 |
73 |
408 |
422 |
403 |
395 |
77 |
414 |
423 |
406 |
403 |
81 |
413 |
419 |
405 |
404 |
85 |
405 |
412 |
396 |
399 |
89 |
402 |
412 |
390 |
395 |
93 |
400 |
413 |
393 |
397 |
97 |
393 |
406 |
386 |
391 |
101 |
387 |
404 |
379 |
379 |
104 |
386 |
391 |
371 |
366 |
mean (week 1–13) |
246 |
243 |
239 |
232 |
mean (week 14–52) |
367 |
367 |
357 |
335 |
mean (week 53–104) |
402 |
413 |
394 |
390 |
a: interim evaluation occurred during week 67
Table 3: Effects on food consumption after tricaprylin exposure
|
food consumption per animal per day (g) |
|||
weeks on study |
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
2 |
14.2 |
13.7 |
12.5 |
11.4 |
5 |
16.9 |
15.9 |
16.0 |
14.4 |
9 |
17.1 |
16.5 |
16.4 |
13.6 |
13 |
13.0 |
12.1 |
9.9 |
8.9 |
17 |
20.2 |
16.9 |
16.0 |
13.5 |
21 |
15.8 |
14.9 |
12.5 |
10.0 |
25 |
18.3 |
18.3 |
16.5 |
13.5 |
29 |
17.8 |
16.2 |
14.0 |
12.2 |
33 |
17.8 |
16.3 |
16.0 |
13.7 |
37 |
18.3 |
15.6 |
14.2 |
12.1 |
41 |
15.2 |
12.8 |
11.5 |
8.8 |
45 |
16.7 |
14.9 |
12.5 |
10.8 |
49 |
20.3 |
17.7 |
15.8 |
13.3 |
53 |
18.2 |
16.2 |
14.2 |
12.1 |
57 |
20.4 |
17.5 |
14.1 |
12.7 |
61 |
17.9 |
16.5 |
14.2 |
12.5 |
65 |
16.8 |
13.7 |
11.9 |
10.6 |
69 |
18.6 |
17.3 |
16.5 |
15.6 |
73 |
16.8 |
14.1 |
12.9 |
10.2 |
77 |
17.7 |
14.3 |
12.9 |
11.2 |
81 |
17.7 |
14.5 |
13.2 |
10.7 |
85 |
15.9 |
14.3 |
12.2 |
10.3 |
89 |
13.9 |
12.6 |
10.6 |
9.5 |
93 |
16.6 |
14.4 |
15.9 |
15.1 |
97 |
16.5 |
12.3 |
12.3 |
12.9 |
101 |
13.7 |
12.3 |
9.4 |
8.7 |
104 |
13.5 |
10.6 |
9.2 |
7.6 |
mean |
17.0 |
15.1 |
13.6 |
11.8 |
Table 4: Haematology data after tricaprylin exposure at the 15-month interim evaluation
|
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
number of animals |
9 |
10 |
8 |
7 |
haematocrit (%) |
45.6 ± 1.1 |
50.7 ± 2.7 |
49.2 ± 2.3 |
51.7 ± 2.0* |
haemoglobin (g/dL) |
15.6 ± 0.4 |
17.3 ± 0.8 |
16.7 ± 0.6 |
17.5 ± 0.6* |
erythrocytes (106/ µL) |
8.77 ± 0.31 |
9.72 ± 0.41 |
9.30 ± 0.34 |
9.91 ± 0.32* |
*: significantly different from control by Dunn´s or Shirley´s test (P ≤ 0.05)
Table 5: Organ weights of the kidney (right) after tricaprylin exposure at the 15-month interim evaluation
|
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
number of animals |
10 |
10 |
10 |
7 |
body weight at necropsy |
430 ± 15 |
419 ± 11 |
402 ± 15 |
406 ± 12 |
absolute |
1.349 ± 0.04 |
1.23 ± 0.036 |
1.194 ± 0.041* |
1.328 ± 0.053 |
relative |
3.15 ± 0.07 |
2.95 ± 0.07 |
2.98 ± 0.07 |
3.27 ± 0.08 |
*: significantly different from the control by William´s or Dunnett´s test (P ≤ 0.05)
Organ weights are given in grams; organ-weight-to body-weight ratios are given as mg organ/g bw
Table 6: Histopathological findings after tricaprylin exposure
|
|
control |
2390 mg/kg bw/day |
4770 mg/kg bw/day |
9540 mg/kg bw/day |
non-neoplastic |
nephropathy incidence |
46/50 |
42/50 |
45/50 |
27/49 |
|
nephropathy severity |
2.0 ± 0.12 |
1.5 ± 0.13 |
1.7 ± 0.11 |
0.9 ± 0.13 |
neoplastic |
exocrine pancreas hyperplasia |
8/49 |
9/49 |
18/49 |
28/50 |
|
exocrine pancreas adenoma |
2/49 |
6/49 |
13/49 |
18/50 |
|
forestomach: basal cell hyperplasia |
4/50 |
7/50 |
12/49 |
21/52 |
|
forestomach: squamous cell papilloma |
0/50 |
0/50 |
3/50 |
10/53 |
|
mononuclear cell leukemia |
23/50 |
28/50 |
22/50 |
9/53 |
|
pancreatic islet hyperplasia |
6/49 |
5/48 |
3/49 |
1/49 |
|
pancreatic islet adenoma/carcinoma |
5/49 |
2/48 |
3/49 |
1/49 |
For the interpretation of carcinogenic effects, please see Section 7.7, study entry "NTP, 1994, 2y, rat, gavage, RL2".
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