Registration Dossier

Toxicological information

Exposure related observations in humans: other data

Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans.
Author:
Bookstaff, R.C. et al.
Year:
2003
Bibliographic source:
Regul Toxicol Pharmacol.; 37(1):133-48.

Materials and methods

Type of study / information:
Clinical safety study.
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
To confirm the expected safety of Ethyl oleate (EO) in humans, a total of 235 subjects participated in a 12-week trial where two levels of ethyl oleate in a milk-based beverage were investigated: 8 g/day in a single serving (approximately 0.1 g/kg) and 16 g/day taken in two divided servings (approximately 0.2 g/kg). Adverse events (AEs) were recorded throughout the 12-week trial. In addition, a brief physical exam (including vital signs and body weight), ECGs, fasting serum chemistry profile, serum lipid profile, and urinalysis were performed at baseline and after study completion.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Ethyl oleate (EO)
- Analytical purity: no data

Method

Ethical approval:
other: Institutional Review Board approval was obtained before the study was started.
Details on study design:
This was a 12-week, double-blind, randomised, parallel, and vehicle-controlled trial in normal, healthy subjects at a single centre in Florida, USA. Two hundred and thirty five (235) subjects were randomised to five groups according to their initial body weight and body mass index (BMI). Individuals over 25 were generally considered overweight (National Heart, Lung, and Blood Institute, 1998).

Subjects were eligible for the study if they were aged 18-65 years, in generally goof health, had a BMI of 25.0-34.9, had maintained their weight within 4 kg over the 3 months prior to entry, and were willing to maintain current dietary habits/ practises and physical activity status. Subjects were excluded if they were pregnant or nursing, were using any drugs requiring bioavailability monitoring (e.g., warfarin, digitalis), had food restrictions, food allergies, or other food intolerances (such as lactose intolerance), or had a high energy intake/expenditure (e.g., athletes in training).
Other than the requirement to consume the assigned test product either once or twice a day per protocol, subjects were on a self-selected diet with no study-imposed calorie or macronutrient restrictions.
At the screening visit, subjects gave a medical history and received an electrocardiogram (ECG) and a physical examination, including measurement of weight and vital signs. In addition, fasting samples were taken for complete blood count (CBC) and differential count; serum chemistry profile; lipid profile; total free fatty acid (FFA) profile; determination of thyroid stimulating hormone (TSH), thyroxin (T4), and haemoglobin A1c (HgbA1c) levels; and urinalysis. Female subjects also underwent urine pregnancy tests. Body weights and vital signs were measured and adverse effects volunteered by the subjects were recorded at each subsequent visit.
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: oral feed. The EO was formulated into a milk-based beverage.

TYPE OF EXPOSURE MEASUREMENT:
Clinical and laboratory measurements: Complete blood counts and differential counts, serum chemistry, lipid, and FFA profiles were repeated at weeks 2, 4, 8 and 12, and determinations of TSH, T4, and HgbA1c levels and urinalyses were repeated at week 12. Physical examinations and ECGs were also performed at the week 12 visit. Adverse events, reported voluntarily by the subjects, were recorded throughout the 12 week trial. Clinically significant AEs were followed to resolution by the principle investigator.

EXPOSURE LEVELS:
One group was given ethyl oleate (EO) at a dose of 8 g/day, as a single serving at breakfast in a milk-based beverage. Another group was given 16 g/day, in 8 g divided servings, at breakfast and mid-afternoon.

Three control groups included: the milk-based beverage given once per day or twice per day, and a triacylglycerol control of 8 g high oleic safflower oil given once per day (8 g TG group) in the milk-based beverage.

EXPOSURE PERIOD: 12 weeks

Results and discussion

Results:
This study showed that there were no clinically significant negative effects from consuming ethyl oleate at levels up to 16 g/day (approximately 200 mg/kg bw) for 12 weeks.

Any other information on results incl. tables

Table 3 displays product exposure in terms of days of study participation. Average exposure to EO products was 77.4 days or the 8 g EO group and 73.9 days for the 16 g EO group. 213 subjects completed all 12 weeks. Thirteen subjects were unable to meet the protocol or reconsidered their participation and voluntarily withdrew, four subjects were lost to follow-up, and five subjects withdrew due to adverse events (AEs).

The five AE-related discontinuations were distributed as follows: two in the base beverage groups (one each in the once per-day and twice-per-day groups), one in the 8 g TG group, and two in the EO groups (none in the 8g EO group and two in the 16 g EO group). The two AE-related discontinuations in the 16 g EO group were mild-moderate GI events similar to those in the control groups.

The total number of AEs reported and the percent of subjects reporting AEs were comparable across all groups. Profiles of mild/moderate/severe AEs, doubtfull/possible/probable AEs, and multiple AEs/subjects were also comparable between the EO groups and the control groups.

Overall, for a study of this magnitude and duration, the incidence of TPR-AEs was low. With approximately 47 subjects per group and approximately 77 days on study, there were approximately 3619 subjects-days per group for subjects to report AEs. The number of subjects reporting TPR-AEs was comparable across all groups. The majority of the reports involved the digestive system with no clinically meaningful difference across treatments.

There were no clinically significant differences between groups for shifts in any of the clinical laboratory tests: CBC, differenitial, serum chemistry parameters, TSH, T4, HgbA1c, or urinalysis parameters. Likewise, there were no EO exposure-related clinically significant changes in any of the lipid parameters (See Table 4 for details).

Table 3. Overall adverse event profile.

 

 

Base 1x (n=47)

Base 2x (n=47)

8g TG (n=46)

8g EO (n=47)

16g EO (n=48)

Total number of AEs reported

83

58

60

83

85

Nr. (%) mild severity

46 (55%)

34 (59%)

37 (62%)

61 (74%)

49 (58%)

Nr. (%) moderate severity

34 (41%)

24 (41%)

21 (35%)

21 (25%)

35 (41%)

Nr. (%) severe

3 (4%)

0 (0%)

2 (3%)

1 (1%)

1 (1%)

Total number of AEs reported

83

58

60

83

85

Nr. (%) doubtful causality

76 (92%)

47 (81%)

50 (83%)

74 (89%)

67 (79%)

Nr. (%) possible causality

7 (8%)

9 (16%)

10 (17%)

9 (11%)

12 (14%)

Nr. (%) probably causality

0 (0%)

2 (3%)

0 (0%)

0 (%)

6 (7%)

Nr.(%) of subjects reporting AEs

35(74%)

29(62%)

27(59%)

32(68%)

36(75%)

Nr. (%) reporting 1 AE

13(28%)

14(30%)

12(26%)

10(21%)

15(31%)

Nr. (%) reporting 2 AEs

13(28%)

5(11%)

7(15%)

10(21%)

8(17%

Nr.(%) reporting > 2 AEs

9(19%)

10(21%)

8(17%)

12(26%)

13(27%)

Number of TPR-AEs

7

11

10

9

18

Nr. (%) reporting TPR-AEs

7(15%)

5(13%)

7(15%)

7(15%)

9(19%)

Number of SAEs

1

0

0

2

0

Number of TPR-SAEs

0

0

0

0

0

Number of withdrawals due to AEs

1

1

1

0

2

Number of withdrawals due to SAEs

1

0

0

0

0

1x, once daily; 2x, twice daily; TG, triglycerol; EO, ethyl oleate; AE, adverse event; TPR, test product related (possible or probable causality); SAE, serious adverse event.

 

Table 4. Lipid Parameters.

 

Base 1x

Base 2x

8 g TG

8 g EO

16 g EO

Triacylgcerols

 

 

 

 

 

Baseline mg/dL (N)

120.2 (47)

126.0 (47)

122.0 (46)

122.2 (57)

123.1 (48)

Post-study-baseline change mg/dL (N)

19.5 (43)

16.3 (43)

6.3 (43)

8.5 (43)

17.9 (41)

Free fatty acids

 

 

 

 

 

Baseline meq/L (N)

0.44 (47)

0.55 (47)

0.64 (46)

0.49 (47)

0.44 (48)

Post-study-baseline change mg/dL (N)

0.08 (43)

-0.06 (43)

-0.11 (43)

0.00 (43)

0.10 (41)

Total cholesterol

 

 

 

 

 

Baseline mg/dL (N)

203.3 (47)

195.0 (47)

196.4 (46)

201.5 (47)

201.5 (48)

Post-study-baseline change mg/dL (N)

2.7 (43)

6.7 (43)

-1.1 (43)

-3.2 (43)

3.7 (41)

LDL cholesterol

 

 

 

 

 

Baseline mg/dL (N)

126.6 (47)

119.8 (47)

122.8 (46)

125.2 (47)

12.8 (47)

Post-study-baseline change mg/dL (N)

-0.1 (43)

2.2 (43)

-3.8 (43)

-4.2 (43)

-0.1 (41)

HDL cholesterol

 

 

 

 

 

Baseline mg/dL (N)

52.7 (47)

50.2 (47)

49.1 (46)

51.9 (47)

49.3 (47)

Post-study-baseline change mg/dL (N)

-1.1 (43)

1.3 (43)

1.2 (43)

-0.7 (43)

1.0 (41)

1x, once daily; 2x, twice daily; TG, triglycerol; EO, ethyl oleate.

 

Applicant's summary and conclusion