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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001
Reference Type:
publication
Title:
Opinion of the Scientific Committee on Food on Additional information on “energy” drinks
Year:
2003
Bibliographic source:
EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Scientific Opinions C2 - Management of scientific committees II; scientific co-operation and networks Scientific Committee on Food SCF/CS/PLEN/ENDRINKS/16 Final
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: US Food and Drug Administration Redbook II Guidelines (FDA, 1993).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Taurine
EC Number:
203-483-8
EC Name:
Taurine
Cas Number:
107-35-7
Molecular formula:
C2H7NO3S
IUPAC Name:
2-aminoethanesulfonic acid

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Taurine was dissolved in deionised water and given orally by gavage once daily.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks (90d)
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: functional observation battery conducted at 6 and 12 weeks on control and 1000 mg/kg groups.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at the time of dosing and about 1 hour after dosing.

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Significant behavioural changes were observed 1 hour after dosing.
Increased activity was recorded in all treated groups compared with controls, particularly in females. The increase in frequency and number of animals exhibiting this behaviour was similar in 300 and 600 mg/kg males and females and greatest in the 1000 mg/kg groups. The frequency was similar in the first and last months of the study showing that tolerance did not develop over time.
Chewing on forelimbs and hindlimbs was also seen in a few animals among 600 and 1000 mg/kg males and in all groups of treated females. The frequency was highest among 1000 mg/kg females.
A functional observation battery conducted at 6 and 12 weeks on control and 1000 mg/kg groups. There were occasional observations in the treated group, mostly in females, of greater alertness in the home cage, cage biting, higher arousal in the open field, more energetic reactions to approach, touch and startle response stimuli and jumping, biting or attacking in response to tail pinch. However, all but one of these behaviours was seen in only single animals and none of the differences were statistically significant.
Impaired performance on the rotarod was seen in both sexes of the 1000 mg/kg group; the mean length of time they remained on the rotarod compared with controls was reduced by 49 % and 52 % in males and females respectively at 6 weeks and by 24 % and 18 % in males and females respectively at 12 weeks. Due to high variability within groups, none of these reductions were statistically significant.
In a 60 minute test for locomotor activity run on individual animals at 6 and 12 weeks, a significant reduction in mean ambulatory activity and a non-significant reduction in mean total activity were seen in 1000 mg/kg males at 6 weeks. There were no effects in males at 12 weeks or in females at 6 or 12 weeks.
Mortality:
no mortality observed
Description (incidence):
There were no treatment-related deaths.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Only transient higher body weight gains in some treated groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was unaffected by treatment.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were some statistically significant differences in haematological parameters measured at 4, 8 and 13 weeks between treated and control groups, but the differences were small and none were seemingly treatment-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were some statistically significant differences in clinical chemistry parameters measured at 4, 8 and 13 weeks between treated and control groups, but the differences were small and none were seemingly treatment-related.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
There was a dose-related reduction in urinary pH in both sexes, which was probably attributable to the presence of acidic taurine in the urine.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Small but significant reductions in absolute and relative thyroid/parathyroid gland weights in males at 1000 mg/kg and in females at 300, 600 and 1000 mg/kg were attributable to control values that were relatively high compared with laboratory historical controls and concurrent controls.
Because of the differences in thyroid weights at necropsy, serum TSH and T4 were measured. The only finding was a significant reduction in TSH levels in 600 mg/kg males at 4 weeks.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related gross or microscopic findings in any organs or tissues, including the thyroid.

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
clinical signs
Key result
Dose descriptor:
other: Observed Safe Level
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not measured/tested
Remarks:
From FEEDAP Panel estimated Observed Safe Limit (OSL) in humans to be 6 g/person per day (corresponding to 100 mg/kg bw per day).

Target system / organ toxicity

Key result
Critical effects observed:
no
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
System:
nervous system

Any other information on results incl. tables

Males                                     Females

Dose (mg/kg bw/day)              0          300      600      1000    0          300       600     1000

Number of animals                  20        20        20        20        20        20         20       20

Observations

Increased activity                   1/1       5/4       4/4       11/8     3/2       36/10   29/10   62/16  

Chewing of forelimb(s)          0/0      0/0       2/2       3/3      0/0      3/2       3/3       11/7

Chewing of hindlimb(s)         0/0      0/0       0/0       1/1      0/0       1/1       2/2       2/2

Chewing of cage                    0/0      0/0       0/0       1/1      0/0       0/0       1/1       2/2

Hyper-reactive to touch          0/0     0/0     0/0       1/1     0/0       0/0       0/0    0/0

Applicant's summary and conclusion

Conclusions:
The results of this sub-chronic study show that 1000 mg/kg bw/day is a clear effect level for behavioural changes while the lower doses of 300 and 600 mg/kg bw/day are marginal effect levels in males but clear effect levels in females. Thus, a NOAEL for behavioural effects in rats has not been established.
Therefore, a GLP-and OECD-compliant neurotoxicity study was conducted (please see chapter 7.9.1). Based on these results no compound-related effects were reported at any dose with respect to locomotor activity testing or FOB parameters (including home cage, handling, open field, sensory, neuromuscular, or physiological observations). EFSA (2009) concluded that the results of this study are sufficient to address the behavioral concerns previously raised, and provide evidence for a NOAEL of 1,000 mg/kg body weight/day in the original toxicity study (i.e., WIL, 2001 ). A NOAEL of 1 ,656 mg/kg body weight was determined based on a lack of adverse physiological or behavioral effects following this 13 week exposure via drinking water in the follow-up neurological study.