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Description of key information

The results of this sub-chronic study in rats provided further useful information in that it showed no significant changes in pathological measures, no persistent effects on body weight or food consumption and no histopathological changes in organs or tissues in any dose group, but it did show the occurrence of significant behavioural effects (increased activity and self-chewing), and possibly impaired motor performance, which could be mediated via a pharmacological action on the central nervous system.

These results 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.

Exposure to taurine is unavoidable as it is a natural constituent of the body and is present in foods of animal origin. Spitze et al. (2003) determined the taurine content of a variety of foodstuffs. Animal muscle tissue, particularly fish flesh, contained high concentrations of taurine. The mean daily exposure to taurine from omnivore diets has been estimated to range from 9–40 (lowest range values) to up to 200–400 mg/person per day (top range values) (Rana and Sanders, 1986; Laidlaw et al., 1990; Hayes and Trautwein, 1994).

The EFSA FEEDAP Panel estimates the Observed Safe Limit (OSL) in humans to be 6 g/person per day (corresponding to 100 mg/kg bw per day). Exposure resulting from the consumption of foodstuffs and "energy drinks" together would amount to about one-third of the OSL.

The highest, as well as the most recent, of the top range estimates is 400 mg/person per day (Hayes and Trautwein, 1994), equal to 6.7 mg/kg bw per day for a 60-kg person. This value is 150 times lower than the NOAEL of 1000 mg/kg bw per day in laboratory animals and 15 times lower than the human OSL (100 mg/kg bw per day).

Furthermore, taurine is used in more than 30 clinical investigations in humans in conditions including diabetes, epilepsy, congestive heart failure, hypertension, liver disease and cystic fibrosis, concluding that “No adverse health effects attributable to taurine have been reported over a period of 30 years. In many cases taurine has proved medically beneficial.”

Literature:

Hayes KC and Trautwein EA, 1994. Modern nutrition in health and disease. In: Taurine. Lea & Febiger, Philadelphia, 477–485 (cited in the SCF opinion 1999).

Laidlaw SA, Grosvenor M and Koppele JD, 1990. The taurine content of common foodstuffs. Journal of Parenteral and Enteral Nutrition, 14, 183–188.

Spitze AR, Wong DL, Rogers QR and Fascetti AJ, 2003. Taurine concentrations in animal feed ingredients; cooking influences taurine content. Journal of Animal Physiology and Animal Nutrition, 87, 251–262.

Rana SK and Sanders TAB, 1986. Taurine concentrations in the diet, plasma and breast milk of vegans compared with omnivores. British Journal of Nutrition, 56, 17–27.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
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
Species:
rat
Strain:
not specified
Sex:
male/female
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
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
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
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.
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).
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
System:
nervous system

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

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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Justification for classification or non-classification