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Key value for chemical safety assessment

Effects on fertility

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Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Additional information

Creatine is an endogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. Creatine is part of the diet and can be present in meat and fish in concentrations of 2-7 g/kg. In addition it is used as food supplement to increase muscle weight. In 2004 the European Food Safety Authority (EFSA) published a record which stated that oral long-term intake of 3g pure creatine per day is risk-free (Question number: EFSA-Q-2003-125). Sub-acute repeated dose toxicity in rodents (28 day) and epidemiological data don’t raise concern with regards to the use of creatine as food supplement. The reports of damage to the kidneys by creatine supplementation have been scientifically refuted (Gualano, et al. (2008). Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. European Journal of Applied Physiology, 103(1), Number 1 (2008), 33-40; Kreider, et al (2003). Long-term creatine supplementation does not significantly affect clinical markers of health in athletes. Molecular and Cellular Biochemistry 244, 1-2; 95-104). Even though there is a broad range of data from epidemiological and sub-acute studies available data don’t cover all parameters that would be monitored in Reproduction/Developmental Toxicity Tests according to OECD 414 and OECD 421, respectively. However, conducting studies according to OECD 414 and 421 in rodents is not scientifically justified as the limit dose used in those tests (1000 mg/kg/d) would not exceed the amount of creatine present in the diet. This can be shown by the following assumptions: 1) Physiological concentration and diet: According to scientific literature a 70 kg person carries a physiological amount of 120 g creatine and metabolizes 2000 – 4000 mg creatine per day. Half of this amount (1000 – 2000 mg/person/d) is synthesized endogenously in the liver, kidney and pancreas. The other 1000 – 2000 mg/person/day are delivered via the diet. The amount of endogenously synthesized creatine decreases when more creatine is provided by the diet. Examples of food with a high content of creatine are fish (2000 - 10000 mg/kg), meat (4500 – 5000 mg/kg), or milk (100 mg/kg). 2) Experimental conditions & conclusion: The daily endogenous synthesis in humans is in the range of 14 – 28 mg creatine/kg body weight/d. The same amount is supplied by diet. Obviously, the daily turnover of 28 – 56 mg creatine/kg bw is of no concern for humans. To measure any detrimental effects in an animal model the applied dose would need to exceed this value. The standard assessment factor for converting data from Reproduction/Developmental Toxicity Tests to humans is 200 (AF2 for converting sub-chronic to chronic; and AF 100 for accounting intra- and interspecies variation). Thus to even reach the standard daily human turnover a dose of 5600 mg applied to rat would be necessary. 5600 mg/kg/d is far above the limit dose of 1000 mg/kg/d used in a standard OECD 414 and OECD 421 study, respectively. Conducting a study at limit dose in rats is thus not suited to derive any data on non-physiological conditions in humans. Thus a study according to OECD 414 and OECD 421 applying the limit or any lower dose is not scientifically justified. The same is true for studies on repeated dose toxicity (90-Day; OECD 408).

Effects on developmental toxicity

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Reference
Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Abnormalities:
not specified
Developmental effects observed:
not specified

Justification for classification or non-classification