N-amidinosarcosine

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Meets generally accepted scientific standards, well documented and acceptable for assessment. Justification for read-across: When dissolved in water there is no chemical difference between creatine monohydrate and creatine. The crystal water contained in creatine monohydrate does not account for the toxicity profile of the compound. However, it has to be considered that the results obtained with creatine monohydrate have to be converted to the respective creatine concentration as creatine has a lower molecular weight (131.1332 g/mol) compared to creatine monohydrate (149.1484 g/mol). 100 mg creatine monohydrate per liter correspond to approx. 88 mg creatine per liter.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Long-term creatine supplementation does not significantly affect clinical markers of health in athletes

Author:

Kreider, R.B.; Melton, C.; Rasmussen,C.J.; Greenwood, M.; Lancaster, S.; Cantler, E.C.; Milnor, P.; Almada, A.L.

Year:

2003

Bibliographic source:

Molecular and Cellular Biochemistry 244: 95–104, 2003

Materials and methods

Type of study / information:

Publication: The result of a cohort study with 98 football players that were administered in an open label manner creatine or non-creatine containing supplements following training sessions over a 21-month period are reported. The long-term safety of creatine supplementation was elucidated by quantitative clinical chemistry and analysis of urine samples.

Endpoint addressed:

repeated dose toxicity: oral

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Cohort study: This study examined the effects of long-term creatine supplementation on a 69-item panel of serum, whole blood, and urinary markers of clinical health status in athletes. Over a 21-month period, 98 Division IA college football players were administered in an open label manner creatine or non-creatine containing supplements following training sessions.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N-(aminoiminomethyl)-N-methyl-Glycine, monohydrate

Cas Number:

6020-87-7

Molecular formula:

C4H9N3O2*H2O

IUPAC Name:

N-(aminoiminomethyl)-N-methyl-Glycine, monohydrate

Details on test material:

- Name of test material (as cited in study report): Creatine monohydrate

Method

Ethical approval:

not specified

Remarks:

The individuals volunteered to participate in the study

Details on study design:

One hundred and sixteen National Collegiate Athletic Association (NCAA) Division IA college football players (subjects were 19.2 ± 2 years (range 18–23 years), 185 ± 8 cm (range 173–191 cm), 101 ± 18 kg (range 70–148 kg)) volunteered to participate in this study over a 2 year period. Approximately 65 subjects volunteered to participate during the first year and about 40 subjects volunteered to participate in the second year of the study. Of these, 98 subjects donated pre and at least one subsequent blood and urine sample during the course of the study.
Subjects who chose to take creatine were administered in an open label manner 15.75 g/day of creatine monohydrate for 5 days and an average of 5 g/day thereafter in 5–10 g doses following supervised training sessions. Supplement intake was monitored and recorded in order to document creatine intake.
Training duration, type, and general intensity as well as environmental conditions were recorded. Training averaged of 118 ± 68 min per session with an average intensity of 3.3 ± 1 on a 1–5 scale where 1 was equivalent to a walk-through practice prior to games and 5 was equivalent to game competition. Environmental conditions during training and competition ranged from 8–37°C (mean 24.2 ± 8°C) and 20–98% relative humidity (52.2 ± 16%).

Fasting blood and 24-h urine samples were collected on as many athletes willing to provide samples at 0, 1, 1.5, 4, 6, 10, 12, 17, and 21 months of training (typically 30–55 per testing session).

Subjects observed an overnight 8-h fast prior to donating blood samples.

Standard clinical analysis (SmithKline Beecham Clinical Laboratories; Ann Arbor, MI, USA) and a complete metabolic clinical chemistry panel (Olympus AU5200 automated chemistry analyzer; Melville, NY, USA) were run. Cell blood counts with percent differentials and platelet determination were run on whole blood samples using a Coulter STKS automated analyzer using standard procedures (Coulter Inc., Hialeah, FL, USA).

Urine samples were collected in 24-h collection containers according to standard procedures. A 15-item urinalysis was performed using the Clinitek Atlas ® automated urine chemistry analyzer (Bayer Diagnostics, Tarrytown, NY, USA). Furthermore the plasma creatinine, urine creatinine, and
creatinine clearance using high performance liquid chromatography (HPLC) were determined.

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE: orally: Creatine monohydrate was added to sport drinks or carbohydrate/protein drinks that were offered to the players following training sessions, practices, and games by research assistants working with the strength and conditioning staff

TYPE OF EXPOSURE MEASUREMENT: Personal sampling/ Biomonitoring (urine) / Biomonitoring blood: Fasting blood and 24-h urine samples were collected at 0, 1, 1.5, 4, 6, 10, 12, 17, and 21 months of training

EXPOSURE LEVELS:

EXPOSURE PERIOD: 21 month period

POSTEXPOSURE PERIOD:

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:

Results and discussion

Results:

No significant differences (p = 0.51) between creatine users and non-users in the quantitative panel of blood and urine markers assessed.No significant differences (p > 0.05) were observed among groups in any of the quantitative markers analyzed with the exception that significant interactions were observed
in sodium, chloride, and hematocrit which were not of physiological or clinical relevance. No apparent differences were observed among groups in the qualitative urinary assessment of color, appearance, glucose, bilirubin, ketones, hemoglobin, total protein, nitrates, leukocyte esterase, white blood cells, red blood cells, epithelial cells, bacteria, amorphic cyrstals, or calcium oxalate.

Applicant's summary and conclusion

Conclusions:

The results of this study show that long-term creatine supplementation (up to 21-months) does not appear to adversely effect markers of health status in athletes undergoing intense training in comparison to athletes who do not take creatine.

Executive summary:

Results of the present study indicate that short and long-term creatine supplementation (up to 21 months) does not appear to adversely affect clinical markers of health status in a large number of athletes undergoing intense training in comparison to athletes who do not take creatine.

Results of the present study showed that no significant differences were observed among creatine and non-creatine users in serum creatinine, urinary creatinine excretion, or creatinine clearance.

Concerns that creatine intake increases muscle and/or liver damage could not be verified in this study. Higher levels of muscle/and or liver enzymes (i.e. creatine kinase, CK) are reported for athletes in comparison to untrained individuals. In this study no significant differences were observed among creatine and non-creatine users in CK values and lactate dehydrogenase (LDH), aspartate aminotransferase (AST), or alanine aminotransferase (ALT) values.

Therefore, Creatine monohydrate is not considered to adversely affect the renal function or increase muscle and/or liver damage in individuals.

Justification for read-across:

When dissolved in water there is no chemical difference between creatine monohydrate and creatine. The crystal water contained in creatine monohydrate does not account for the toxicity profile of the compound. However, it has to be considered that the results obtained with creatine monohydrate have to be converted to the respective creatine concentration as creatine has a lower molecular weight (131.1332 g/mol) compared to creatine monohydrate (149.1484 g/mol). 100 mg creatine monohydrate per liter correspond to approx. 88 mg creatine per liter.