Registration Dossier

Administrative data

Description of key information

Based on the results of reliable studies on primary skin and eye irritation according OECD guideline 404 and 405, respectively,

Creatine monohydrate is considered to be not irritating.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-9-16 to 1997-9-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Broekman Institute, Someren, The Netherlands
- Age at study initiation: > 6 weeks
- Weight at study initiation: < 3.5 kg
- Housing: individually
- Diet (e.g. ad libitum): standard laboratory rabbit diet
- Water (e.g. ad libitum): free access to tap-water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
water
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g of the test substance; moistened with water
Duration of treatment / exposure:
4 h
Observation period:
skin reactions were assessed at approximately 1, 24, 48 and 72 hours after removal of the dressings and test substance
Number of animals:
3 of either sex
Details on study design:
TEST SITE
- Area of exposure: 2x3 cm²
- Type of wrap if used: micropore tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): removal of dressing and of remaining test substance using a tissue moistened with tap-water and subsequently a dry tissue
- Time after start of exposure: 4 hours

SCORING SYSTEM: numerical scoring
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
1297
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
1298
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
1300
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
1297
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
1298
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
1300
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No skin irritation was caused by 4 hours exposure to creatine monohydrate. There was no evidence of a corrosive effect on the skin.
Other effects:
No staining of the treated skin by the test substance was observed. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

No edema and erythema after 4 hours of exposure; scoring of erythema and edema: for all three animals after 1, 24, 48 and 72 hours score 0.

Interpretation of results:
GHS criteria not met
Conclusions:
Creatine Monohydrate does not have to be classified and has no obligatory labelling requirement for skin irritation.
Creatine Monohydrate is not irritating.
Executive summary:

A primary dermal irritation study with creatine monohydrate in the rabbit (4-hour semi-occlusive application) was conducted based on the OECD guideline No. 404, "Acute Dermal Irritation/Corrosion".

Three male rabbits (at least 6 weeks old; weight: 1893-2069 g) were exposed to 0.5 grams of creatine monohydrate moistened with water (equivalent to 0.44 g creatine) to 2x3 cm clipped skin in the dorsal area for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure. Irritation was graded according a numerical scoring system. No skin irritation was caused by 4 hours exposure to creatine monohydrate. In this study creatine monohydrate is not irritating to the skin and does not have to be classified.

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-11-17 to 1997-11-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Broekman Institute, Someren, The Netherlands
- Age at study initiation: at least 6 weeks
- Weight at study initiation: less than 3.5 kg
- Housing: individually in labelled cages
- Diet (e.g. ad libitum): free access
- Water (e.g. ad libitum): free access
- Acclimation period: at least 5 days before start of the treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 °C
- Humidity (%): 50 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 69.8 +/- 0.5 mg (a volume of approximately 0.1 ml)
Duration of treatment / exposure:
upon application eye closed for one second and subsequently not rinsed
Observation period (in vivo):
The eyes of each animal were examined approximately 1, 24,48 and 72 h after instillation of the test substance
Number of animals or in vitro replicates:
3 animals of either sex
Details on study design:
SCORING SYSTEM: numerical scoring
TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
1492
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
1494
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
1510
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
1492
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
1494
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
1510
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
1492
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
1492
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
1510
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Eyelids, Nictitating membrane
Basis:
animal #1
Remarks:
1492
Time point:
24/48/72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Eyelids, Nictitating membrane
Basis:
animal #2
Remarks:
1494
Time point:
24/48/72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
1510
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Other effects:
There was no evidence of ocular corrosion. Remnants of the test substance were present in the eye of one animal and on the outside of the eyelid of another animal on day 1.
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Table 1: Mean values of eye irritation scores (24, 48 and 72 h after instillation)

Animal No.

Mean 24 – 72 hours

 

Corneal opacity

Iris

Conjunctivae Redness

Conjunctivae Chemosis

1492

0

0

0.3

0

1494

0

0

0.3

0

1510

0

0

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations, creatine monohydrate does not have to be classified and has no obligatory labelling for eye irritation.0
Creatine monohydrate is not irritating.
Executive summary:

In a primary eye irritation study according to the OECD guideline 405 "Acute Eye Irritation/Corrosion" single samples of approximately 70 mg creatine monohydrate (a volume of approximately 0.1 ml) which is equivalent to 61.54 mg creatine (or 0.088 ml respectively) were instilled into the conjunctival sac of one eye of each of three male albino rabbits (New Zealand White; Source: Broekman Institute; at least 6 weeks old; body weight < 3.5 kg). The eyes were not washed. Observations were made 1, 24, 48 and 72 hours after instillation. Irritation was scored with a numerical scoring system. The irritation consisted of redness, chemosis and/or discharge, and had completely resolved within 24 hours in one animal and within 48 hours in the two other animals. Iridic irritation grade 1 was observed in two animals on day 1 only. In this study creatine monohydrate is not an eye irritant and does not have to be classified.

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

A primary dermal irritation study with creatine monohydrate in the rabbit (4-hour semi-occlusive application) was conducted based on the OECD guideline No. 404, "Acute Dermal Irritation/Corrosion".

No skin irritation was caused by 4 hours exposure to creatine monohydrate. In this study creatine monohydrate is not irritating to the skin and does not have to be classified.

An eye irritation study according to the OECD guideline 405 "Acute Eye Irritation/Corrosion" was conducted. The irritation consisted of redness, chemosis and/or discharge, and had completely resolved within 24 hours in one animal and within 48 hours in the two other animals. Iridic irritation grade 1 was observed in two animals on day 1 only. In this study creatine monohydrate is not an eye irritant and does not have to be classified.

Justification for classification or non-classification

Based on the available data Creatine monohydrate is considered to not irritating to the skin and eye.