2-imino-1-methylimidazolidin-4-one

Endpoint summary

Description of key information

There are two reliable studies available covering primary dermal and eye irritation potential in rabbits.

Among them an acute eye irritation/corrosion study according to OECD 405 and an acute dermal irritation study according to OECD 404. Creatinine is shown to be not irritating.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28.01.2002 - 12.02.2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Extertal, Germany
- Age at study initiation: approx. 10 weeks
- Weight at study initiation: 1869, 1818, 1832 g
- Housing: Housed single (male) or with two animals (female) single in steel cages with a plastic bottom mould and a habitat of 5445 square centimeters at the bottom and an overall height of 600 millimeters.
- Diet (e.g. ad libitum): The animals received food "2123" from Altromin International, Lage, Germany as pelleted diet. The food was offered ad libitum.
- Water (e.g. ad libitum): Normal tap water from municipal sources (Stätische Werke Krefeld AG, Abt. 2 TGW, 47804 Krefeld, Germany) was supplied to the animals ad libitum via bottels with rubber stoppers and steel pipes.
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 °C (17-23 °C)
- Humidity (%): 30 - 70 %
- Air changes (per hr): 8 times/hour

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

physiological saline

Controls:

no

Amount / concentration applied:

To ensure that the test substance gets in close contact to the skin 0.5 g of the test substance was moistened with 0.5 mL saline solution.

Duration of treatment / exposure:

The test substance was removed after 4 hours exposure time.

Observation period:

Examination of the treated skin sites was made 1 hour, 4 hours and approximately 24, 48, 72 hours and 7 days after application of the test substance.

Number of animals:

one male and two females

Details on study design:

- 24 hours before dosing a part of the fur on both sides of the dorso-lumbal region of each animal was removed by shearing with an electrical shaving machine exposing an area of skin approximately 10 x 15 cm. Care was taken to avoid abrading the skin and only animals with healthy skin were used in the experiment
- test substance was applied to the front region of both test sites on a gauze pad (3x2 cm) each and held in place by strips of Blenderm (3 M company, St. Paul, USA). The back region behind the gauze was used as control region.

Scoring System:
see "any other information on materials and methods incl. tables"

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

Rabbit 501

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:

Rabbit 503

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:

Rabbit 502

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:

Rabbit 501

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:

Rabbit 503

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:

Rabbit 502

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 3 min, 1 h, 4 h, 24 h, 48 h, 72 h and 7 d

Score:

0

Max. score:

8

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No erythema and oedema and no other dermal response were observed at any time point. The numerical scores to the erythema and oedema formations are presented in table 1 under "any other information on results incl. tables"
The Primary Irritation Index was calculated to be "0" scores of maximum "8" possible scores.

Other effects:

Systmemic toxic symptoms caused by the test substance were not observed during the whole study.
Body weight gain was positive and within the normal range.

Table 1: Numerical scores to the erythema and oedema formations.

	Rabbit 1 (Female)							Rabbit 2 (Female)							Rabbit 3 (Male)
	3 min	1 h	4 h	24 h	48 h	72 h	7 d	3 min	1 h	4 h	24 h	48 h	72 h	7 d	3 min	1 h	4 h	24 h	48 h	72 h	7 d
Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Oedema	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study the test substance Creatinine was classified as "non-irritant" to skin.

Executive summary:

Creatinine was tested regarding its irritation potential towards the skin according to OECD 404 ("Acute Dermal Irritation/Corrosion"). The potential to cause inflammatory or corrosive changes upon first contact with skin was assessed by occluded application of the test substance for four hours to the shorn skin of two male and one female rabbit, strain New Zealand White. Dermal reactions were assessed 1, 4, 24, 48, 72 hours and 7 days after removal of the test substance.

Systemic toxic symptoms after application were not observed at any time during the study. Body weight development was positive and within normal ranges. No erythema and oedema and no other dermal response were observed at any time point. The Primary Irritation Index was calculated to be "0" from "8" possible scores.

Under the conditions of this study the test substance Creatinine was classified as "non-irritant" to skin.

Reference 2

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

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04.02.2002 - 19.02.2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River, Extertal, Germany
- Age at study initiation: approx. 11 weeks
- Weight at study initiation: 1987.4 g, 2020.9 g and 2062.7 g
- Housing: Single housed in steel cages with a plastic bottom mould and a habitat of 5445 square centimeters at the bottom and an overall height of 600 millimeters. A non-barrier system with air was used.
- Diet: ad libitum, Supplier: Altromin International, Lage, Germany; Type: 2023; Batch No. 0733
- Water: ad libitum normal tap water from municipal sources
- Acclimation period: The animals were used for a skin irritation test before, where the test substance was classified as non-irritating. The animals were observed for their health condition, therefore it was assured that the animals were in good condition for this investigation and no acclimation period was needed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 8 times/hour

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 g of the test substance was applied into the right eye by pulling the lower eyelid away from the eyeball to form a cup.

Observation period (in vivo):

Examination of the treated eyes was made 1 hour and approximately 24, 48, 72 hours and 7 days after the application of the test substance.

Number of animals or in vitro replicates:

One male and two females were used.

Details on study design:

See "any other information on material and methods"

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

Rabbit 501

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:

Rabbit 503

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:

Rabbit 502

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:

Rabbit 501

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:

Rabbit 503

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:

Rabbit 502

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

Rabbit 501

Time point:

24/48/72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 48 h

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

Rabbit 503

Time point:

24/48/72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

Rabbit 502

Time point:

24/48/72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

Rabbit 501

Time point:

24/48/72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

Rabbit 503

Time point:

24/48/72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

Rabbit 502

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Other effects:

Systemic toxic symptoms caused by the test substance were not observed during the whole study.
Body weight gain was positive and within normal range.

The Primary Irritation Index was used to classify the test substance as follows:

0 -11: non-irritant

12 - 25: midly irritating

26 - 56: moderately irritant

57 - 110: severe irritant

The Primary Irritation Idex for Creatinine was calculated to be 4 if the maximum value after one hour exposure was chosen for calculation.

Ocular Lesions:

Slight redness of the conjunctivea (injectionn of the blood vessels) was observed in all animals one hour after application of the test substance and slight chemosis was observed in two animals one hour after application. Only one animal showed a slight redness of the conjunctivae 24 hours after application. The eyes of all three rabbits were normal from the 24 hour examination on. The numerical scores awarded to the ocular reactions elicited by the test substance are presented in the following table:

		Rabbit 501(female)					Rabbit 503 (female)					Rabbit 502 (male)
		1h	24h	48h	72h	7d	1h	24h	48h	72h	7d	1h	24h	48h	72h	7d
Cornea	A	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	B	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Iris	A	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivae	A	1	1	0	0	0	1	0	0	0	0	0	0	0	0	0
	B	1	0	0	0	0	1	0	0	0	0	1	0	0	0	0
	C	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Individual body weights:

Body weight gain was positive and within normal range. The data is given in the following table:

Rabbit number and sex	Weight at day 0 [g]	Weight at day 7 [g]
501 (female)	2020.9	2147.0
503 (female)	1987.4	2157.5
502 (male)	2062.7	2155.2

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study the substance Creatinine could be classified as non-irritant to the eyes

Executive summary:

The substance Creatinine was tested regarding to its irritation potential towards eyes and adjacent muscous membranes of experimental animals according to OECD Guideline No. 405 ("Acute Eye Irritation/Corrosion").

The potential to cause damage to the conjunctiva, iris and corea was assessed by single application of the test substance into the lower conjunctival sac of the eyes of two male and one female rabbit, strain New Zealand White. 0.1 g of the test substance was applied. Ocular reactions were assessed 1, 24, 48, 72 hours and 7 days after removal of the test substance. Systemic toxic symptoms after application were not observed at any time during the study. Body weight development was positive and within normal ranges.

Slight redness of the conjunctivae (injection of the blood vessels) was observed in all animals one hour after application of the test substance and slight chemosis was observed in two animals one hour after application. Only one animal showed a slight redness of the conjunctivae 24 hours after application. The eyes of all three rabbits were normal from the 24 hour examination on.

Under the conditions of this study the test substance Creatinine was classified as non-irritant to the eyes.

Reference 2

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)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Creatinine is non-irritating to the skin. The test item showed no irritant effects on the intact skin after a contact time of 4 hours. No skin reactions were recorded throughout the observation period of 7 days. There were no significant body weight changes during the contact and observation period.

In an acute eye irritation study the potential of Creatinine to cause damage to the conjunctiva, iris and corea was assessed by a single application of the test substance. Ocular reactions were assessed 1, 24, 48, 72 hours and 7 days after removal of the test substance.

Slight redness of the conjunctivae (injection of the blood vessels) was observed in all animals one hour after application of the test substance and slight chemosis was observed in two animals one hour after application. Only one animal showed a slight redness of the conjunctivae 24 hours after application. The eyes of all three rabbits were normal from the 24 hour examination on. Therefore the test results indicate the absence of relevant irritation of the test substance to the cornes and the iris and only negligible potency to irritate the conjunctivae after one ocular application of the test substance Creatinine.

Justification for classification or non-classification

Creatinine is neither irritating/corrosive to the skin nor irritating to the eyes based on the results of appropriate guideline studies.