Potassium carbamoylcarbamate

Endpoint summary

Description of key information

In a skin irritation/corrosion study on rabbits conducted in accordance with OECD Testing Guideline 404 and under GLP, the test substance produced a primary irritation index of 0.5 and was classified as a MILD IRRITANT to rabbit skin according to the Draize classification scheme. However, the test substance did not meet the criteria for classification as an irritant or corrosive according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or the Classification, Labelling and Packaging (CLP) Regulation (EC) No. 1272/2008. Therefore, under the conditions of this study, potassium allophonate is not considered to be irritating to the skin. In an eye irritation study on rabbits conducted in accordance with OECD Testing 405 and under GLP, no corneal or iris abnormalities were observed in the eyes of any animal at any time point. All three animals demonstrated mild conjunctival redness and discharge within 1 and 4 hours which resolved by the 24-h observation period. No fluorescein staining was present in the eyes of the animals at any time point during the study. Therefore, under the conditions of this study, potassium allophonate is not considered to be irritating to the eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed under GLP/OECD guideline without deficiency.

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Male New Zealand White rabbits from Harlan UK Ltd, Bicester (HsdIf:NZW strain).
- Age at study initiation: 12 to 13 weeks old.
- Weight at study initiation: 2.2 to 2.5 kg
- Housing:Individually housed in cages.
- Diet (e.g. ad libitum):Global Diet 2930C (Harlan Teklad, Bicester, UK) was freely available to the animals at all times.
- Water (e.g. ad libitum):Mains water was provided, ad libitum, via cage-mounted water bottles.
- Acclimation period: 7 to 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):15 to 21 degrees C
- Humidity (%):Humidity did not fall below the limit specified in the protocol (45%).
- Air changes (per hr):15 to 20
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From 14 February 2012 to 28 February 2012.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):500 mg

VEHICLE
- Amount(s) applied (volume or weight with unit):none

Duration of treatment / exposure:

4 hours

Observation period:

15 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: A 30 x 20 mm area on the closely clipped dorsum.
- % coverage:100%
- Type of wrap if used: none

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Lightly brushed clean of any solid residues and swabbed with moist cotton wool.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Erythema & eschar Grade
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate erythema 3
Severe erythema (beet redness) or eschar formation preventing reading of erythema 4

Oedema Grade
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (edges raised approximately 1 mm) 3
Severe oedema (raised more than 1 mm and extending beyond the dermal test site) 4

The scores for erythema and oedema at the 24 and 72 hour readings were totalled for the three test rabbits (12 values) and this total was divided by six to give the primary irritation index of the test article.

Primary Irritation Index Classification of Irritancy

0 Non irritant
>0 to 2 Mild irritant
>2 to 5 Moderate irritant
>5 to 8 Severe irritant

Irritation parameter:

primary dermal irritation index (PDII)

Score:

ca. 0.5

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24 h

Score:

0.333

Max. score:

4

Reversibility:

fully reversible within: 14 d

Remarks on result:

other: very slight erythema in one animal

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 48 h

Score:

0.333

Max. score:

4

Reversibility:

fully reversible within: 14 d

Remarks on result:

other: very slight erythema in one animal

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 72 h

Score:

0.667

Max. score:

4

Reversibility:

fully reversible within: 14 d

Remarks on result:

other: well-defined erythema in one animal

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

- Very slight erythema was noted at one treated skin site at 24 and 48 hours after patch removal. Well-defined erythema was noted at this site 72 hours after patch removal with very slight erythema and fissuring present on Day 8. No evidence of skin irritation was noted at this treated skin site on Day 15.
- No evidence of skin irritation was noted at the other two treated skin sites during the observation period.

Table1
Individual dermal reactions

Animal number, sex, initial body weight and final body weight	Dermal reaction	Observation time after removal of patches
		Imm	1 hour	24 hours	48 hours	72 hours	7 days	14 days
4M (2.3 - 2.4 kg)	Erythema/Eschar formation	0	0	1	1	2	1	0
	Oedema formation	0	0	0	0	0	0	0
	Other	-	-	-	-	-	FS	-
5M (2.5 - 2.6 kg)	Erythema/Eschar formation	N/A	0	0	0	0	N/A	N/A
	Oedema formation	N/A	0	0	0	0	N/A	N/A
	Other	N/A	-	-	-	-	N/A	N/A
6M (2.2 - 2.4 kg)	Erythema/Eschar formation	N/A	0	0	0	0	N/A	N/A
	Oedema formation	N/A	0	0	0	0	N/A	N/A
	Other	N/A	-	-	-	-	N/A	N/A
Sum of 24  and 72 hour readings (S)					:	3
Primary Irritation Index (S/6)					:	3/6 = 0.5
Classification					:	MILD IRRITANT

Key:

Imm         Immediately after removal of patch

FS           Fissuring

N/A         Not applicable

Table 2
Individual Daily and Mean Scores for Dermal Irritation Following 4 Hour Exposure

Dermal reaction	Observation Time	Individual Scores � Rabbit Number and Sex
		4M	5M	6M
Erythema/Eschar Formation	24 Hours	1	0	0
	48 Hours	1	0	0
	72 Hours	2	0	0
Total		4	0	0
Mean Score		1.3	0.0	0.0
Oedema Formation	24 Hours	0	0	0
	48 Hours	0	0	0
	72 Hours	0	0	0
Total		0	0	0
Mean Score		0.0	0.0	0.0

 

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

The test article produced a primary irritation index of 0.5 and was classified as a MILD IRRITANT to rabbit skin according to the Draize classification
scheme. The test article did not meet the criteria for classification as irritant or corrosive according to the Globally Harmonized System of
Classification and Labelling of Chemicals (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed according to GLP/OECD guideline without deficiency.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: 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:Male New Zealand White rabbits from Harlan UK Ltd, Bicester (HsdIf:NZW strain).
- Age at study initiation:Approximately 12 weeks old.
- Weight at study initiation:2.3 to 2.7 kg
- Housing:Rabbits were individually housed.
- Diet (e.g. ad libitum):Global Diet 2930C (Harlan Teklad, Bicester, UK), ad libitum.
- Water (e.g. ad libitum):Mains water was provided, ad libitum, via cage-mounted water bottles.
- Acclimation period: 7 to 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):15 to 21 degrees C
- Humidity (%):Humidity did not fall below the limit specified in the protocol (45%).
- Air changes (per hr):15 to 20
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From 19 March 2012 to 30 March 2012.

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):100 mg of powdered test article.


VEHICLE
- Amount(s) applied (volume or weight with unit):none

Duration of treatment / exposure:

72 hours

Observation period (in vivo):

The treated animals were examined for ocular changes approximately 30 minutes, one and four hours after treatment and on Days 2, 3 and 4 (at
approximately 24, 48 and 72 hours post treatment).

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done):no

SCORING SYSTEM:
-The "initial sting" response was assessed and recorded immediately after instillation of the test article on Day 1.
The response was graded according to the following scheme:
Response of animal Grade Sting response
No response 0 None
A few blinks only, normal within two minutes 1 Practically none
Rabbit blinks and attempts to open eye but reflex closes it 2 Slight
Rabbit keeps eye shut and puts pressure on it, may rub eye 3 Moderate
Rabbit holds eye tightly shut, may struggle or squeal 4 Marked

Grading of Ocular Reactions
CONJUNCTIVAE
Grade
(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson colour, individual vessels not easily discernible 2
Diffuse beefy red appearance 3

(B) Chemosis (refers to lids and/or nictitating membrane)
No swelling 0
Any swelling above normal 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half-closed 3
Swelling with lids more than half-closed 4

(C) Discharge
No discharge 0
Any discharge greater than normal (not including the small amount normally present in the inner canthus of normal animals) 1
Discharge with moistening of lids and hairs just adjacent to the lids 2
Discharge with moistening of lids and hairs for a considerable area around the eye 3

TOTAL SCORE = (A + B + C) x 2 MAXIMUM TOTAL = 20

IRIS (D) Grade
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection (any of these or any combination thereof); iris still reacting to light (a sluggish reaction is an effect) 1
Haemorrhage, gross destruction, no reaction to light (any or all of these) 2

TOTAL SCORE = D x 5 MAXIMUM TOTAL = 10

CORNEA Grade
(E) Degree of opacity (most dense area used)
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible 1
Easily discernible translucent areas; details of iris slightly obscured 2
Nacreous areas; no details of iris visible; size of pupil barely discernible 3
Opaque cornea; iris not discernible through opacity 4

(F) Area of cornea involved
One quarter (or less) but not zero 1
Greater than one quarter but not more than half 2
Greater than half but not more than three quarters 3
Greater than three quarters, up to whole area 4

TOTAL SCORE = (E x F) x 5 MAXIMUM TOTAL = 80

MAXIMUM TOTAL SCORE POSSIBLE = 110

TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: all time points

Score:

0

Max. score:

80

Irritation parameter:

iris score

Basis:

mean

Time point:

other: all time points

Score:

0

Max. score:

10

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 0.5 h, 1 h

Score:

6.7

Max. score:

20

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 4 h

Score:

2

Max. score:

20

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 0.5 h, 1 h

Score:

6.7

Max. score:

110

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: maximum group mean score (based on effects on the conjunctivae at 1 hour)

Irritant / corrosive response data:

- There were no corneal or iridial effects noted.
- Minimal to moderate conjunctival irritation was noted in all treated eyes 0.5 and 1 hour after instillation, with minimal conjunctival irritation persisting in two treated eyes 4 hours after instillation. No signs of irritation were observed at 24, 48 or 72 hours.
- The eyes of all rabbits were overtly normal by the 24 hour examination.

Table1

Individual ocular response

Rabbit number, sex , initial and final body weights	7 Male (2..3 - 2.4 kg)						8 Male (2.7 - 2.6 kg)						9 Male (2.6- 2.6 kg)
	Initial sting response = 2						Initial sting response = 2						Initial sting response = 2
Time after treatment	½ hr	1 hr	4 hrs	24 hrs*	48 hrs*	72 hrs	½ hr	1 hr	4 hrs	24 hrs*	48 hrs*	72 hrs	½ hr	1 hr	4 hrs	24 hrs*	48 hrs*	72 hrs
CORNEA
E = Degree of Opacity	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
F = Area of Opacity	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Score (E x F) x 5	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
IRIS
D =  Reaction	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Score (D x 5)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
CONJUNCTIVAE
A = Redness	1	1	0	0	0	0	1	1	0	0	0	0	1	1	1	0	0	0
B = Chemosis	0	0	0	0	0	0	1	1	0	0	0	0	1	1	0	0	0	0
C = Discharge	1	1	1	0	0	0	2	2	0	0	0	0	2	2	1	0	0	0
Score (A + B + C) X 2	4	4	2	0	0	0	8	8	0	0	0	0	8	8	4	0	0	0
Total Score	4	4	2	0	0	0	8	8	0	0	0	0	8	8	4	0	0	0

                                Key:

                                *              Fluorescein applied to cornea

 

 

Table2
Individual total scores and group mean scores

Rabbit Number and Sex	Individual total scores at:
	1 hour	24 hours	48 hours	72 hours
7 Male	4	0	0	0
8 Male	8	0	0	0
9 Male	8	0	0	0
Group Total	20	0	0	0
Group Mean Score	6.7	0	0	0

 

Table3
Interpretation of results according to GHS

Rabbit Number and Sex	Observation Time		Corneal Opacity	Iridial Inflammation	Conjunctival Redness	Conjunctival Chemosis
7 Male	24 Hours		0	0	0	0
	48 Hours		0	0	0	0
	72 Hours		0	0	0	0
Total			0	0	0	0
Mean Score			0	0	0	0
8 Male	24 Hours		0	0	0	0
	48 Hours		0	0	0	0
	72 Hours		0	0	0	0
Total			0	0	0	0
Mean Score			0	0	0	0
9 Male		24 Hours	0	0	0	0
		48 Hours	0	0	0	0
		72 Hours	0	0	0	0
Total			0	0	0	0
Mean Score			0	0	0	0

 

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

The test article produced a maximum group mean score of 6.7 and was considered to be a minimal irritant according to the modified version of the
system described by Kay and Calandra.
The test article did not meet the criteria for classification as irritant according to the Globally Harmonized System of Classification and Labelling of
Chemicals (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A skin irritation/corrosion test on rabbits (OECD Testing Guideline 404; Covance [2012d]) and an eye irritation test on rabbits (OECD Testing Guideline 405; Covance [2012e]) were conducted with potassium allophonate to assess the potential irritation/corrosion effects. Under the test conditions, potassium allophonate was considered not irritating to skin and eyes according to GHS or the CLP Regulation (Regulation [EC] No. 1272/2008).

In addition, two in vitro skin irritation/corrosion tests (OECD Testing Guidelines 439 and 431; Covance [2012d]) and an in vitro ocular irritation/corrosion test (OECD Testing Guideline 437; Covance [2012e]), were conducted on potassium allophonate. Under the in vitro test conditions, potassium allophonate was not considered corrosive to the skin or eyes.

References:

Covance. 2012d. Potassium Allophonate: Assessment of Skin Irritation/Corrosion. Testing laboratory: Covance Laboratories Ltd Otley Road, Harrogate North Yorkshire HG3 1PY ENGLAND. Report no.: 8249559. Owner company: Kerr Fire Fighting Chemicals, Ashcroft Road, Knowsley Industrial Park, Kirkby, Liverpool L33 7TS. Report date: 2013-01-07.

Covance. 2012e. Potassium Allophonate: Assessment of Ocular Irritation. Testing laboratory: Covance Laboratories Ltd Otley Road, Harrogate North Yorkshire HG3 1PY ENGLAND. Report no.: 8249560. Owner company: Kerr Fire Fighting Chemicals, Ashcroft Road, Knowsley Industrial Park, Kirkby, Liverpool L33 7TS. Report date: 2013-01-07.

Justification for selection of skin irritation / corrosion endpoint:
Study performed under Good Laboratory Practices (GLP)/Organisation for Economic Co-operation and Development (OECD) testing guidelines.

Justification for selection of eye irritation endpoint:
Study performed under GLP/OECD guidelines.

Effects on skin irritation/corrosion: slightly irritating

Justification for classification or non-classification

In a GLP/OECD Testing Guideline 404 skin irritation study, slight erythema was observed in a single animal at 24 and 48 hours (score = 1 out of a maximum score of 4) and well-defined erythema was observed at 72 hours (score = 2). No erythema was observed in the other two animals at any observation and no edema was observed in any animal at any observation. All irritation was fully resolved by 15 days post-application. Therefore, since an erythema scored at 2 was only observed at 72 hours and in a single animal, potassium allophonate is not classified as a skin irritant according to GHS and the CLP regulation.

In a GLP/OECD eye irritation study, minimal to moderate conjunctival irritation was noted in all treated eyes 0.5 and 1 hour after instillation, with minimal conjunctival irritation persisting in two treated eyes 4 hours after instillation. No signs of irritation were observed at 24, 48 or 72 hour post-application. Therefore, since potassium allophonate does not meet the criteria for classification as irritant or corrosive according to GHS or the CLP Regulation (Regulation [EC] No. 1272/2008), potassium allophonate is not classified as an eye irritant.