Potassium carbamoylcarbamate

Endpoint summary

Description of key information

Potassium allophonate was evaluated for acute toxicity via the oral, inhalation and dermal routes in studies using standard methodology. These studies indicate a low potential for acute toxicity when administered through oral, inhalation, or dermal routes. Based on the available data, the oral LD50 was greater than 2000 mg/kg in female rats (OECD Testing Guideline 423) and the dermal LD50 was greater than 2000 mg/kg (OECD Testing Guideline 402). For acute Inhalation toxicity in rats (OECD Testing Guideline 436), the LC50 value is greater than 2.26 mg/L, which was the highest achievable aerosol concentration under the study conditions.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 days

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Following GLP/OECD gulidline with no deficiency.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

other: HsdHan:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

Species, strain and supplier: Female (nulliparous, non-pregnant) HsdHan™:WIST strain rats were obtained from Harlan UK Ltd, Bicester.

Acclimatisation period and allocation to study: Rats were arbitrarily selected from the delivery boxes and allocated to the appropriate number of
cages using a sequence that reduced selective bias. The condition of the animals was assessed daily throughout the acclimatisation period of 6 to 8 days.Overtly healthy animals were arbitrarily allocated to the study groups at least one day prior to dosing. At the start of the study the rats were 8 to 9 weeks of age and weighed 170 g to 192 g on Day -1. The weight variation did not exceed ±20% of the mean weight.

Caging:The animals were housed in groups of up to five during the acclimatisation period. From the day prior to dosing (Day –1), the rats were
housed in groups of three in similar cages.

Diet, water and bedding: SQC(E) Rat and Mouse Maintenance Diet No 1, from Special Diets Services Ltd, Witham, UK was freely available to the animals at all times, except for a period of fasting from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing. Each batch
of diet had been analysed for specific constituents and contaminants by the manufacturer.
Mains water was provided, ad libitum, via cage-mounted water bottles. The water had been periodically analysed for specific contaminants.
Certificates of analysis for contaminant levels in each batch of diet or in the water supply were consigned to central files at this laboratory.
Environment: The animal rooms were designed to permit 15 to 20 air changes per hour. The temperature and humidity ranges were 20 to 24 degrees C and 45% to 65% humidity, respectively. Daily recordings of maximum and minimum temperature and humidity were made. The rooms were
illuminated by fluorescent strip-lights for twelve hours daily.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.
Dose levels were expressed gravimetrically and in terms of test article received (without regard to purity or active content).
Individual doses (mL) were calculated using the fasted body weights of the rats on the morning of dosing (Day 1) and the dose volume of 10 mL/kg.
The test article was dispersed in purified water. The formulated concentration was calculated from the selected dose level and the dose volume of 10 mL/kg. All formulations were used within two hours of preparation.
The formulations were maintained on a magnetic stirrer to ensure homogeneity.

Doses:

2000 mg/kg

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
All animals were examined at the beginning and end of the working day throughout the acclimatisation and study periods to ensure they were in
good health.
Rats were weighed on Day 1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: yes
- Clinical signs:Clinical signs were recorded immediately post dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours
post dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Individual records of clinical
signs were maintained for each treated rat.
- Other examinations performed: none.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Mortality Ratio 0/6

Clinical signs:

other: No clinical signs seen throughout the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute median lethal oral dose level of the test article, Potassium Allophonate, was found to exceed 2000 mg/kg.
The test material was considered to have no significant acute toxic risk in respect of its acute oral toxicity and did not meet the criteria for
classification according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

reliable without restriction

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

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:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

other: HsdHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Male and female (nulliparous, non-pregnant) HsdHan:WIST strain rats from Harlan UK Ltd, Bicester.
- Age at study initiation:8 to 12 weeks old.
- Weight at study initiation:193 to 222 g (males) and 214 to 219 g (females).
- Fasting period before study: none
- Housing:
- Diet (e.g. ad libitum):SQC(E) Rat and Mouse Maintenance Diet No 1, from Special Diets Services Ltd, Witham, 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: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20 to 24 degrees C
- Humidity (%):45% to 65%
- Air changes (per hr):15 to 20
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From 14 December 2011 to 28 December 2011

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: purified water

Details on inhalation exposure:

VEHICLE
- Composition of vehicle (if applicable):H2O
- Concentration of test material in vehicle (if applicable):25% w/v
- Justification of choice of vehicle: During the method development it was found that the target concentration of 5 mg/L specified in the protocol could not be achieved using the test article as supplied. The test article was therefore prepared as a solution in purified water at a concentration of 25% w/v.


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:1-4μm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):3.46 μm

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: target concentration of 5 mg/L specified in the protocol could not be achieved

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

ca. 4 h

Concentrations:

2.26mg/L.

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Treated rats were observed at hourly intervals, commencing 30 minutes after the start of exposure, until the end of the working day. An additional observation was made when the animals were returned to their home cage (approximately 10 minutes after the end of the exposure). Animals were then observed once daily to the last day of the observation period. Individual records of clinical signs were
maintained for each treated rat.
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical signs and body weight.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.26 mg/L air

Based on:

test mat.

Mortality:

negative

Clinical signs:

other: Signs of reaction to treatment were confined to vocalisation, red coloured staining on the head, unkempt appearance and wet fur. The signs developed from 10 minute after the end of the exposure period and lasted up to 3.5 hours after the end of the expos

Body weight:

All rats gained weight during the first and second weeks of the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute median lethal concentration of potassium allophonate was found to exceed 2.26 mg/L. It was not possible to classify the test material according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), as it was not possible to obtain a respirable particle size at a concentration of greater than 5 mg/L.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 260 mg/m³ air

Quality of whole database:

Reliable without restriction.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 days

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 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

other: HsdHan: WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Male and female (nulliparous, non-pregnant) HsdHan:WIST strain rats.
- Age at study initiation: Approximately 9 to 10 weeks old on Day 1.
- Weight at study initiation: Range of 185 g to 310 g.
- Housing: During the acclimatisation period, four rats of the same sex were group caged. From the day prior to dosing (Day –1), each rat was
individually housed in a similar cage. After completion of the Day 3 observations animals allocated to the main study were returned to group housing.
- Diet (e.g. ad libitum):SQC(E) Rat and Mouse Maintenance Diet No 1, from Special Diets Services Ltd, Witham, 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. The water had been periodically analysed for specific contaminants.
- Acclimation period:The condition of the animals was assessed daily throughout the acclimatisation period of 7 to 14 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20 to 24 degrees C
- Humidity (%):45% to 65%
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From 11 January 2012 to 01 February 2012.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Electric clippers were used to remove all hair from the dorsum on the day before dosing. The dermal test site was an area of at least 10% of the total body surface on the clipped dorsum of the rat. The total surface area (cm2) for each animal was calculated according to the largest animal in each
group using the following formula:
Surface area (cm2) = K x body weight (g)2/3 (where K = 9)
Individual dose weights (mg) were calculated from the body weights of the rats on the morning of dosing (Day 1).
The test article was spread as uniformly as possible over the dermal test site. The test article was moistened with purified water in order to maximise dermal contact. A dense gauze patch was placed over the treated skin and retained in place by an elasticated, open-weave, adhesive compression
bandage. This was wrapped securely around the torso of the animal. The dressing was removed approximately 24 hours after application. The
dermal test site of each rat was lightly brushed clean of any solid residues and swabbed with water-moistened cotton wool before the animal was
returned to the holding cage.

Duration of exposure:

24 hours

Doses:

2000mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were examined at the beginning and end of the working day throughout the acclimatisation
and study periods to ensure they were in good health.Animals were weighed on Day 1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical signs were recorded immediately post dose, at approximately 15 and 30
minutes post dose, hourly between 1 and 4 hours post dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period.

Statistics:

none

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: There were no apparent clinical signs of reaction to treatment.

Gross pathology:

No macroscopic changes were noted at necropsy.

Other findings:

Well defined erythema was noted at the treatment sites of three males and two females on removal of the dressings at the end of the exposure
period. No other dermal reactions were noted.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute median lethal dermal dose of Potassium Allophonate to rats was found to exceed 2000 mg/kg.
The test material was considered to have no significant acute toxic risk in respect of its acute dermal toxicity and did not meet the criteria for
classification according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Reliable without restriction.

Additional information

Acute toxicity studies are available testing potassium allophonate by the oral, inhalation and dermal routes of exposure. In a limit dose study, no mortality was observed in rats when dosed with potassium allophonate via gavage; therefore, the oral LD50 is >2000 mg/kg (Covance, 2012a). No mortality occurred in a 4-hour inhalation toxicity study in which rats were exposed (nose only) to an aerosol of potassium allophonate at 2.26 mg/L, resulting in a 4-hour LC50 > 2.6 mg/L (Covance, 2012b). In a dermal limit study, no mortality was observed following a 24-hour application of potassium allophonate; therefore, the dermal LD50 was > 2000 mg/kg (Covance, 2012c).

References:

Covance. 2012a. Potassium Allophonate: Acute Oral Toxicity Study in the Female Rat (Acute Toxic Class). Testing laboratory: Covance Laboratories Ltd Otley Road Harrogate North Yorkshire HG3 1PY ENGLAND. Report no.: 8249563. Owner company: Kerr Fire Fighting Chemicals, Ashcroft Road, Knowsley Industrial Park, Kirkby, Liverpool L33 7TS. Report date: 2013-01-08.

Covance. 2012b. Potassium Allophonate: Acute 4-Hour (Nose Only) Inhalation Toxicity Study in the Rat (Acute Toxic Class Method). Testing laboratory: Covance Laboratories Ltd Otley Road, Harrogate North Yorkshire HG3 1PY ENGLAND. Report no.: 8249564. Owner company: Kerr Fire Fighting Chemicals, Ashcroft Road, Knowsley Industrial Park, Kirkby, Liverpool L33 7TS. Report date: 2013-01-09.

Covance. 2012c. Potassium Allophonate: Acute Dermal Toxicity Study in the Rat. Testing laboratory: Covance Laboratories Ltd Otley Road, Harrogate North Yorkshire HG3 1PY ENGLAND. Report no.: 8249565. Owner company: Kerr Fire Fighting Chemicals, Ashcroft Road, Knowsley Industrial Park, Kirkby, Liverpool L33 7TS. Report date: 2013-01-04.

Justification for selection of acute toxicity – oral endpoint
Study performed under Good Laboratory Practices (GLP)/Organisation for Economic Co-operation and Development (OECD) testing guidelines.

Justification for selection of acute toxicity – inhalation endpoint
Study performed under GLP/OECD guidelines.

Justification for selection of acute toxicity – dermal endpoint
Study performed under GLP/OECD guidelines.

Justification for classification or non-classification

The oral and dermal LD50s are both greater than 2000 mg/kg; therefore, they are greater than the thresholds requiring classification per the Globally Harmonised System of Classification and Labelling (GHS). The 4 -hour inhalation LC50 was greater than 2.26 mg/L, which is the highest achievable aerosol concentration when following the OECD Testing Guideline 436. Therefore, based on the available data, it is concluded that potassium allophonate is not classifiable as an acute oral, dermal or inhalation toxicant.