Potassium carbamoylcarbamate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

134 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

3 338 mg/m³

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance

AF for interspecies differences (allometric scaling):

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

5

Justification:

ECHA Guidance

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

3 786 mg/kg bw/day

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance

AF for interspecies differences (allometric scaling):

10

Justification:

ECHA Guidance

AF for intraspecies differences:

5

Justification:

ECHA Guidance

Acute/short term exposure

DNEL related information

Additional information - workers

The most relevant routes of potential exposure to potassium allophonate to workers are the dermal and inhalation routes. Based on the available acute toxicity data (oral, dermal, inhalation), potassium allophonate is not likely an acute toxicant and, therefore, derivation of Derived No Effect Level (DNEL) for long-term exposures (DNELlong-term) will be sufficient to control potential risks associated with short-term exposures. In addition, based on the available data, potassium allophonate is not likely irritating to either the eyes or skin, or sensitising to the skin. Therefore, based on the available data, potassium allophonate does not appear to elicit local toxicity effects. As such, derivation of a DNEL for local effects is not necessary. Therefore, only a long-term DNEL will be derived for potassium allophonate. Based on the paucity of repeat dose toxicity data available specifically on potassium allophonate, data on urea will be used for read-across. The highest quality repeat dose study available is a 12-month carcinogenicity screening assay with urea, in which F-344 rats and C57BL/6 mice (50/sex/group) were exposed to urea in the diet at concentrations of 4500, 9000 or 45000 ppm for 12 months. No biologically significant effects attributable to the test substance were seen and therefore the NOAEL was deemed to be 45000 ppm. As summarized in the USEPA Integrated Risk Information System (IRIS) document on urea (USEPA, 2011), the approximate dose levels from this study were calculated to be 0, 379, 757, or 3,786 mg/kg-day for male F344 rats; 0, 419, 838, or 4,191 mg/kg-day for F344 females; 0, 644, 1,288, or 6,442 mg/kg-day for male C57BL/6 mice; and 0, 655, 1,311, or 6,553 mg/kg-day for C57BL/6 females. For purposes of derivation of the DNEL, the lowest No Observable Adverse Effect Level (NOAEL) from the one-year study of 3786 mg/kg/day for male rats will be used. Because no repeat dose dermal or inhalation studies are available, route-to-route extrapolation from the oral NOAEL will be utilised. No data are available on the bioavailability of the test substance in rats versus humans for the oral route of administration. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route. For route-to-route extrapolation from an oral dose to an inhalation dose the starting point needs to be modified to correct for the breathing volume of the rat and respiratory volume under standard conditions (6.7 m3/person) versus under conditions of light activity for workers (10 m3/person). Based on the European Chemicals Agency's (ECHA) recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans. Therefore, the inhalation starting dose = oral NOAEL (rat) x 1/(0.38 m3/kg/day) x 6.7m3/10m3. In addition, ECHA recommends in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e., the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. Therefore, the inhalation starting dose for the worker population = 3786 mg/kg/day x 1/(0.38 m3/kg/day) x 6.7m3/10m3 x 0.5 = 3338 mg/m3. For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered for both the dermal and oral routes. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route. In addition, it will be assumed that dermal absorption will not be higher than oral absorption. Therefore, the starting dose for calculation of the dermal DNEL is 3786 mg /kg/day. The assessment factor (AF) for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the ECHA recommended AS factor is 4. So the interspecies AF is equal to 4 x 2.5 = 10. However, for the inhalation route, an AS factor is not used. Therefore, for inhalation, only an interspecies factor of 2.5 is used. ECHA (2010) recommends an AF of 5 for intraspecies variability in workers. In accordance with ECHA’s guidelines (2010), a sub-chronic study usually refers to a study of 90 days in length and a chronic study is one that is 1.5 to 2 years. As the key study is a one-year study, for purposes of derivation of a DNEL, it will be assumed that it is a sub-chronic study. The AF for extrapolation from a subchronic toxicity study to a chronic is 2. The total AF used to derive the systemic DNELlong-term for the inhalation route for the worker is 25 (2.5 x 5 x 2). The total AF used to derive the systemic DNEL long-term for the dermal route for the worker is 100 (10 x 5 x 2). Worker DNELlong-term for the inhalation route = 3338/25 = 134 mg /m3. Worker DNELlong-term for the dermal route = 3786/100 = 38 mg /kg/day.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

3 786 mg/kg bw/day

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance

AF for interspecies differences (allometric scaling):

10

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

3 786 mg/kg bw/day

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance

AF for interspecies differences (allometric scaling):

10

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance

Acute/short term exposure

DNEL related information

Additional information - General Population

The most relevant route of potential exposure for potassium allophonate to the general population is the dermal and oral routes. Based on the available acute toxicity data (oral, dermal, inhalation), potassium allophonate is not likely an acute toxicant and, therefore, derivation of Derived No Effect Level (DNEL) for long-term exposures (DNELlong-term) will be sufficient to control potential risks associated with short-term exposures. In addition, based on the available data, potassium allophonate is not likely irritating to either the eyes or skin, or sensitising to the skin. Therefore, based on the available data, potassium allophonate does not appear to elicit local toxicity effects. As such, derivation of a DNEL for local effects is not necessary. Therefore, only a long-term DNEL will be derived for potassium allophonate. Based on the paucity of repeat dose toxicity data available specifically on potassium allophonate, data on urea will be used for read-across. The highest quality repeat dose study available is a 12 -month carcinogenicity screening assay in which F-344 rats and C57BL/6 mice (50/sex/group) were exposed to urea in the diet at concentrations of 4500, 9000 or 45000 ppm for 12 months. No biologically significant effects attributable to the test substance were seen and therefore the No Observable Adverse Effect Level (NOAEL) was deemed to be 45000 ppm. As summarized in the USEPA Integrated Risk Information System (IRIS) document on urea (USEPA, 2011), the approximate dose levels from this study were calculated to be 0, 379, 757, or 3,786 mg/kg-day for male F344 rats; 0, 419, 838, or 4,191 mg/kg-day for F344 females; 0, 644, 1,288, or 6,442 mg/kg-day for male C57BL/6 mice; and 0, 655, 1,311, or 6,553 mg/kg-day for C57BL/6 females. For purposes of derivation of the DNEL, the lowest NOAEL from the one-year study of 3786 mg/kg/day for male rats will be used. The assessment factor (AF) for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the European Chemicals Agency (ECHA)-recommended AS factor is 4. So, the interspecies AF is equal to 4 x 2.5 = 10. The ECHA Guidance (2010) recommends an AF of 10 for intraspecies variability in the general population. In accordance with ECHA’s guidelines (2010), a sub-chronic study usually refers to a study of 90 days in length and a chronic study is one that is 1.5 to 2 years. As the key study is a one-year study, for purposes of derivation of a DNEL, it will be assumed that it is a sub-chronic study. The AF for extrapolation from a subchronic toxicity study to a chronic is 2. The total AF used to derive the systemic DNELlong-term for the dermal and oral routes for the general population is 200 (10 x 10 x 2). General population DNELlong-term for the oral/dermal routes = 3786/200 = 19 mg/kg bw/day.