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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
12
Dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Assessment factors to be used in DNEL calculation:

Allometric scaling factor for rat to man - 4

Intraspecies Factor - 3 (worker) - Factors based on the ECETOC report about variability within a population. Since metabolism is unlikely to be an influence on the toxicity there is less likely to be significant variability across the population groups

Factor for "other differences" - 1

The toxicity of AMP appears to be dependant upon the route of exposure, rate of metabolism and the degree of absorption. The route of exposure and degree of absorption are taken into account elsewhere. The differences in metabolism are taken into account by the Allometric scaling factor. There is no other reason why humans would be more sensitive to AMP than dogs or rats. Thus a factor of 1 is proposed.

Duration of exposure extrapolation - 1

A 2-generation study is the starting point for the DNEL derivation, however the consistency between the NOEL of this and that of the repeated dose studies in the rat and the dog (including the 1 yr study in the dog) supports the use of a lower factor than the standard one. Thus an assessment factor of 1 is taken.

Quality of the database - 1

Dose response - 1

The database is extensive, and the dose response is clear for the endpoint of concern.

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Acute exposure - Systemic effects

Inhalation/Dermal - AMP is not classified for acute toxicity and thus no acute DNEL for systemic effects is required.

Acute exposure - Local effects

Dermal - AMP is irritating to the skin but data are insufficient to calculate a local DNEL

Inhalation - AMP is also irritating to the respiratory tract. It is considered that the irritation following inhalation would not occur at levels lower than the systemic DNEL for inhalation. Also, the volatility of AMP is low such that acute inhalation exposures are unlikely. Therefore no additional DNEL has been calculated.

Long term exposure - systemic effects

Assessment factor of 12 (worker) taken into account for Dermal DNEL.

Assessment factor of 3 taken into account for Inhalation. (see Above)

Extrapolation from Oral to dermal route will use a factor of 8 to take into consideration the kinetic differences between oral and dermal route and the difference between rats and humans in dermal penetration (refer to TK section). For applications where the pH is between 7 and 9.5, an additional factor of 10 will be used due to the difference between salt and base form. Therefore there will be 2 dermal DNELs for workers due to the pH differences in the different applications. The uses that have pH 7-9.5 or >9.5 are noted in chapter 9 and 10.

Inhalation absorption is considered to be 100% in humans and oral absorption is considered to be 100% in humans and dogs (based on the ADME data).

Starting point for the DNEL derivation is 11 mg/kg bw/day (refer to Repeated dose summary)

Dermal DNEL - Systemic effects (AMP pH 9.5 and higher)

Modification of Starting point - Oral to Dermal extrapolation

Modified NOEL = 11 * (8) = 88 mg/kg bw/day

DNEL (Worker) = 88/12 = 7.3 mg/kg bw/day

Dermal DNEL - Systemic effects (AMP pH 7 - 9.5)

Modification of Starting point - Oral to Dermal extrapolation

Modified NOEL = 11 * 80 = 880 mg/kg bw/day (factor of 8 for rat to human penetration difference and factor of 10 for salt vs Base difference = 80)

DNEL (Worker) = 880/12 = 73 mg/kg bw/day

Inhalation DNEL - Systemic effects

Modification of Starting point (oral to inhalation)

Inhalation NOEC in humans = 11*(1/0.38) * 0.67 = 19.4 mg/m3

Inhalation DNEL (worker) = 19.4 / 3 = 6.5 mg/m3            

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
37 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
8
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.46 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
8
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Overall assessment factor (AF):
8
Dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Assessment factors to be used in DNEL calculation:

Allometric scaling factor for rat to man - 4

Factor for "other differences" - 1

The toxicity of AMP appears to be dependant upon the route of exposure, rate of metabolism and the degree of absorption. The route of exposure and degree of absorption are taken into account elsewhere. The differences in metabolism are taken into account by the Allometric scaling factor. There is no other reason why humans would be more sensitive to AMP than dogs or rats. Thus a factor of 1 is proposed.

Duration of exposure extrapolation - 1

A 2-generation study is the starting point for the DNEL derivation, however the consistency between the NOEL of this and that of the repeated dose studies in the rat and the dog (including the 1 yr study in the dog) supports the use of a lower factor than the standard one. Thus an assessment factor of 1 is taken.

Quality of the database - 1

Dose response - 1

The database is extensive, and the dose response is clear for the endpoint of concern.

Intraspecies Factor - 6 (consumer) - Factors based on the ECETOC report about variability within a population. Since metabolism is unlikely to be an influence on the toxicity there is less likely to be significant variability across the population groups.

Acute exposure - Systemic effects

Inhalation/Dermal - AMP is not classified for acute toxicity and thus no acute DNEL for systemic effects is required.

Acute exposure - Local effects

Dermal - AMP is irritating to the skin but data are insufficient to calculate a local DNEL

Inhalation - AMP is also irritating to the respiratory tract. It is considered that the irritation following inhalation would not occur at levels lower than the systemic DNEL for inhalation. Also, the volatility of AMP is low such that acute inhalation exposures are unlikely. Therefore no additional DNEL has been calculated.

Long term exposure - systemic effects

Assessment factor of 24 (consumer) taken into account for Dermal and oral DNEL.

Assessment factor of 6 taken into account for Inhalation DNEL. (see above)

Extrapolation from Oral to dermal route will use an additional factor of 8 to take into consideration the kinetic differences between oral and dermal route and the difference between rats and humans in dermal penetration (refer to TK section). For Consumer applications where the pH is between 7 and 9.5, an additional factor of 10 will be used due to the difference between salt and base form.

Inhalation absorption is considered to be 100% in humans and oral absorption is considered to be 100% in humans and rats (based on the ADME data).

Starting point for the DNEL derivation is 11 mg/kg bw/day (refer to Repeated dose summary)

Dermal DNEL - Systemic effects (AMP pH 7 - 9.5)

Modification of Starting point - Oral to Dermal extrapolation

Modified NOEL = 11 * 80 = 880 mg/kg bw/day (factor of 8 for rat to human penetration difference and factor of 10 for salt vs Base difference = 80)

DNEL (consumer) = 880/24 = 37 mg/kg bw/day

Inhalation DNEL - Systemic effects

Modification of Starting point (oral to inhalation)

Inhalation NOEC in humans = 11*(1/1.15) = 9.6 mg/m3

Inhalation DNEL (consumer) = 9.6 / 6 = 1.6 mg/m3                    

Oral DNEL - Systemic effects

NOAEL = 11 mg/kg bw/day

Assuming oral absorption via rat and human is 100%, Human NOAEL = 11 mg/kg bw/day

DNEL = 11/ 24 = 0.46 mg/kg bw/day