Ammonium chloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

43.97 mg/m³

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

other: 8 h European limit value for ammonia (2000/39/EC)

Value:

14 mg/m³

Modified dose descriptor starting point:

other: 8 h European limit value for ammonia corrected for ammonium chloride (2000/39/EC)

Value:

43.97 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a 8 h European limit value for ammonia (2000/39/EC) is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the 8 h European limit value for ammonia (2000/39/EC).

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

1

Justification:

Intraspecies differences are fully covered by the 8 h European limit value for ammonia (2000/39/EC).

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

128.9 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):

12

Dose descriptor starting point:

NOAEL

Value:

1 104.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 546.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal DNEL for systemic effects is derived using the NOAEL of > 1104.6 mg/kg bw obtained from a 30 months oral feeding study in rats (Lina, 2004). The NOAEL is corrected to 1546.4 mg/kg bw by multiplying with 7/5 (to account for differences between exposure frequency in experimental studies and human worker population).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

An extrapolation factor of 1 was used because the DNEL was derived from an OECD 451 with a treatment duration of 3 months (life time study).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans according to ECHA Guidance on information requirements and chemical safety assessment: Chapter R.8 is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

3

Justification:

See "Explanation for hazard conclusion".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Based on the physico-chemical properties as well as reported uses of ammonium chloride, exposure of the human worker population via skin and inhalation are considered to be relevant routes of exposure. Therefore, DNELs for the dermal and inhalation route are derived.

Relevant Toxicology Data

Ammonium chloride is harmful if swallowed (UN GHS Category 4 oral; CLP). The oral route is however not an anticipated route of exposure for the worker population. Ammonium chloride also causes irritation upon contact with the eye. Since available data does not show dose-response correlations, a DN(M)EL for local irritation to the eye can not be derived. A qualitative assessment of this endpoint will be performed.

Workers - Hazard via inhalation

In several EU member states, an occupational exposure limit (OEL) (of 10 mg/m³) already exists for ammonium chloride fumes and inhalable dusts. In Switzerland, a limit value of 3 mg/m³ is in place for respirable ammonium chloride aerosols. In our product, respirable particles which can reach the alveolar region of the lung are not present. Therefore the above DNEL of 43.97 mg/m³, which was derived based on the European Limit Value of ammonia sufficiently covers any risk for the particle size distribution present. In case of a further pulverization of the BASF product (by a down stream user) such that the percentage of inhalable and respirable particles should increase, a new harzard and risk assessment of the modified product will be needed.

Workers – Hazard via dermal route

Step 1: Selection of the relevant dose descriptor (starting point):
The dermal DNEL for systemic effects is derived using the NOAEL of > 1104 mg/kg bw obtained from a 30 months oral feeding study in rats (Lina, 2004).

Step 2: Modification of the starting point
A worker DNEL (long-term dermal exposure) is derived. As a worst case consideration, absorption via the oral and dermal routes is assumed to be equally efficient. Hence to extrapolate from the oral to the dermal route, a factor of 1 is applied.

Relevant dose descriptor (NOAEL): 1104.6 mg/kg bw/day
Frequency of exposure used in study: 7 days/week
Frequency of exposure of the worker: 5 days/week
ABS (oral rat): 100 %
ABS (dermal human): 100 %
 
Corrected dermal NOAEL for worker:
= 1104.6 mg/kg bw/d x (100/100) x 7/5 = 1546.4 mg/kg bw/d. 
 
Step 3: Use of assessment factors: 12
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (worker): 3
Exposure duration AF: 1 (life time study)
 
In conclusion, long term systemic dermal DNEL, workers = 128.9 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.4 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):

1

Dose descriptor starting point:

other: 8 h European limit value for ammonia (2000/39/EC)

Value:

14 mg/m³

Modified dose descriptor starting point:

other: 8 h European limit value for ammonia corrected for ammonium chloride (2000/39/EC)

Value:

43.97 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a 8 h European limit value for ammonia (2000/39/EC) is available, which is already corrected for the prolonged exposure duration of 24 hours (consumers).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the 8 h European limit value for ammonia (2000/39/EC).

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

1

Justification:

Intraspecies differences are fully covered by the 8 h European limit value for ammonia (2000/39/EC).

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

55.2 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):

20

Dose descriptor starting point:

NOAEL

Value:

1 104.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 104.6 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

An extrapolation factor of 1 was used because the DNEL was derived from an OECD 451 with a treatment duration of 3 months (life time study).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans as described in the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

See "Explanation for hazard conclusion".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

55.2 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):

20

Dose descriptor starting point:

NOAEL

Value:

1 104.6 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 104.6 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

An extrapolation factor of 1 was used because the DNEL was derived from an OECD 451 with a treatment duration of 3 months (life time study).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans as described in the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

See "Explanation for hazard conclusion".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

55.2 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Based on the physico-chemical properties as well as reported uses of ammonium chloride, exposure of the general population via the oral, dermal and inhalation routes are relevant.

Relevant Toxicology Data

Ammonium chloride is harmful if swallowed (UN GHS Category 4 oral; CLP). It is assumed however that effects occurring after single short term exposure are sufficiently controlled by the long-term DNEL. Ammonium chloride also causes irritation upon contact with the eye (UN GHS Category 2). Since available data does not allow for the derivation of a DN(M)EL, a qualitative assessment of this endpoint was performed.

General population – Hazard via inhalative route

The DNEL for long-term exposure via inhalation for consumers is derived from the eight hour - limit value derived for the worker population, viz. 43.97 mg/m³.

This limit value is corrected for:

the reduced breathing volume of 6.7 m³ for consumers, as opposed to 10 m³ for workers,

the prolonged exposure duration of 24 hours (consumers), as opposed to 8 hours for workers

for differences in exposure frequency: 7 days/week (consumer), 5 days/week (worker).

A factor of 1.67 for intra-species differences is also included.

The inhalation DNEL for the consumer is thus calculated as follows:

[43.97 mg/m³ x (10/6.7) x (8/24) x (5/7)]/1.67 = 9.4 mg/m³.

In conclusion, long term systemic inhalation DNEL, general population = 9.4 mg/m³

General population – Hazard via dermal route

Step 1: Selection of the relevant dose descriptor (starting point):
The dermal DNEL for systemic effects is derived using the NOAEL of > 1104 mg/kg bw obtained from a 30 months oral feeding study in rats (Lina, 2004).

Step 2: Modification of the starting point
A general population DNEL (long-term dermal exposure) is derived. As a worst case consideration, absorption via the oral and dermal routes is assumed to be equally efficient. Hence to extrapolate from the oral to the dermal route, a factor of 1 is applied.

Relevant dose descriptor (NOAEL): 1104.6 mg/kg bw/day
Frequency of exposure used in study: 7 days/week

Frequency of exposure of general population: 7 days/week
ABS (oral rat): 100 %
ABS (dermal human): 100 %
 
Corrected dermal NOAEL for worker:
= 1104.6 mg/kg bw/d x (100/100) x 7/7 = 1104.6 mg/kg bw/d 
 
Step 3: Use of assessment factors: 20
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (general population): 5
Exposure duration AF: 1 (life time study)

In conclusion, long term systemic dermal DNEL, general population = 55.2 mg/kg bw/day

General population – Hazard via oral route

Step 1: Selection of the relevant dose descriptor (starting point):
The dermal DNEL for systemic effects is derived using the NOAEL of > 1104 mg/kg bw obtained from a 30 months oral feeding study in rats (Lina, 2004).

Step 2: Modification of the starting point
A general population DNEL (long-term oral exposure) is derived. To extrapolate from the oral to the oral route, a factor of 1 is applied.

Relevant dose descriptor (NOAEL): 1104.6 mg/kg bw/day
Frequency of exposure used in study: 7 days/week

Frequency of exposure of general population: 7 days/week
 
Corrected dermal NOAEL for worker:
= 1104.6 mg/kg bw/d x 7/7 = 1104.6 mg/kg bw/d 
 
Step 3: Use of assessment factors: 20
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (general population): 5
Exposure duration AF: 1 (life time study)

In conclusion, long term systemic oral DNEL, general population = 55.2 mg/kg bw/day

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