Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.7 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.7 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC

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:
2.75 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.75 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Additional information - workers

The DNELs for workers are based on the NOAEL obtained in a 3 -generation oral (dietary) reproductive toxicity study in rats. The NOAEL was ≥275 mg/kg bw/day. The possibility of using the NOAEL from the two-year carcinogenicity study in rats as the starting point for the DNEL calculation was explored. However, this calculation gave higher DNELs and therefore was less sensitive.

The DNELs are based on a NOAEL for the active acid, and as such are applicable to ATMP acid, as well as sodium, potassium and ammonium salts. With regard to the ammonium salt, there are no repeated dose toxicity data on this salt of ATMP. However, administration of this salt can be assumed to lead to the systemic effects observed following the independent administration of ATMP and ammonia (and salts). Therefore the repeated dose toxicity of ammonia is of relevance. In a 13 week repeated-dose feeding study in rats given ammonium sulfate up to 1,975 mg/kg bw/day, no effects were observed on body weight, food consumption or hematological and clinical parameters. However, increased kidney weights (in males and females) and increased liver weights (females) were observed at the highest dose without histopathological changes. The NOAEL was 1,975 mg/kg bw/day for females and 886 mg/kg bw/day for males (diarrhea). Therefore the ammonium salt is not expected to be more toxic than ATMP acid, sodium or potassium salts, and the derived DNELs are adequate to protect against the potential adverse effects of all salts of ATMP.

ATMP ammonium salt is not classified for human health. Aqueous ammonia is subject to formal specific concentration limits for hazard classification according to the CLP regulations. However in ATMP salt preparations the pH falls into a neutral pH range and the proportion of free ammonia in salt products is very small, being dominated by the highly soluble form NH4+which is of low bioavailability. As explained in the ammonia category SIAR, “As pH decreases, the concentration of ammonium ion increases with respect to decreases of unionized ammonia concentrations. However, the toxicity of the unionized ammonia is considered several orders of magnitude greater than the more abundant ammonium ion”. Some relevant toxicity data are available for relevant ammonia salts which would under normal conditions have pH in the neutral range; the pH of the tested substances is not reported but is assumed to be the same.

The NOAEL from oral repeated dose studies with ammonium salts (assumed to have pH in the neutral range) is 250 mg/kg bw/d (based on increased alkaline phosphatase and decreased total protein in blood). There are no effects on reproduction or foetal development. There is an existing inhalatory OEL for ammonia of 14 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.39 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.39 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC

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:
1.38 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.38 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.38 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.38 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

The DNELs for workers are based on the NOAEL obtained in a 3 -generation oral (dietary) reproductive toxicity study in rats. The NOAEL was≥275 mg/kg bw/day. The possibility of using the NOAEL from the two-year carcinogenicity study in rats as the starting point for the DNEL calculation was explored. However, this calculation gave higher DNELs and therefore was less sensitive.

The DNELs are based on a NOAEL for the active acid, and as such are applicable to ATMP acid, as well as sodium, potassium and ammonium salts. With regard to the ammonium salt, there are no repeated dose toxicity data on this salt of ATMP. However, administration of this salt can be assumed to lead to the systemic effects observed following the independent administration of ATMP and ammonia (and salts). Therefore the repeated dose toxicity of ammonia is of relevance.In a 13 week repeated-dose feeding study in rats given ammonium sulfate up to 1,975 mg/kg bw/day, no effects were observed on body weight, food consumption or hematological and clinical parameters. However, increased kidney weights (in males and females) and increased liver weights (females) were observed at the highest dose without histopathological changes. The NOAEL was 1,975 mg/kg bw/day for females and 886 mg/kg bw/day for males (diarrhea). Therefore the ammonium salt is not expected to be more toxic than ATMP acid, sodium or potassium salts, and the derived DNELs are adequate to protect against the potential adverse effects of all salts of ATMP.

ATMP ammonium salt is not classified for human health. Aqueous ammonia is subject to formal specific concentration limits for hazard classification according to the CLP regulations. However in ATMP salt preparations the pH falls into a neutral pH range and the proportion of free ammonia in salt products is very small, being dominated by the highly soluble form NH4+which is of low bioavailability. As explained in the ammonia category SIAR, “As pH decreases, the concentration of ammonium ion increases with respect to decreases of unionized ammonia concentrations. However, the toxicity of the unionized ammonia is considered several orders of magnitude greater than the more abundant ammonium ion”. Some relevant toxicity data are available for relevant ammonia salts which would under normal conditions have pH in the neutral range; the pH of the tested substances is not reported but is assumed to be the same.

The NOAEL from oral repeated dose studies with ammonium salts (assumed to have pH in the neutral range) is 250 mg/kg bw/d (based on increased alkaline phosphatase and decreased total protein in blood). There are no effects on reproduction or foetal development. There is an existing inhalatory OEL for ammonia of 14 mg/m3.