Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
490 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
36
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
144
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
145 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

For hydrotalcite studies with hydrotalcite are available, and, in addition, data from other substances were considered for read across purposes: P93 (aluminium-magnesium-zinc-carbonate-hydroxide), Alcamizer 5 (aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate), aluminium ion and magnesium ion.

 

Considering the available data on hydrotalcite and read across substances, the following starting points are considered relevant for the setting of DNELs:

 

Endpoint/test type

Test substance

Result/effect

Classification

Acute toxicity

Rat oral LD50

P93

Alcamizer 5

>2000 mg/kg bw

>2000 mg/kg bw

No

Rat dermal LD50

Alcamizer 5

> 2000 mg/kg bw

No

Rat inhalation LC50

P93

Alcamizer 5

5.17 mg/L (5170 mg/m3)

5.16 mg/L (5160 mg/m3)

No

Skin irritation

hydrotalcite

P93

Alcamizer 5

Slight irritant

Non-irritant

Non-irritant

No

Eye irritation

hydrotalcite

P93

Alcamizer 5

Mild irritant

Mild irritant

Non-irritant

No

Skin sensitization

P93

Alcamizer 5

Non-sensitiser (GPMT)

Non-sensitiser (GPMT)

No

Short term toxicity

28-day oral, rat

Hydrotalcite

 

 

P93

 

no systemic or local effects up to 2000 mg/kg bw/day (6-month rat; supporting)

NOAEL ≥ 1000 mg/kg bw/day; no systemic or local effects observed

No

Genotoxicity

In vitro studies

Hydrotalcite

P93

 

 

Alcamizer 5

negative

negative, chromosome aberration and mouse lymphoma test

negativeand chromosome aberration

No

Long term toxicity and carcinogenicity

Overall chronic toxicity (based on studies with dissociation products)

P93 (based onHydrotalciteand Zn2+, Al3+, Mg2+)

Overall oral NOAEL of 605 mg/kg bw/day (calculated from a NOAEL of Al taking into consideration the Al content) (BMS071023.03, d.d. 23-10-07). NOAEL is based on decreased body weight gain and food consumption

No

Carcinogenicity

P93 (based on Zn2+, Al3+, Mg2+)

There is no concern for a direct carcinogenic action of Zn2+, Al3+ or Mg2+ and the analogue P93 is considered negative for carcinogenicity (BMS071023.03, d.d.). Therefore, hydrotalcite – containing Al3+ and Mg2+ – is considered to be of no concern for carcinogenicity.

No

Reproductive toxicity

Fertility

P93 (based on Zn2+, Al3+, Mg2+)

 

Overall oral NOAEL for fertility of 605 mg/kg bw/day (calculated from oral NOAEL for Al taking into consideration the Al content) (BMS071023.03, d.d. 23-10-07). The NOAEL is based on absence of effects (highest conc tested).

No

Developmental toxicity and teratogenicity

P93 (based on Zn2+, Al3+, Mg2+)

Overall oral NOAEL for developmental toxicity of 151 mg/kg bw/day (calculated from a NOAEL for Al of 13 mg/kg bw/d from a rat study taking into consideration the Al content) (071023.03, d.d. 23-10-07; and EHC 194, 1997). The NOAEL is based on decreased ossification of the skull bones, increased incidence of vertebral and sternebrae, and reduced foetal weight and tail length. Maternal toxicity included reduced weight gain during pregnancy.

No

 

 

Route-to-route extrapolation

Route-to-route extrapolation is considered necessary for the long-term systemic dermal and inhalation DNELs for the general population and workers, since only oral toxicity data are available.

 

In the Risk Assessment of P93 performed by the Dutch Competent Authorities (BMS071023.03, d.d.), the following values are considered for absorption:

- oral absorption: 50%

- dermal absorption: 1% (based on the physico-chemical properties)

- inhalation absorption: 1% (considering the particle size inhalation exposure will be negligible)

However, the value of 50% for oral absorption is considered a rather high estimate. In general this value is taken if no data are available on oral bioavailability. The value of 50% is an arbitrary choice that recognizes that the GI tract is designed to favour the absorption in ingested substances into the body but that, in most cases, not all of the ingested material will be bioavailable. If there is evidence to suggest poor oral bioavailability, for example the substance is a poorly soluble particulate, then it may be more appropriate to assume that only 10% of the administered dose is systemically available (IGHRC Guidelines, 2006).

In case of P93, based on the very low water solubility (< 9 µg/L) and the low solubility in n-octanol (< 0.47 mg/L), an oral absorption of 10% may be considered more appropriate for risk assessment purposes.

 

Therefore the following values will be used for route-to-route extrapolation:

- oral absorption: 10%

- dermal absorption: 1%

- inhalation absorption: 1%

 

 

Derivation of DNELs

 

The DNELs for human exposure are derived according to the ECETOC guidance (Technical report No 110, 2010).

In the absence of classification for systemic and local effects after acute oral inhalation exposure and for local effects after dermal exposure to P93 and Alcamizer5 for acute toxicity, no acute DNELs are considered applicable.

 

In the absence of local effects after repeated exposure to hydrotalcite, analogues or dissociation products (i.e. ions), no long-term DNELs for local effects are considered applicable.

 

The following DNELs will be derived:

 

Systemic:

Long-term oral - general population

Long-term inhalation - general population

Long-term inhalation - workers

Long-term dermal - general population

Long-term dermal - workers

 

A risk assessment has already been performed by the RIVM and TNO in The Netherlands for P93 (BMS071023.03, d.d.). In this risk assessment it wasconcluded that the NOAEL for chronic toxicity for P93 was derived from the NOAEL for Zn2+ as worst case (compared to Al3+ and Mg2+) taking into consideration the content of Zn2+ in P93:  

“A 28-day oral toxicity study in rats with P93 is available, in which a NOAEL of ≥1000 mg/kg bw/day is established. Several oral (sub)chronic, fertility and developmental toxicity studies are available with dissociation products, for which an overall NOAEL of 6.48 mg/kg bw/day is calculated. Based on the large difference between the NOAEL from the 28-day toxicity study with P93 and the overall NOAEL based on the reproduction toxicity studies with the dissociation products, it can be concluded that dissociation of P93 after oral exposure will either be at a low rate, or will not occur at all. Furthermore, dissociation of P93 via dermal or inhalation exposure is even considered more unlikely than via oral exposure. Therefore, the NOAEL of 6.48 mg/kg bw/day based on the individual metal ions and hydrotalcite, is not considered to be applicable for risk assessment purposes of P93 (BMS071023.03, d.d. 23-10-07).”

The NOAEL of 2000 mg/kg bw/d from the 6-month rat study with hydrotalcite confirms that the above reasoning is also applicable to hydrotalcite. However, parameters investigated in this study are limited.

Based on the above considerations and the fact that hydrotalcite is a complex non-soluble salt similar to P93 without Zn2+ in it, the NOAEL derived for Al3+ was used for derivation of the NOAEL for hydrotalcite taking into consideration the Al3+ content in hydrotalcite. Therefore, the NOAEL of 52 mg/kg bw/d for Al3+ was converted to the NOAEL for hydrotalcite using 8.6% Al3+ content resulting in a NOAEL of 605 mg/kg bw/d. Copying the evaluation from RIVM, the NOAEL of 1000 mg/kg bw/d is used as starting point for risk assessment.

 

All DNELs are external values..

 

Long-term oral, systemic effects

 

General population

Starting point: NOAEL of ≥ 1000 mg/kg bw/day from an oral subacute toxicity study in rats (no effects observed).

 

Safety factors:

-      Interspecies extrapolation: 4 (rat to human)

-      Intraspecies extrapolation: 5

-      Exposure duration: 6 (assuming chronic exposure of the general population)

-      Dose response: 1

-      Quality of the data base: 2 data from read-across substance

Total safety factor: 240

 

Based on the above, the long-term DNEL for systemic effects after oral exposure of the general population is set at 4.2 mg/kg bw/day.

 

 

Long-term inhalation, systemic effects

 

Worker

Starting point: NOAEL of ≥ 1000 mg/kg bw/day from an oral subacute toxicity study in rats (no effects observed).

 

Corrected inhalatory NOAEC   = 1000 * 1/0.38a* 10/1b* 6.7/10c                                                         

                                              = 17632 mg/m3

 

a: 8 hour ventilation rate rat

b: oral/inhalation absorption

c: 8 hour ventilation rate human/respiratory volume light activity worker

 

Safety factors:

-      Interspecies extrapolation: 1 (correction for caloric demand already included in dose descriptor starting point)

-      Intraspecies extrapolation: 3

-      Exposure duration: 6 (assuming chronic worker exposure)

-      Dose response: 1

-      Quality of the data base: 2 (data from read-across substance)

Total safety factor: 36

 

Based on the above, the long-term DNEL for systemic effects after inhalation worker exposure is set at 490 mg/m3.

 

 

General population

Starting point: NOAEL of ≥ 1000 mg/kg bw/day from an oral subacute toxicity study in rats (no effects observed).

 

Corrected inhalatory NOAEC   = 1000 * 1/1.15a* 10/1b

 

                                              = 8696 mg/m3

 

a: 24 hour ventilation rate rat

b: oral/inhalation absorption

 

 

Safety factors:

-      Interspecies extrapolation: 1(correction for caloric demand already included in dose descriptor starting point)

-      Intraspecies extrapolation: 5

-      Exposure duration: 6 (assuming chronic exposure of the general population)

-      Dose response: 1

-      Quality of the data base: 2 (data from read-across substance)

Total safety factor: 60

 

Based on the above, the long-term DNEL for systemic effects after inhalation exposure of the general population is set at 145 mg/m3.

 

 

Long-term dermal, systemic effects

 

Worker

Starting point: NOAEL of ≥ 1000 mg/kg bw/day from an oral subacute toxicity study in rats (no effects observed).

 

Corrected dermal NOAEL = 1000 x 10/1a= 10000 mg/kg bw/day

 

a: oral/dermal absorption

 

Safety factors:

-      Interspecies extrapolation: 4

-      Intraspecies extrapolation: 3

-      Exposure duration: 6 (assuming chronic worker exposure)

-      Dose response: 1

-      Quality of the data base: 2 (data on read-across substance)

Total safety factor: 144

 

Based on the above, the long-term DNEL for systemic effects after dermal worker exposure is set at 69 mg/kg bw/day.

 

 

General population

Starting point: NOAEL of ≥ 1000 mg/kg bw/day from an oral subacute toxicity study in rats (no effects observed).

 

Corrected dermal NOAEL = 1000 x 10/1a= 10000 mg/kg bw/day

 

a: oral/dermal absorption

 

Safety factors:

-      Interspecies extrapolation: 4

-      Intraspecies extrapolation: 5

-      Exposure duration: 6 (assuming chronic exposure of the general population)

-      Dose response: 1

-      Quality of the data base: 2 (data on read-across substance)

Total safety factor: 240

 

Based on the above, the long-term DNEL for systemic effects after dermal exposure of the general population is set at 42 mg/kg bw/day.