Dicerium tricarbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/m³

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:

3.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

The Derived No-Effect Levels (DNEL) were calculated using the recommendations of the ECHA "Guidance on information requirements and chemical safety assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health" (May 2008).

 

The adverse effects selected for DNEL derivation were considered to bear a threshold mode of action.

 

Dermal exposure:

The study selected for dermal DNEL derivation is the OECD 422 -compliant study in rats (CIT, 2008) where no significant systemic toxicity was observed up to the highest tested dose, i.e. 450 mg/kg b.w./day.

 

-      Dose descriptor: NOAEL = 450 mg/kg bwin rats

 

-      Corrected dose descriptor: No correction was applied (dermal NOAEL = oral NOAEL because both oral and dermal absorptions are considered negligible)

 

-      Assessment factors:

Interspecies differences =4(default value for rats)

Other toxicokinetic differences =1(based on ECETOC and AGS recommendations)

Intraspecies differences =5(default value for workers)

Differences in exposure duration =6(default value for subacute to chronic exposure extrapolation)

Dose-response issues =1(use of a NOAEL as a starting point)

Quality of the database =1(complete and reliable data)

 

=> Global assessment factor = 120

 

-      DNEL calculation:

Worker-DNEL long-term for dermal route, systemic effects = 450 / 120 =3.75 mg/kg bw

 

Inhalation exposure:

The study that could have been used for inhalation DNEL derivation is the 90 -day repeat-dose inhalation toxicity study in rats (BRL, 1994), exposure of cerium oxide, analagous to dicerium tricarbonate. However, the effects that were observed in this study on the respiratory tract and lymphoreticular system following prolonged inhalatory exposure to poorly soluble particles can be considered as species-specific and bearing low relevance to the human situation (Ref.ILSI Risk Science Institute. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhalation Toxicology, 12: 1-17, 2000). Lung overload-related inflammatory response is commonly observed in rats following inhalation exposure to poorly soluble particles. The concept of overload applies specifically to poorly soluble particles with low cytotoxicity, such as cerium dioxide. The distribution of the retained particles within the lung compartments varies between species. It has been shown that during chronic inhalation exposure, particles are retained to a greater degree in interstitial locations in lungs of non-human primates and dogs than in lungs of rats, and that the interspecies differences in particle location might contribute to corresponding differences in tissue response (Ref. Snipes MB. Current information on lung overload in non-rodent mammals: contrast with rats. Inhalation Toxicology, 8(suppl): 91 -109, 1996). These differences combined with the fact that human macrophages have five times the volume of rat macrophages are considered to account for the tendency of rats to respond to poorly soluble particles with more chronic inflammation and epithelial responses compared to humans (Ref. Oberdörster G. Toxicokinetics and effects of fibrous and non-fibrous particles. Inhalation Toxicology, 14: 29-56, 2002).

Therefore the critical effect for DNEL derivation was deemed irrelevant to humans. In order to set a limit exposure value, the unspecific Occupational Exposure Level of 3 mg/m3 applicable to respirable dusts used in most of the European countries was considered instead.

Worker-DNEL long-term for inhalation route, systemic effects =3 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/m³

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:

1.88 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

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.88 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

DNEL related information

Additional information - General Population

The Derived No-Effect Levels (DNEL) were calculated using the recommendations of the ECHA "Guidance on information requirements and chemical safety assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health" (May 2008).

 

The adverse effects selected for DNEL derivation were considered to bear a threshold mode of action.

 

-      Acute toxicity:

In the absence of any relevant toxic effect and in particular any acute toxicity hazard leading to Classification & Labelling, no specific DNEL was derived.

 

-      Irritation/Corrosion:

In the absence of irritation effects related to the test substance, no specific DNEL was derived.

 

-      Sensitization:

In the absence of skin sensitization effects related to the test substance, no specific DNEL was derived.

 

-      Repeat-dose toxicity:

 

Dermal exposure:

The study selected for dermal DNEL derivation is the OECD 422 -compliant study in rats (CIT, 2008) where no significant systemic toxicity was observed up to the highest tested dose, i.e. 450 mg/kg b.w./day.

 

-      Dose descriptor: NOAEL = 450mg/kg bwin rats

 

-      Corrected dose descriptor: No correction was applied (dermal NOAEL = oral NOAEL because both oral and dermal absorptions are considered negligible)

 

-      Assessment factors:

Interspecies differences =4(default value for rats)

Other toxicokinetic differences =1(based on ECETOC and AGS recommendations)

Intraspecies differences =10(default value for general population)

Differences in exposure duration =6(default value for subacute to chronic exposure extrapolation)

Dose-response issues =1(use of a NOAEL as a starting point)

Quality of the database =1(complete and reliable data)

 

=> Global assessment factor = 240

 

-      DNEL calculation:

General population-DNEL long-term for dermal route, systemic effects = 450 / 240 = 1.88mg/kg bw

 

Inhalation exposure:

The study that could have been used for inhalation DNEL derivation is the 90 -day repeat-dose inhalation toxicity study in rats (BRL, 1994) with cerium oxide, analagous to dicerium tricarbonate. Similarly to the worker situation (see discussion above), the effects were considered as species-specific and not appropriate for DNEL derivation.

In order to set a limit exposure value, the unspecific Occupational Exposure Level of 3 mg/m3 applicable to respirable dusts and used in most of the European countries was considered, taking account of an additional assessment factor of 2 because of the default factors for intraspecies differences between workers (5) and general population (10).

General population-DNEL long-term for dermal route, systemic effects = 3/2 =1.5 mg/m3