Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
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:
0.114 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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:
medium hazard (no threshold derived)

Additional information - workers

General considerations

Inhalation exposure is the most relevant route for assessing occupational risk in humans. Based on the physicochemical properties of DCDPS and the large differences in operational temperature, two distinct forms of inhalation exposure need to be addressed:

·       Exposure to a vapour at operational temperatures above the melting point (149°C) and

·       Exposure to a poorly soluble dust at ambient temperatures. Vapour exposure at ambient temperatures is negligible due to the extremely low vapour pressure of 1.5 * 10 -5 Pa at 25 °C.

An extrapolation of the local effects on the respiratory tract due to chronic inhalation of particulate matter can be made based on the derivation of the German MAK-value for insoluble and poorly soluble dusts:

·       4 mg/m³ for the inhalable fraction (total dust)

·       1.5 mg/m³ for the alveolar/respirable fraction (fine dust)

The derivation was based on an initial epidemiological cross-sectional study taking into account collectives totalling about 13000 persons exposed to various kinds and amounts of dust and the composition of the dusts (DFG 1975).

These MAK values are intended to prevent from unspecific effects which all insoluble and poorly soluble dusts can produce in the respiratory organs, effects such as impairment of airway clearance by overloading, chronic inflammatory changes in the bronchial mucosa and obstructive ventilation disorders.

This value can be applied together with a substance specific OEL based on systemic effects.

In case of DCDPS chronic bronchial reaction (CBR) parameters do not apply for all types of dust toxicity. Additionally bioavailability due to a minor dissolution in the bronchoalveolar liquid (water solubility: 0.86 mg/L at 20°C) and due to oral ingestion following retrograde mucociliary transport in the respiratory tract need to be considered with respect to systemic toxicity.

A worker inspires only part of the total dust in his breathing zone (inspirable fraction) which is governed by the flow rates into the nose and mouth. The transport and deposition of a DCDPS dust in the respiratory passages can be estimated by the aerodynamic diameter of the particles. The median aerodynamic diameter (d 0.5) of solid DCDPS is 238 µm. The particle size distribution is steep with only < 8% of the total particles within the size of the inhalable fraction (<100 µm) and none within the size of the respirable fraction (<10 µm).

Particles with an aerodynamic diameter between 10 and 100 µm usually are deposited in the nasopharyngeal region and cannot penetrate distal to the pharynx. The mucous layer of the ciliated nasal surface propels insoluble particles by the movement of the cilia. Deposited particles which are transferred to the digestive system by means of the mucociliary cleansing mechanism of the respiratory tract can be absorbed there and become biologically active.


Identification of key values

The most sensitive systemic effect on the oral route of exposure is an adaptive increase in liver metabolism. A NOEL 1.5 mg/kg bw/day of was identified in a 2 year feeding study in rats based on a significant increase in liver weights accompanied by centrilobular hepatocellular hypertrophy (NIH 2001). In the same bioassay no indications for a carcinogenic potential of DCDPS were identified. This supports the conclusion from the available set of in vitro and in vivo assays that no evidence for a genotoxic mode of action can be derived.

There were no indications for reproductive toxicity in a screening study for this endpoint and in all repeated dose toxicity assays.

DNEL derivation

Acute/short-term exposure – systemic effects – dermal and inhalation DNEL

According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C & L has been identified. DCDPS is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and long-term exposure – local effects – dermal and inhalation DNEL

DCDPS is not sensitizing but classified for eye irritation (Xi, R36; GHS cat2). However, no dose-response data exist with respect to eye irritation. No data on local effects after inhalation are available. Thus, no DNELs can be derived for local effects and a qualitative approach regarding an adequate selection of the respective risk management measures (RMMs) at the workplaces is appropriate and in accordance to the REACh guidance part E.

Long-term exposure – systemic effects dermal DNEL

The long-term dermal DNEL for systemic effects is calculated based on a route to route extrapolation from a chronic oral gavage study assuming identical absorption rates for both routes (absorption rate factor = 1.0). The starting value is the NOAEL (oral, rat, 7 d per week) of 1.5 mg/kg. The animals were continuously exposed while workers are exposed only 240 d/year.

Derivation of corrected NOEL:

NOEL(corrected) = 1.5 mg/kg bw * 1.0 * 365/240 = 2.28 mg/kg bw

The NOEL for repeated dose toxicity was based on unspecific enzyme induction in the liver of rats. There is no indication e.g. for a specific receptor mediated mode of action and thus species differences in sensitivity are unlikely (remaining uncertainties = 1.0). The assessment factor is the product of: 

allometric scaling:                 4 (rat to human)

remaining uncertainties:        1

intraspecies worker:            5

Exposure duration:              1

Quality of whole database:  1

Dose-response:                   1

DNELdermal, chronic worker: 2.28 mg/kg bw/d / 20 = 0.114 mg/kg bw/d

 

Long-term exposure – systemic effects – inhalation DNEL

A) Assessment of vapor exposure, bioavailability via the lung:

Using a route to route extrapolation from a chronic oral gavage study (oral, rat, 7 d per week) the following DNEL could be calculated. A breathing volume of 0.38 m³/kg bw in 8 h is assumed for the rat. As workers are expected to exert light activity in comparison to resting activity of the animals a breathing volume correction factor of 0.67 (6.7 m³/10 m³) is used. An oral bioavailability of 100 % can be assumed (Matthews et al., 1996), while due to lack of data for absorption via the inhalation route 100 % bioavailability is assumed. The animals were continuously exposed while workers are exposed only 240 d/year (365/240 = 1.52).

Derivation of the corrected NOEC:

NOEC(corrected) = 1.5 mg/kg bw/day * 1/0.38 m³/kg * 0.67 * 1 * 1.52 = 4.02 mg/m³.

The NOEL for repeated dose toxicity was based on an unspecific enzyme induction in the liver of rats. There is no indication e.g. for a specific receptor mediated mode of action and thus species differences are unlikely (remaining uncertainties = 1.0).

The assessment factor is the product of:

allometric scaling:                 1 (does not need to be applied in case an external dose descriptor is used, mg/m3 )

remaining uncertainties:         1

intraspecies worker:             5

exposure duration:               1

quality of whole database:    1

Dose-response:                   1

DNEL: 4.02 mg/m³ / 5 = 0.80mg/m³

 

B) Assessment of dust exposure, oral bioavailability:

As described above particles deposited in the bronchiotracheal area are transferred to the digestive system by means of the mucociliary cleansing mechanism. Therefore the DNEL for the inhalable fraction of DCDPS dust could be extrapolated from the oral (dermal) DNEL.

0.114 mg/kg bw/day x 70 kg / 10 m³ = 0.80 mg/m³day

 

The DNELs derived by both approaches are identical. The DNEL of 0.80 mg/m³ is considered reasonable in order to protect:

a) against the systemic inhalative absorption of the vapour and

b) against local and systemic effects of the inhalable fraction of a DCDPS dust (oral systemic bioavailability due to retrograde mucociliary transport).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
0.037 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

There are only industrial uses of DCDPS. Therefore, no DNELs for the general population have to be derived.

In order to evaluate a possible contamination of man via the environment the only key value which needs to be presented in this context is the oral DNEL for long term systemic effects.

Long-term exposure – systemic effects oral DNEL

The long-term oral DNEL for systemic effects is calculated based on a chronic oral gavage study. The starting value is the NOAEL (oral, rat, 7 d per week) of 1.5 mg/kg.

The NOEL for repeated dose toxicity was based on unspecific enzyme induction in the liver of rats. There is no indication e.g. for a specific receptor mediated mode of action and thus species differences in sensitivity are unlikely (remaining uncertainties = 1.0). The assessment factor is the product of: 

allometric scaling:                        4 (rat to human)

remaining uncertainties:                1

intraspecies general population:    10

Exposure duration:                      1

Quality of whole database:          1

Dose-response:                         1

DNELdermal, chronic worker: 2.28 mg/kg bw/d / 40 = 0.0375 mg/kg bw/d