Registration Dossier

Administrative data

Workers - 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:
DNEL (Derived No Effect Level)
Value:
0.502 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Value:
2.51 mg/m³
AF for differences in duration of exposure:
1
Justification:
local effects on respiratory tract
AF for interspecies differences (allometric scaling):
1
Justification:
local effects
AF for other interspecies differences:
1
Justification:
rodents like the rat are in general more sensitive compared to humans as the rat's ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC

Workers - 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-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Justification for the non-equivalence of the test material to the submission substance identity

HDI Trimer MEKO blocked is always produced and marketed as dissolved in solvent. Thus, the substance is expected to be handled and used in a form of a mixture of the registered substance in the solvent. It was concluded that testing the mixture for acute effects (acute toxicity studies, eye and skin irritation and sensitization) was more relevant than testing the registered substance as workers would be exposed to the mixture rather than to the pure substance. However, for long-term effects (repeat dose and reproductive studies), it has been concluded to test the registered substance instead of the mixture considering that the route of exposure is the inhalation route and the solvent could present inhalation long-term toxicity properties.

To conclude as a consequence in the endpoint study records, when toxicological studies were performed on the mixture, the test material was not ticked when requesting if equivalent to submission substance identity .

Discussion: DNELs

HDI Trimer MEKO-blocked is classified as a skin sensitizer.

The derivation of DNEL is assessed for workers only and by inhalation and dermal routes.

According to the physico-chemical and toxicological properties, HDI Trimer MEKO blocked is unlikely to be systemically absorbed at a significant rate. As determined in the long-term studies, only local effects were observed after HDI Trimer MEKO blocked exposure. Hence, extrapolation of the DNEL for systemic effects is not relevant.

1.DNEL for acute exposure-local effects

1.1Dermal route

A sensitization study was conducted according to the Guinea-Pig Maximisation Test and showed positive results. Considering that no dose response relationship was observed in this study, it is difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

1.2Inhalation

Derivation of an acute inhalation DNEL by extrapolation from a long-term inhalation DNEL

Cf 2.2 DNEL for long-term inhalation exposure

The DNEL for acute toxicity could be set for a reference period of 15 min at 3 times the value (default value) of the long term DNEL.

Acute inhalation DNEL extrapolated = 0.502*3 = 1.50 mg/m3

2.DNEL for long-term exposure-local effects

2.1 Dermal route

A sensitization study was conducted according to the Guinea-Pig Maximization Test and showed positive results. Considering that no dose response relationship was observed in this study, it is difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

 

2.2 Inhalation

The long-term DNEL inhalation exposure for local effects is derived from the repeated dose toxicity study by inhalation (90d) (L. Ma Hock, 2010)

In this long-term study, 3 concentrations have been tested: 5, 25 and 150 mg/m3.

At the clinical examination (mortality, clinical observation, BW, food consumption, rectal temperature, ophthalmology), no effect or changes has been observed.

At the clinical pathology, a statistically significant increase treatment related of absolute and relative weights has been observed in the lungs of both males and females at 150 mg/m3. The gross lesions have been observed in the mediastinal lymph nodes at 150 and 25 mg/m3.

At histopathology, only local effects have been observed in the respiratory tract.

Ø      Nasal cavity: subepithelial lymphoid infiltrates in the septum of the nasal cavity

Ø      Trachea: goblet cells and hyperplasia and inflammation of the respiratory epithelium and granuloma in the carina

Ø      Lungs: granulomatus inflammation and lympho-reticular hyperplasia with development of granulomas in the BALT

Ø      Mediastinal lymph nodes: lympho-reticular hyperplasia with development of multifocal granulomas

Moreover in hematology, an increase of neutrophil counts and total white blood cells is noticed, considered as a systemic effect in response to the inflammation and irritation of the respiratory tract after test substance exposure.

Table 1.2:Calculation of long-term DNEL by inhalation for local effects for HDI Trimer MEKO-blocked

Worker

Local / Long-term DNEL / inhalation

Step a : determination of the critical dose

Key study

Ma-Hock L., 90-day inhalation study in Wistar rats liquid aerosol

Relevant dose descriptor

NOAEC = 5.00 mg/m3

Step b : Correct starting point– factor for uncertainties

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

-

(local effects)

Modification for exposure

(experiment and human)

6/8

Modification for respiratory volume

6.7/10

Correct starting point = relevant dose descriptor / overall factor for uncertainties

2.51 mg/m3

Step c : assessment factors

Interspecies differences

- Differences in metabolic rate per b.w. (allometric scaling)

-  Remaining differences

 

1(local effects)

1(effects on respiratory tract)

Intraspecies differences

5

(worker, local effects)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

1(local effects on respiratory tract)

Issues related to dose-response

1(DNEL is derived from a NOAEC)

Quality of whole database

1

Overall assessment factor

5

DNEL calculation

0.502 mg/m3

Justification for the interspecies (remaining differences) assessment factor

Rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.

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:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

The substance is not used in the public domain and exposure of consumers is thus not to be expected.