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:
0.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
LOAEC
Value:
3 mg/m³
AF for dose response relationship:
3
Justification:
The assessment factor was used for extrapolation from LOAEC to NOAEC.
AF for differences in duration of exposure:
1
Justification:
An AF for time-extrapolation is not justified concerning local respiratory tract effects.
AF for interspecies differences (allometric scaling):
1
Justification:
According to the REACH TGD, Section R.8.4.3.1, allometric scaling should not be applied (allometric scaling factor of 1) since local effects are independent of the basic metabolic rate.
AF for other interspecies differences:
1
Justification:
Enzyme polymorhisms are of minor importance regarding local respiratory irritation. In addition, due to the higher respiratory rate of rodents that leads to a greater respiratory tract burden as compared to humans, the effects observed in rats may overestimate exposure. Therefore, when extrapolating to humans no additional interspecies AF for ‘remaining differences’ is justified.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The database is of high quality.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Long-term exposure – local effects

Inhalation exposure is the most relevant route for assessing occupational risk of this substance in humans. As a point of departure for derivation of a long-term inhalation DNEL a subacute aerosol inhalation study in rats is available for assessment (Triazine Task Force, 2011). This study was carried out according to OECD guideline 412 in compliance with GLP at liquid aerosol concentrations of 3, 10, 30 and 100/50 mg/m³ (Due to severe clinical findings and premature death in the high dose group test concentration was reduced to 50 mg/m³ after two (males) or one (female) exposures and was stopped after five (females) or six (males) exposures). In conclusion, exposure of male and female Wistar rats to liquid aerosol of the test substance caused concentration–related local irritation of the respiratory tract. The maximum tolerated dose (MTD) was clearly exceeded at the initial high concentration of 100 mg/m³ due to severe clinical findings, the concentration was lowered to 50 mg/m³ after the first exposure day for females and the second exposure day for males, respectively. The lowered high concentration led to premature death and was interrupted on study day 6 and 7, for females and males, respectively. The local irritation was manifested as gasping, intermittent respiration and respiration sound and confirmed by histological changes of nasal cavity, larynx and lung. Systemic toxicity was not observed in clinical chemistry, hematology nor in histological examinations up to 30 mg/m³. As the high concentration group was terminated, no statement concerning systemic effect on that concentration could be made. The reduced body weight gain and premature death were considered to be associated to the severe local irritation. Based on histopathology findings in larynx, trachea and lung, a NOAEC could not be established for the local irritation effect under the current study conditions. For systemic effects the NOAEC was established at 30 mg/m³.

 

The LOAEC of 3 mg/m³ was established for local effects after repeated inhalation exposure and is considered to be the most sensitive dose descriptor and point of departure for DNEL derivation.

 

The following assessment factors (AF) were used for the derivation of the long-term DNEL for inhalation exposure:

Inter-species factor: 1

According to the REACH TGD, Section R.8.4.3.1, allometric scaling should not be applied (allometric scaling factor of 1) since local effects are independent of the basic metabolic rate. Furthermore, enzyme polymorhisms are of minor importance in such cases. In addition, due to the higher respiratory rate of rodents that leads to a greater respiratory tract burden as compared to humans, the effects observed in rats may overestimate exposure. Therefore, when extrapolating to humans no additional interspecies AF for 'remaining differences' is justified.

Intra-species factor (worker): 5 (default)

Exposure duration factor (subacute to chronic): 1

Modification of the starting point to account for time scaling is not appropriate as the toxic effect is mainly driven by exposure concentration (local effect in respiratory tract). Since local effects are largely concentration-dependent, exposure time is of minor importance in such cases. Due to the fact that the local effects are driven by local exposure peaks, the effects are not expected to worsen with exposure duration.

Dose-response: 3

LOAEL to NAEL extrapolation; suggested for the majority of cases according to REACH TGD, Section R.8.4.3.1.

Quality of whole database: 1 (default; the database is of high quality)

 

The DNEL is calculated as follows:

DNEL (worker, long-term inhalatory exposure, local effects): 3 mg/m³ / (5 x 3) = 0.2 mg/m³

 

The following DNELs / DMELs were not derived

Oral DNEL

In an industrial setting, ingestion is not an anticipated route of exposure.

Dermal DNEL - Local effects

The skin sensitizing effect of the substance can only be assessed in a qualitative manner. However, by the following highly accepted operational conditions (OCs) and risk management measures (RMMs) the risk for workers is considered to be controlled:

-       Appropriate skin coverage based on potential for contact/exposure

-       Use of suitable chemical resistant gloves + basic training and specific activity training

-       Avoid frequent and direct contact with substance, minimisation of manual phases

-       Regular cleaning of equipment and work area

-       Supervision in place to check that the RMMs in place are being used correctly and OCs followed

 

Dermal DNEL - Systemic effects

Skin sensitization is the leading acute effect and no signs of systemic toxicity were observed at the acute limit dose of 4000 mg/kg bw. Therefore, the derivation of DNELs for systemic effects after dermal exposure is misleading. In this context, protection from sensitisation is protecting from any kind of potential systemic toxicity on the dermal route of exposure.

 

Inhalation DNEL - Acute/short-term exposure

Based on the available data on acute toxicity no sufficiently robust DNEL can be set. However, the exclusive industrial chemical use of this substance in closed systems ensures that peak concentrations exceeding the long-term inhalation DNEL will not occur.

Inhalation DNEL - Systemic effects

Acute and subacute aerosol inhalation studies with the registered substance inrats clearly showed that local effects in the respiratory tract and the lungs are the leading effect after short-term and long-term inhalation exposure. Therefore, the derivation of DNELs for systemic effects after inhalation exposure is misleading. In this context, protection from aerosol inhalation is protecting from any kind of potential systemic toxicity via the inhalation route of exposure.

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:
no hazard identified
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

The test substance is neither marketed to the general public nor intentionally added to consumer products. Also, consumer products do not contain substances from which the test substance is intended to be released. Thus, the derivation of DNELs for the general population is not required.