Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the derivation of all DNELs a NOAEL of 200 mg/kg bw/day obtained in a subchronic oral repeated dose (90 days) study in rats (0, 50, 200 and 400/500 mg/kg bw) was chosen as dose descriptor starting point.

For workers:

Corrected inhalatory NOAEC = oralNOAEL x 1/sRVanimal x ABS oral-rat / ABS inh-human x sRVhuman/wRV

The standard respiratory volume (sRV) for the 8 h exposure is 0.38 m³/kg bw for rats and 6.7 m³ (per person) in humans. The default 8-h respiratory volume of a worker (wRV) is 10 m³ taking increased activity into account. It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption.

This results in the following equation:

Corrected inhalatory NOAEC = 200 mg/kg bw/d x (1/0.38 m³/kg bw) x (0.5 / 1) x (6.7 m³ / 10 m³) = 176.3 mg/m³

AF for dose response relationship:
1
Justification:
The descriptor starting point is a NOAEL. The dose response relationship is considered unremarkable.
AF for differences in duration of exposure:
2
Justification:
Dose descriptor starting point is the NOAEL of a subchronic study.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The data base is adequat and of good quality (taking into account reliability and consistency across different studies and endpoints).
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties.
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:
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:
2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For the derivation of all DNELs a NOAEL of 200 mg/kg bw/day obtained in a subchronic oral repeated dose (90 days) study in rats (0, 50, 200 and 400/500 mg/kg bw) was chosen as dose descriptor starting point.

For workers:

Corrected dermal NOAEL = oralNOAEL x (ABS oral-rat / ABS dermal-rat) x (ABS dermal-rat / ABS dermal-human)

It is assumed that oral and dermal absorption rates are equal.

This results in the following equation:

Corrected dermal NOAEL = 200 mg/kg x 1 / 1 = 200 mg/kg

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
Dose descriptor starting point is the NOAEL of a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for differences between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.
AF for the quality of the whole database:
1
Justification:
The data base is adequat and of good quality (taking into account reliability and consistency, across different studies and endpoints).
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

In general, the calculation of a DNEL is based on the observed effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, November 2012). Dermal and inhalative intakes are the possible exposure routes for workers.

The establishment of an acute toxicity DNEL set for effects occurring after a single exposure of a few minutes up to 24 hours is unnecessary for TMT, as the long-term DNEL is sufficient to ensure, that these effects do not occur. Anhydrous TMT has a very low vapour pressure (5.45E-14 Pa at 25°C) at room temperature and as a consequence, the inhalation via vapours can be considered negligible. In addition, anhydrous TMT is a very hygroscopic solid and is therefore only transported and used for preparation of a commercial solution. The development of dust is not possible because the substance is delivered in tight bags.Thus, peak exposure significantly higher than the average daily exposure and the long-term DNEL are very unlikely. Based on the available data it is not possible to derive DNELs for local effects, since local irritation on skin and eyes are the leading effects which do not provide dose-response data. Therefore, a qualitative assessment is conducted and appropriate risk management measures will be identified.

As starting point for derivation of the DNEL, a NOAEL of 200 mg/kg bw/day (for systemic effects) was used which was found in a subchronic toxicity study performed according to OECD guideline 408 (2015 -0078 -DGT). In this GLP guideline study TMT 55 was administered via gavage at concentrations of 50, 200 and 500/400 mg anhydrous TMT/kg bw/day for 90 days. A NOAEL of 200 mg/kg bw/day for male rats was derived based on mortality and histopathological findings in the kidneys at the highest dose tested. This NOAEL was selected as relevant dose descriptor.

 

Inhalation

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation.

It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption.

Besides this, the interspecies difference between rat and human has to be taken into account. Therefore, the no observed effect level has to be corrected by the risk assessor 6.7 / 0.38*10 regarding breathing volume and frequency. Thus, the corrected starting point for workers was 176.3 mg anhydrous TMT/m³/day for inhalation.

Subsequently assessment factors (AF) are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (5), duration extrapolation: subchronic - chronic (2).

The DNEL is calculated according to the formula DNEL = (corrected starting point) /(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 7.1 mg anhydrous TMT/m³ for workers.

 

Dermal

For calculation of the DNEL for long-term dermal systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. It is assumed, that oral and dermal absorption rates are equal, since the skin absorption potential (0.055 mg/cm²/h) is assigned to a high dermal absorption of 80% based on the QSAR results for anhydrous TMT taking into account the respective molecular weight, log Pow and water solubility (for details refer to IUCLID chapter 7.1 toxicokinetics, metabolism and distribution). Thus the corrected starting point for workers was 200 mg anhydrous TMT/kg bw/day for the dermal route.

Subsequently, following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (5) and duration extrapolation: subchronic - chronic (2).

As a consequence, the resulting DNEL for long-term dermal systemic effects is 2 mg anhydrous TMT/kg bw/day for workers.

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

TMT is only handled in industrial or professional settings (for details refer to IUCLID section 3.5 or to CSR section 2). Since exposure for the general public is precluded, DNELs for the general population are not relevant and thus not derived.