Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
152.8 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):
15
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2 292 mg/m³
AF for dose response relationship:
1
Justification:
according to ECHA REACH Guidance
AF for differences in duration of exposure:
3
Justification:
according to Batke et al., 2011
AF for interspecies differences (allometric scaling):
1
Justification:
not neccessary for inhalation
AF for other interspecies differences:
1
Justification:
based on toxicokinetic behaviour
AF for intraspecies differences:
5
Justification:
according to ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH Guidance
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:
216.6 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):
60
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
13 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
according to ECHA REACH Guidance
AF for differences in duration of exposure:
3
Justification:
according to Batke et al., 2011
AF for interspecies differences (allometric scaling):
4
Justification:
according to ECHA REACH Guidance
AF for other interspecies differences:
1
Justification:
based on toxicokinetic behaviour
AF for intraspecies differences:
5
Justification:
according to ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH Guidance
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:
no hazard identified

Additional information - workers

No DNELs have been derived for the short-term dermal and inhalation exposure of 2-amino-2-(hydroxymethyl)propane-1,3-diol hydrochloride, (TRIS-HCl) for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure.

No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of TRIS-HCl.

The long-term systemic DNELs for TRIS HCl for the dermal and for the inhalation route of the worker are calculated based on the systemic NOAEL of ≥ 1000 mg/kg bw/day, derived from the reproductive/developmental toxicity screening study (reference 7.8.1 -1), which was performed with the test material 1,3-Propanediol, 2-amino-2-(hydroxymethyl)-, (Trometamol).

The study is chosen as the starting point for derivation of the long-term systemic, dermal DNEL for the worker: To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], route-to-route extrapolation is applied. The differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2.1, 2012).

A quantitative study of percutaneous absorption of TRIS HCl in-vitro was carried out on human abdominal skin placed in a FRANZ diffusion cell (reference 7.1.2 -1). The percutaneous absorption of TRIS HCl through human skin was very low. Less than 1% of the applied dose was found. Taking into account that the washing waters contained more than 90% of the applied dose, a dermal uptake of 10% has to be regarded as a worst case scenario. A further correction factor of 1.3 was used to account for the molar mass difference when comparing the target substance TRIS HCl with the source substance Trometamol, resulting in a NOAEL worker (TRIS HCl, 8h) of 13000 mg/kg bw/d.

The long-term systemic DNEL for inhalation systemic effects is again based on the reproduction/developmental toxicity screening test performed according to OECD 421 (reference 7.8.1 -1). This study is chosen as the starting point for deriving the DNEL. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, 2012), the oral NOAEL should be converted into an inhalation NOAEC by route-to-route extrapolation: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 h exposure). Additionally, it should be taken into account that during 8 hours light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). Considering these differences, the corrected starting point for the worker is a NOAEC of 1763.2 mg/m³. The absorption via the inhalation route is considered to be in the same order as via the oral route. A further correction factor of 1.3 was used to account for the molar mass difference when comparing the target substance TRIS HCl with the source substance Trometamol, resulting in a NOAEC worker (TRIS HCl, 8h) of 2292 mg/m³.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, Version 2.1, 2012) were used when applicable to derive the DNELs. Several AFs for which there is specific additional information available were refined.

The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic behaviour indicates that TRIS HCl will not be metabolised, when absorbed. An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the worker.

Bioavailable levels of TRIS HCl are rapidly eliminated by the kidneys and no relevant metabolism is expected. Thus the AF for remaining interspecies differences has been set at 1.

An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the worker. In the reproduction/developmental toxicity screening test (OECD 421) that is used to derive the long-term DNELs, rats were exposed for at least 29 days (approximately 54 days for the females and 29 days for the males). Based on a publication (Batke et al., Toxicol Lett. 2011, 205(2):122-9), an AF of 3 has been chosen in this case, as it reflects the exposure duration accurately. The study by Batke et al. performed an assessment of the time extrapolation factors based on the comparison of NOELs from different duration studies. Batke et al. concluded that in the majority of cases a factor of 3 is sufficient to convert the subacute exposure duration to chronic exposure duration. As in the present case, the NOAEL corresponds to the highest dose tested with no evidence of treatment-related adverse effects, a factor of 3 can be used.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
37.7 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):
30
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 130.5 mg/m³
AF for dose response relationship:
1
Justification:
according to ECHA REACH Guidance
AF for differences in duration of exposure:
3
Justification:
according to Batke et al., 2011
AF for interspecies differences (allometric scaling):
1
Justification:
not neccessary for inhalation
AF for other interspecies differences:
1
Justification:
based on toxicokinetic behaviour
AF for intraspecies differences:
10
Justification:
according to ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH Guidance
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:
DNEL (Derived No Effect Level)
Value:
108.3 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):
120
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
13 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
according to ECHA REACH Guidance
AF for differences in duration of exposure:
3
Justification:
according to Batke et al., 2011
AF for interspecies differences (allometric scaling):
4
Justification:
according to ECHA REACH Guidance
AF for other interspecies differences:
1
Justification:
based on toxicokientic behaviour
AF for intraspecies differences:
10
Justification:
according to ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH Guidance
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:
10.8 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):
120
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
according to ECHA REACH Guidance
AF for differences in duration of exposure:
3
Justification:
according to Batke et al., 2011
AF for interspecies differences (allometric scaling):
4
Justification:
according to ECHA REACH Guidance
AF for other interspecies differences:
1
Justification:
based on toxicokientic behaviour
AF for intraspecies differences:
10
Justification:
according to ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
according to ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
according to ECHA REACH Guidance
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

No DNELs have been derived for the short-term oral, dermal and inhalation exposure of 2-amino-2-(hydroxymethyl)propane-1,3-diol hydrochloride, (TRIS-HCl) for consumers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure.

No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of TRIS-HCl.

The long-term systemic DNELs for TRIS HCl for the oral, dermal and for the inhalation route of the consumer are calculated based on the systemic NOAEL of ≥ 1000 mg/kg bw/day, derived from the reproductive/developmental toxicity screening study (reference 7.8.1 -1), which was performed with the test material 1,3-Propanediol, 2-amino-2-(hydroxymethyl)-, (Trometamol).

For derivation of the oral DNEL for long-term systemic effects, no route to route extrapolation is required.

The study is chosen as the starting point for derivation of the long-term systemic, dermal DNEL for the consumer: To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], route-to-route extrapolation is applied. The differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2.1, 2012).

A quantitative study of percutaneous absorption of TRIS HCl in-vitro was carried out on human abdominal skin placed in a FRANZ diffusion cell (reference 7.1.2 -1). The percutaneous absorption of TRIS HCl through human skin was very low. Less than 1% of the applied dose was found. Taking into account that the washing waters contained more than 90% of the applied dose, a dermal uptake of 10% has to be regarded as a worst case scenario. A further correction factor of 1.3 was used to account for the molar mass difference when comparing the target substance TRIS HCl with the source substance Trometamol, resulting in a NOAEL consumer (TRIS HCl, 8h) of 13000 mg/kg bw/d.

The long-term systemic DNEL for inhalation systemic effects is again based on the reproduction/developmental toxicity screening test performed according to OECD 421 (reference 7.8.1 -1). This study is chosen as the starting point for deriving the DNEL. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, 2012), the oral NOAEL should be converted into an inhalation NOAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 h exposure). Therefore, the corrected starting point for the consumer is a NOAEC of 869.6 mg/m³. The absorption via the inhalation route is considered to be in the same order as via the oral route. A further correction factor of 1.3 was used to account for the molar mass difference when comparing the target substance TRIS HCl with the source substance Trometamol, resulting in a NOAEC consumer (TRIS HCl, 8h) of 1130.5 mg/m³.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, Version 2.1, 2012) were used when applicable to derive the DNELs. Several AFs for which there is specific additional information available were refined.

The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic behaviour indicates that TRIS HCl will not be metabolised, when absorbed. An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the consumer.

Bioavailable levels of TRIS HCl are rapidly eliminated by the kidneys and no relevant metabolism is expected. Thus the AF for remaining interspecies differences has been set at 1.

An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the consumer. In the reproduction/developmental toxicity screening test (OECD 421) that is used to derive the long-term DNELs, rats were exposed for at least 29 days (approximately 54 days for the females and 29 days for the males). Based on a publication (Batke et al., Toxicol Lett. 2011, 205(2):122-9), an AF of 3 has been chosen in this case, as it reflects the exposure duration accurately. The study by Batke et al. performed an assessment of the time extrapolation factors based on the comparison of NOELs from different duration studies. Batke et al. concluded that in the majority of cases a factor of 3 is sufficient to convert the subacute exposure duration to chronic exposure duration. As in the present case, the NOAEL corresponds to the highest dose tested with no evidence of treatment-related adverse effects, a factor of 3 can be used.