Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
620
Dose descriptor starting point:
NOAEC
Value:
62 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
31.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

- Differences in metabolic rate per b.w. (allometric scaling) : not relevant for dose level from inhalation study

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

- Modification for exposure (experiment in animal and human) : 6/8 (different conditions of exposure human/animal)

- Modification for the respiratory volume : 6,7/10 (respiratory rate difference under standard conditions and under conditions of light activity for 8 hours)

=> Correct starting point = relevant dose descriptor / overall factor for uncertainties = 31.2 mg/m3

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute
AF for interspecies differences (allometric scaling):
1
Justification:
not necessary same effects observed in several species
AF for other interspecies differences:
1
Justification:
not necessary same effects observed in several species
AF for intraspecies differences:
5
Justification:
worker
AF for the quality of the whole database:
1
Justification:
several studies showing same effect
AF for remaining uncertainties:
10
Justification:
Issues related to dose-response: severity
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
0.06 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 033
Dose descriptor starting point:
NOAEL
Value:
62 mg/m³
Modified dose descriptor starting point:
NOAEL
Value:
18 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

- Conversion into dermal NOAEL (in mg/kg bw/day) by using a 6 h respiratory volume of 0.29 m3/kg bw for the rat.

- Conservative default for route to route: 100% for inhalation and 100% for dermal absorption

=> corrected strating point = relavant dose descriptor / overall factor for uncertainties = 18 mg/kg/day

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not necessary same effects observed in several species
AF for other interspecies differences:
1
Justification:
not necessary same effects observed in several species
AF for intraspecies differences:
5
Justification:
worker
AF for the quality of the whole database:
1
Justification:
several studies showing same effects
AF for remaining uncertainties:
10
Justification:
Issues related to dose-response: severity
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
high hazard (no threshold derived)

Additional information - workers

2,2,2 Trifluoroethanol is self-classified:

- in category 3, Toxic by ingestion (T, H301), in category 3, Toxic if inhaled (T, H331), in Category 1 (Irreversible effects to eyes ; H318:), as Specific Target Organ Toxicants following Repeated Exposure (STOT-RE 2 ; H373), as Presumed human reproductive toxicant, May damage fertility (Repr. 1B; H360F) according to the criteria of Regulation No 1272/2008 (CLP).

1. DNEL for long-term exposure – fertility effects:

1.1 Dermal route

Regarding the self-classification of TFE as Presumed human reproductive toxicant, May damage fertility (Repr. 1B; H360F), qualitative assessment is performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

1.2 Inhalation

The concentration descriptor has been obtained from the repeated dose toxicity study by inhalation considered as a key-study according to the Klimisch scoring (see § 7.5.3).

a) systemic effects - hematological effects

The Lowest Observed Adverse Effect Concentration (LOAEC) is considered to be 51.1 ppm (approximately 213 mg/m3 at 20°C) based on the decrease in the mean corpuscular volume and the decrease in the mean corpuscular hemoglobin in the hematological analysis which were irreversible during the two-week recovery period for the rat group exposed at this dose level.

At the middle level (14.9 ppm corresponding to 62 mg/m3), observed hematological effects were reversible during the 2 -week recovery period. Hence the 62 mg/m3 exposure was considered as the No Observed Adverse Effect concentration (NOAEC) while the No Observed Effect Concentration (NOEC) was assumed to be 5.26 ppm (approximately 22 mg/m3) regarding the absence of effects after 28-day repeated exposure.

 

b) systemic effect - reprotoxic effects

Toxicity to the reproduction as spermatogenesis alteration was observed at the highest concentration (LOEAC) of 51.1 ppm (213 mg/m3). No such effects were observed at mid concentration 14.9 ppm (62 mg/m3) and this concentration was considered as NOEC.

The DNELs were derived for both types of effects in order to determine the lowest DNEL which is protecting from both types of effects (systemic effects and effects on the fertility).

 

The following Tables 1.2 and 1.3 indicate the calculations for the long-term DNELby inhalation for fertility and hematologic effects.


Table 1.2: Calculation of long-term DNEL by inhalation for fertility effects of Trifluoroethanol

Worker

Long-term DNEL / inhalation / fertility (male)

Step a : determination of the critical dose

Key study

Yoshitake 2000 / OECD 412, K1

Relevant dose descriptor

NOEC = 62 mg/m3 based on damages on testis, male rat, inhalation

Step b : Correct starting point – factor for uncertainties

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

-

(not relevant for dose level from inhalation study)

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

-

(same route of exposure rat/human)

Modification for exposure

(experiment in animal and human)

-

(available inhalation data)

Modification for exposure

(experiment in animal and human)

6/8

(different conditions of exposure human/animal)

Modification for the respiratory volume

6.7/10

(respiratory rate difference under standard conditions and under conditions of light activity for 8 hours)

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

31.2 mg/m3

Step c : assessment factors

Interspecies differences

-

not necessary same effects observed in several species

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6

Issues related to dose-response: severity

10

Quality of the whole database

1

Overall assessment factor

300

DNEL calculation

0.10 mg/m3

0.025 ppm*

*DNELppm= 0.10 * 24.05 / 100.06 at 20°C

The long-term DNEL by inhalation for fertility effects is 0.10 mg/m3 in the workercorresponding to 0.025 ppm.


 

 

Table 1.2: Calculation of long-term DNEL by inhalation for hematological effects of Trifluoroethanol

Worker

Long-term DNEL / inhalation / systemic effects (male/female)

Step a : determination of the critical dose

Key study

Yoshitake 2000 / OECD 412, K1

Relevant dose descriptor

NOAEC = 62 mg/m3 based on hematological effects, male rat, inhalation

Step b : Correct starting point – factor for uncertainties

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

-

(not relevant for dose level from inhalation study)

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

-

(same route of exposure rat/human)

Modification for exposure

(experiment in animal and human)

-

(available inhalation data)

Modification for exposure

(experiment in animal and human)

6/8

(different conditions of exposure human/animal)

Modification for the respiratory volume

6.7/10

(respiratory rate difference under standard conditions and under conditions of light activity for 8 hours)

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

31.2 mg/m3

Step c : assessment factors

Interspecies differences

2.5

(remaining differences)

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6

Quality of the whole database

1

Overall assessment factor

75

DNEL calculation

0.42 mg/m3

0.10 ppm*

*DNEL ppm= 0.42 * 24.05 / 100.06 at 20°C

The long-term DNEL by inhalation for systemic effects by inhalation is 0.42 mg/m3 in the workercorresponding to 0.10 ppm.

 

Finally, the lowest obtained DNEL is assumed protecting for both hematological effects and effects on male fertility (damage on the testes) i.e. 0.10 mg/m3 or 0.025 ppm. No short term DNEL calculation is proposed considering that the exposure seems more important than time and is covered by the long term DNEL.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.025 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2 480
Dose descriptor starting point:
NOAEC
Value:
62 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
15.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

- Differences in metabolic rate per b.w. (allometric scaling) : not relevant for dose level from inhalation study

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

- Modification for exposure (experiment in animal and human) : 6/24 (different conditions of exposure human/animal)

=> Corrected starting point = relevant dose descriptor / overall factor for uncertainties = 15.5 mg/m3

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
same effect observed in different species
AF for other interspecies differences:
1
Justification:
same effect observed in different species
AF for intraspecies differences:
10
Justification:
default factor general public
AF for the quality of the whole database:
1
Justification:
several studies showing same effects
AF for remaining uncertainties:
10
Justification:
severity of the effect
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
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:
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:
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:
high hazard (no threshold derived)

Additional information - General Population