2,2,2-trifluoroethanol

Toxicological Summary

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/m^3based 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/m^3
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/m^3
	0.025 ppm*

*DNEL_ppm= 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/m^3based 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/m^3
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/m^3
	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:

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:

high hazard (no threshold derived)