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:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.67 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
75
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

1.     Introduction:

In this dossier, all the toxicological information on Trifluoroacetic acid (TFA) are examined and analyzed in order to define a DNEL (s)/DMEL (s) for each human health endpoints if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008).

2.     Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008)

Trifluoroacetic acid is classified as Skin Corr. 1A (H314, Cause severe skin burns and eye damage) and as Acute Tox. 4 (H332, Harmful if inhaled) according to the CLP regulation (1272/2008 ATP1). Based on the above data no additional self-classification is proposed.

3.     DNELs derivation according to the toxicological profile of TFA

According to the physico-chemical and toxicological properties, TFA will induce local effect by all routes of exposure before systemic effects are expected. As determined in the acute toxicity study by inhalation, only local effects were observed (see below § 3.1.2). Hence, extrapolation of the DNEL for systemic effects is not useful to protect human health. In fact, DNEL for local effects is protecting from both local effects and systemic effects as this DNEL is likely to be lower than the DNEL for systemic effect. Moreover, route to route extrapolation cannot be used for the DNEL calculation considering local effects.

3.1      DNEL for acute exposure - local effects

3.1.1      Dermal route

The pH of a trifluoroacetic acid aqueous solution at 10% (w/w) is 0.45 and the measure of the alkali reserve is 35 g NaOH/g substance. Following the pH-acid/alkali reserve method, the classification as corrosive is predicted for TFA. Hence, in accordance with column 2 of REACH Annex VIII, the in vivo skin irritation study (required in section 8.1.1) and the in vivo eye irritation study (required in section 8.2.1) do not need to be conducted as the substance is a strong acid (pH = 0.45; see § 4.20).

In the absence of irritation study, it is impossible to derive a threshold for the local effects and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

3.1.2      Inhalation route

The concentration descriptor has been obtained from the acute toxicity study by inhalation conducted according to an adapted OECD 403 study plan (see § 7.2.2). The purpose of this acute inhalation study was indeed focalized on the determination of the irritant potential of TFA on the upper respiratory tract in rat rather than the determination of the LC50 parameter.

After 4h inhalation exposure to vapors of TFA, the microscopic examination revealed treatment-related histopathological changes at the second and third levels of the rat nasal cavity within the day following the end of exposure. The histopathological lesions consisted of very slight focal degeneration of the respiratory epithelium lining the dorsal part of the septum.This observed effect was considered as the consequence of irritating local effects of the TFA vapours andwas only observed at the highest tested concentration (300 mg/m3) in 4/5 animals for the second level of the nasal cavity and in 1/5 animal for the third level. Furthermore, this effect was reversible as there was no irritation of the nasal cavity (all levels considered) in the animals necropsied 14 days after treatment. Therefore, considering both the kind of effects and their reversibility, the highest concentration is considered as a NOAEC based on the local irritation observed effects.

Hence, the dose descriptor (see above: NOAEC) is not modified for the 15-minute human occupational exposure and the NOAEC of 300 mg/m3 (nominal concentration considered as a worst-case) is considered.

TFA is corrosive based on the pH (pH=0.45, see §4.20) and the alkali reserve (35 g NaOH/100g substance). Therefore, considering the strong corrosive properties of TFA, it is scientifically unjustified to perform a repeated dose toxicity by inhalation at concentrations recommended by the guidelines, i.e. the limits of concentration leading to classification for target organs. In fact, strong corrosive effects would be observed at these concentrations.

Therefore, an extended acute toxicity study by inhalation has been performed including three concentrations of exposure for NOAEC determination and relevant additional examinations including broncho-alveolar lavage analysis and upper respiratory tract histopathology. Considering that the local effects (irritation inducing destruction of membrane) are mainly driven by concentration rather than by time of exposure, it is assumed that a long-term DNEL for local effects could be derived from the acute DNEL for local effects derived from the acute toxicity study by inhalation, applying a worst-case assessment factor of 6. Moreover, the long-term DNEL for local effects would be protecting from the potential systemic effects since the local effects would be likely observed at lower concentrations taking into account the effects observed in the overall toxicity studies listed in this dossier.

The following Table 3.1.2/1 indicates the acute DNEL by inhalation for local effects calculation.

Table 3.1.2/1:Calculation of acute DNEL by inhalation for local effects for Trifluoroacetic acid

Worker

Acute DNEL / inhalation / Local effects

Step a : determination of the critical dose

Key study

Muijser, 2010 / OECD 403, Kr. 2

Relevant dose descriptor

NOAEC = 300 mg/m3(nominal concentration considered as a worst-case)

Step b : Correct starting point – factor for uncertainties

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)

-

(adverse effects mainly driven by exposure concentration)

Modification for the respiratory volume

0.210 / 0.315

(respiratory rate difference under standard conditions and under conditions of light activity for 15 minutes)

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

200 mg/m3

Step c : assessment factors

Interspecies differences

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

-      Remaining differences (toxicokinetics and toxicodynamics) 

 

-

(local effects)

 2.5

(remaining differences)

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

-

Issues related to dose-response

1

Quality of the whole database

1

Overall assessment factor

12.5

DNEL calculation

16 mg/m3

3.37 ppm*

*DNEL (ppm) = 16 * 24.05 / 114.03 at 20°C

The acute DNEL by inhalation for local effects by inhalation is 16 mg/m3in the worker corresponding to 3.37 ppm.

3.2      DNEL for long-term exposure - local effects

3.2.1      Dermal route

Regarding both the corrosive properties to Trifluoroacetic acid and the absence of irritation study, it is impossible to derive a threshold for the local effects and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

3.2.2      Inhalation route

According to the physico-chemical and toxicological properties, trifluoroacetic acid will induce local effect by all routes of exposure before systemic effects are expected. As determined in the acute toxicity study by inhalation, only local effects were observed. Hence, extrapolation of the DNEL for systemic effects is not useful to protect human health. In fact, DNEL for local effects is protecting from both for local effects and systemic effects as this DNEL is likely to be lower than the DNEL for systemic effect. Therefore, route to route extrapolation cannot be used for the DNEL calculation considering local effects.

The long-term DNEL inhalation exposure for local effects cannot be derived from repeated dose toxicity study by inhalation since this study is not available. As the acute DNEL for inhalation was not based on the lethality data involving too large uncertainties but was derived from NOAEC for reversible local effects on the respiratory tract, the long-term inhalation DNEL for local effects can be extrapolated from the acute inhalation DNEL for local effects (16 mg/m3) by dividing by a worst-case factor of 6 (subacute to chronic duration extrapolation) although the observed adverse effects are mainly driven by the exposure concentration to Trifluoroacetic acid (see above explanation).

Hence, the long-term DNEL for local effects by inhalation is 2.67 mg/m3 for the workers corresponding to 0.56 ppm.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.042 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):
200
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
Not required, starting point is NOAEC
AF for differences in duration of exposure:
2
Justification:
Extrapolation from sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation rat to human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
Not required
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

1.     Introduction

In this dossier, all the toxicological information on Trifluoroacetic acid (TFA) is re-examined and analyzed in order to define a DNEL (s)/DMEL (s) for each human health endpoint if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008).

2.     Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008)

 Trifluoroacetic acid is classified as Skin Corr. 1A (H314, Cause severe skin burns and eye damage) and as Acute Tox. 4 (H332, Harmful if inhaled) according to the CLP regulation (1272/2008 ATP1).

3.     DNELs derivation according to the toxicological profile of TFA

According to the physico-chemical and toxicological properties, TFA will induce local effect by all routes of exposure before systemic effects are expected. However, considering the low concentration exposure via the environment, local effects are very unlikely to occur. Therefore, only DNELs for systemic effects are considered. Moreover, as acute exposure is not relevant for the general population, only long-term DNEL for systemic effects are considered below.

3.1      DNEL for long-term toxicity - systemic effects:

3.1.1      Dermal route:

It is assumed that the general population is not exposed to TFA via the dermal route.

3.1.2      Inhalation route:

It is assumed that the general population is not exposed to TFA vapours at ambient temperature. 

3.1.3      Oral route:

The concentration descriptor has been obtained from a GLP compliant sub-chronic toxicity study according to OECD TG 408. In this study the neutral salt sodium trifluoroacetate was administered to male and female rats at 160, 1600 and 16000 ppm via dietary administration. Based on the observed effects (increase in liver weight, histopathological changes in the liver and changes in haematological parameters, clinical biochemistry and urinalysis), the NOAEL was set at 160 ppm in both sexes (equating approximately to 8.4 mg TFA/kg body weight/day in males and 10.1 mg TFA/kg body weight/day in females). The lowest NOAEL from the 90 -day study is taken forward for DNEL derivation.

Table: Calculation of long-term DNEL by oral route for systemic effects of Trifluoroacetic acid

General population

Long-term DNEL / oral / Systemic effects

Step a : determination of the critical dose

Key study

Bayer, 2007 / rel. 1 (key study)

Relevant dose descriptor

NOAEL = 8.4 mg/kg bw

Step b : Correct starting point – factor for uncertainties

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)

-

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

8.4 mg/kg bw

Step c : assessment factors

Interspecies differences

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

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 4

 

 

2.5

(remaining differences)

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(subacute to chronic)

Issues related to dose-response

1 (NOAEL)

Quality of the whole database

1

Overall assessment factor

200

DNEL calculation

0.042 mg/kg bw/d

 

Hence, the long-term DNEL for systemic effects by oral route is 0.042 mg/kg bw/d for the general population.