Ammonium difluoro[1,1,2,2-tetrafluoro-2-(pentafluoroethoxy)ethoxy]acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.49 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

9

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.14 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

36

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. In the present case, DNELs have been derived according to the ECETOC guidance (ECETOC, Technical Report No. 110, 2010).

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No toxicokinetic studies investigating oral, dermal and inhalation absorption are available.

Acute toxicity

EEA-NH4 is classified for acute toxicity as Harmful if swallowed (Xn, R22 or Acute oral toxicity Cat. 4 - H302). Therefore a DNEL for acute toxicity needs to be derived in case peak exposures occur. However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure peaks (in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure via the oral route therefore does not occur for EEA-NH4. Thus no DNEL has been derived for the oral route of exposure.

EEA-NH4 is not classified for acute systemic dermal or acute inhalation toxicity. Therefore no dermal or inhalation DNEL_acutefor systemic effectshave been derived.

EEA-NH4 causes serious damage to the eyes (Xi, R41 or Eye Damage 1, H318); however, it is not possible to derive a DNEL on the basis of the available data. It is necessary to stipulate risk management measures that prevent the occurrence of eye damage (see chapter 9 and 10 of the CSR). The substance is not irritating and sensitising to skin.

Repeated dose toxicity

A 28-day repeated dose oral toxicity study and an oral reproduction/developmental toxicity screening study were available for assessment. Effects noted in the 28-day study were increased absolute and relative kidney weights from 25 mg/kg bw/day group and higher. Therefore a NOAEL of 5 mg/kg bw/day was derived.

 

In the reproduction/developmental screening study a neonatal NOAEL of 5 mg/kg bw/day was determined based on lower live litter size and clinical findings at 100 mg/kg bw/day and on reduced postnatal survival and lower mean male and female pup body weights in the 25 and 100 mg/kg bw/day groups. The highest tested dose level of 100 mg/kg bw/day was considered to be the NOAEL for effects on fertility due to the lack of effects on reproductive parameters in this study.The NOAEL for systemic toxicity was 5 mg/kg bw/day based on lower mean body weights, body weight gains and food consumption (significantly affected) during lactation days 1-4 in the 100 mg/kg bw/day group females and higher absolute and relative liver weights in the 25 and 100 mg/kg bw/day group males.

DNELs have been derived using both the NOAEL of 5 mg/kg bw/day from the 28-day repeated dose oral toxicity study and the neonatal NOAEL of 5 mg/kg bw/day from the reproduction/developmental screening study. The systemic NOAEL of 5 mg/kg bw/day observed in the reproduction/developmental screening study is not used for DNEL derivation as the neonatal NOAEL results in a lower DNEL (due to a correction for reduced group size, see Tables) and as the figure is similar to the NOAEL from the 28-day repeated dose oral toxicity study resulting in a similar DNEL.

EEA-NH4 is assessed as being non-mutagenic, therefore no DNEL has been derived for this endpoint.

Worker DNELs

 

Long-term – inhalation, systemic effects (based on 28-day oral (gavage) study in rats)

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5.0 mg/kg bw/day	Based on the increased absolute and relative kidney weights.
Step 2) Modification of starting point	2         0.38 m^3/kg bw           6.7 m^3/10 m^3	In case of oral to inhalation route to route extrapolation, in the absence of route-specific information on both routes, a default factor of 2 is applied.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	5.0 x 6.7 / 2 / 0.38 / 10 = 4.4 mg/m^3
Step 3) Assessment factors
Interspecies	1	No assessment factor for allometric scaling needs to be applied in case of oral to inhalation route-to-route extrapolation
Intraspecies	3	Default assessment factor for workers
Exposure duration	3	Since the material is soluble in water (516 mg/L) and is unlikely to accumulate (Log Kow = 1.18) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et al. (2006), Regul Toxicol Pharmacol 46, 202-210)). Combination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.   Note: this factor is based on data from scientific literature not specifically mentioned in the ECETOC documentation.
Dose response	1
Quality of database	1
DNEL	Value
	4.4 / (1 x 3 x 3 x 1 x 1) =0.49 mg/m^3

 

 

Long-term – dermal, systemic effects (based on 28-day oral (gavage) study in rats)

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5.0 mg/kg bw/day	Based on the increased absolute and relative kidney weights.
Step 2) Modification of starting point	1	On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation (see REACH Guidance on information requirements and chemical safety assessment (Chapter R.8.4.2)).
Modified dose-descriptor	5.0 x 1 = 5.0 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling for rat
Intraspecies	3	Default assessment factor for workers
Exposure duration	3	Since the material is soluble in water (516 mg/L) and is unlikely to accumulate (Log Kow = 1.18) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et al. (2006), Regul Toxicol Pharmacol 46, 202-210)). Combination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.   Note: this factor is based on data from scientific literature not specifically mentioned in the ECETOC documentation.
Dose response	1
Quality of database	1
DNEL	Value
	5.0 / (4 x 3 x 3 x 1 x 1) =0.14 mg/kg bw/day

 

 

Long-term – inhalation, systemic effects (based on reproduction/developmental screening study in rats)

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5.0 mg/kg bw/day	Based on live litter size, clinical findings, reduced postnatal survival and lower mean male and female pup body weights.
Step 2) Modification of starting point	2         0.38 m^3/kg bw           6.7 m^3/10 m^3	In case of oral to inhalation route to route extrapolation, in the absence of route-specific information on both routes, a default factor of 2 is applied.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	5.0 x 6.7 / 1 / 0.38 / 10 = 8.8 mg/m^3
Step 3) Assessment factors
Interspecies	1	No assessment factor for allometric scaling needs to be applied in case of oral to inhalation route-to-route extrapolation
Intraspecies	3	Default assessment factor for workers
Exposure duration	1	No assessment factor for exposure duration is needed
Dose response	1
Quality of database	1
Reduced group size	1.4	Assessment factor to correct for differences in group size compared to an OECD guideline 416 study.
DNEL	Value
	8.8 / (1 x 3 x 1 x 1 x 1 x 1.4) =2.1 mg/m^3

 

 

Long-term – dermal, systemic effects (based on reproduction/developmental screening study in rats)

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5.0 mg/kg bw/day	Based on live litter size, clinical findings, reduced postnatal survival and lower mean male and female pup body weights.
Step 2) Modification of starting point	1	On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation (see REACH Guidance on information requirements and chemical safety assessment (Chapter R.8.4.2)).
Modified dose-descriptor	5.0 x 1 = 5.0 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling for rat
Intraspecies	3	Default assessment factor for workers
Exposure duration	1	No assessment factor for exposure duration is needed
Dose response	1
Quality of database	1
Reduced group size	1.4	Assessment factor to correct for differences in group size compared to an OECD guideline 416 study.
DNEL	Value
	5.0 / (4 x 3 x 1 x 1 x 1 x 1.4) =0.30 mg/kg bw/day

 

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

EEA-NH4 will not be placed on the market, therefore DN(M)ELs for the general population have not been determined.