4,4'-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]diphenol; bisphenol AF

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.118 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):

75

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

8.82 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC = 1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [10 mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [1/2] X [6.7 m3/10m3].

Thus, the corrected dose descriptor for inhalation is 8.82 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

0.033 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):

300

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

medium hazard (no threshold derived)

Additional information - workers

NOAEL (systemic toxicity) = 10 mg/kg bw/day; OECD 407; Umano (2012)

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 407 under GLP (Umano 2012).  The substance was administered to 30 male and 30 female Sprague-Dawley rats by oral gavage at dose levels of 10, 30 and 100 mg/kg bw/day for up to 28 consecutive days.  Although there was no recovery phase, this is not a guideline requirement.  The key findings in this study were lower body weight gain at 100 mg/kg/day for males and at 30 and 100 mg/kg/day for females; lower white cell counts in males at 100 mg/kg/day; lower cholesterol levels in both sexes at 100 mg/kg/day; lower cholinesterase and higher bilirubin levels in females at 100 mg/kg/day; longer oestrous cycles in females at 100 mg/kg/day; lower absolute and relative prostate and seminal vesicles weights at 100 mg/kg/day, possibly reflecting the lower body weight; higher adrenal weight in males at 100 mg/kg/day; Leydig cell atrophy at 100 mg/kg/day in 5/10 males; hypertrophy of the adrenal zona fasciculata at 100 mg/kg/day in 8/10 males, 2/10 females; atrophy of mammary glands in 3/10 males at 100 mg/kg/day; decreased haematopoiesis in bone marrow and extramedullary haematopoiesis in spleen at 100 mg/kg/day in 4/10 and 2/10 males, respectively.  Many findings were related to endocrine effects, but had not considered that some may have been secondary to the lower body weights.  Without having the individual data, it is not possible to comment further.  In conclusion, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was 10 mg/kg bw/day due to findings of reduced body weight gain and abnormal estrous cycles in the female rat treated at 30 mg/kg bw/day.

The hazard conclusion for reproductive and developmental toxicology were as follows (OECD 422, Anon., 2011):

NOAEL(fertility) = <30 mg/kg bw/day

NOAEL(development) = No hazard identified

Whilst these endpoints resulted in a classification of category 1B reproductive toxicant, the lower NOAEL of 10 mg/kg bw/day from the repeated dose toxicity study was used for long-term systemic hazard assessment, in accordance with the precautionary principle.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.029 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):

150

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator NOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [10 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2].

Thus, the corrected dose descriptor for inhalation is 0.0290 mg/m3 for the general population.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

In accordance with Annex VIII, Section 8.5.2, Column 2 of REACH, testing by the inhalation route was waived due to low vapour pressure and a use pattern resulting in exposure to humans being considered negligible.  No acute toxicity hazard (leading to classification & labelling) has been identified for the substance following oral and dermal exposure.  No acute inhalation hazard is therefore identified for this substance.

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:

0.017 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):

600

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

0.017 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):

600

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

NOAEL (systemic toxicity) = 10 mg/kg bw/day; OECD 407; Umano (2012)

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 407 under GLP (Umano 2012).  The substance was administered to 30 male and 30 female Sprague-Dawley rats by oral gavage at dose levels of 10, 30 and 100 mg/kg bw/day for up to 28 consecutive days.  Although there was no recovery phase, this is not a guideline requirement.  The key findings in this study were lower body weight gain at 100 mg/kg/day for males and at 30 and 100 mg/kg/day for females; lower white cell counts in males at 100 mg/kg/day; lower cholesterol levels in both sexes at 100 mg/kg/day; lower cholinesterase and higher bilirubin levels in females at 100 mg/kg/day; longer oestrous cycles in females at 100 mg/kg/day; lower absolute and relative prostate and seminal vesicles weights at 100 mg/kg/day, possibly reflecting the lower body weight; higher adrenal weight in males at 100 mg/kg/day; Leydig cell atrophy at 100 mg/kg/day in 5/10 males; hypertrophy of the adrenal zona fasciculata at 100 mg/kg/day in 8/10 males, 2/10 females; atrophy of mammary glands in 3/10 males at 100 mg/kg/day; decreased haematopoiesis in bone marrow and extramedullary haematopoiesis in spleen at 100 mg/kg/day in 4/10 and 2/10 males, respectively.  Many findings were related to endocrine effects, but had not considered that some may have been secondary to the lower body weights.  Without having the individual data, it is not possible to comment further.  In conclusion, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was 10 mg/kg bw/day due to findings of reduced body weight gain and abnormal estrous cycles in the female rat treated at 30 mg/kg bw/day.

The hazard conclusion for reproductive and developmental toxicology were as follows (OECD 422, Anon., 2011):

NOAEL(fertility) = <30 mg/kg bw/day

NOAEL(development) = No hazard identified

Whilst these endpoints resulted in a classification of category 1B reproductive toxicant, the lower NOAEL of 10 mg/kg bw/day from the repeated dose toxicity study was used for long-term systemic hazard assessment, in accordance with the precautionary principle.