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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 902 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to Derive DNELs (2010)
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
DNEL value:
11 708 mg/m³
Explanation for the modification of the dose descriptor starting point:
Within the route to route extrapolation we have taken into account the following corrections: (1) a correction for the exposure duration of the study (6hr/day, 5days/week) to default worker exposure (8hr/day, 5 days/week) and (2) a correction for activity driven differences in respiratory volumes in active workers in comparison to workers in rest (6.7 m3/10 m3). This results in the following: 23300 (original NOAEC from the 13-week rep dose study) * 6/8 * 6.7/10 = 11705 mg/m3.
AF for dose response relationship:
1
Justification:
The relevant and available studies are a 2-wk, 4-wk and 13-wk repeated dose toxicity study and a 2-generation reproductive toxicity study. These have respective NOECs of 5000, 10000, 5000 and 5000 ppm. For the DNEL derivation, the lowest NOEC was used and therefore no additional assessment factor is deemed necessary.
AF for differences in duration of exposure:
1
Justification:
HFO-1234ze will be poorly absorbed, undergoes minimal metabolism, and is rapidly cleared from the body. It will not bioaccumulate. The severity and incidence of effects related to the heart noted in the repeated dose toxicity studies did not increase with increasing exposure duration (based on results from 2-wk, 4-wk, 13-wk and a 2-generation reprotoxicity study). The NOECs in the respective studies were 5000, 10000, 5000 and 5000 ppm. As the 5000 ppm is used as start value for the DNEL derivation, it is considered appropriate to use an assessment factor of 1 in relation to the exposure duration.
AF for other interspecies differences:
1
Justification:
No interspecies factor is applied as the metabolic rate has been shown to be lower in man than in rat. This is further supported by the fact that the determined blood/air partition coefficient in humans is approximately half of the blood/air partition coefficient in rats. The results presented in the pharmacokinetic modeling approach also indicate that considerably higher exposure is required in humans to reach animal dosimetrics.
AF for intraspecies differences:
3
Justification:
HFO-1234ze can be considered as poorly absorbed, and should show minimal differences in toxicological properties between species. An assessment factor of 3 is considered by ECETOC in their draft "Guidance on Assessment Factors to derive DNELs" sufficient to account for intraspecies differences in the worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the studies is high (all K1), and the most sensitive species was used to determine toxicity.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown (no further information necessary)

Additional information - workers

The DNEL for workers was derived in accordance to the ECETOC Guidance on Assessment Factors to Derive DNELs (2010).

In view of the toxicological and physicochemical properties of HFO-1234ze, the dermal exposure was considered as not relevant for workers and DNEL derivation was limited to the exposure by inhalation. In view of the absence of acute toxicity far beyond the threshold criteria for classification, the derivation of an acute DNEL is not deemed as necessary. As no indication of local effects was observed for HFO-1234ze, the long term exposure DNEL was derived for systemic effects only.

The DNEL for long-term exposure - systemic effects for workers is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

1 ppm = 4.66 mg/m3

NOAEC:23300 mg/m3(5000 ppm)

NOAEL 13 wk study – cardiac effects

Step 2) Modification of starting point

6/8

 

 

6.7 m3/10 m3

Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week);

 Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

1

No interspecies factor is applied as the metabolic rate has been shown to be lower in man than in rat. This is further supported by the fact that the determined blood/air partition coefficient in humans is approximately half of the blood/air partition coefficient in rats. The results presented in the pharmacokinetic modeling approach also indicate that considerably higher exposure is required in humans to reach animal dosimetrics.

Intraspecies

3

HF1234ze can be considered as poorly adsorbed, and should show minimal differences in toxicological properties. An assessment factor of 3 is considered by ECETOC in their draft “Guidance on Assessment Factors to derive DNELs” sufficient to account for the intraspecies differences in the worker population

Exposure duration

1

HFO-1234ze will be poorly adsorbed, undergoes minimal metabolism, and is rapidly cleared form the body.  It will not bioaccumulate.  The severity and incidence of effects related to the heart noted in the repeated dose toxicity studies did not increase with increasing exposure time (based on the results of a 2 -wk, 4 -wk, 13 -wk and 2 -generation reproductive toxicity study). The NOECs in the respective studies were 5000, 10000, 5000 and 5000 ppm. As the 5000 ppm is used as start value for the DNEL derivation it considered appropriate to use an assessment factor of 1 in relation to the exposure duration.

Dose response

1

The relevant and available studies are a 2-wk, 4-wk and 13-wk repeated dose toxicity study and a 2-generation reproductive toxicity study. These have respective NOECs of 5000, 10000, 5000 and 5000 ppm. For the DNEL derivation, the lowest NOEC was used and therefore no additional assessment factor is deemed necessary. 

Quality of database

1

The quality of the studies is high (all K1), and the most sensitive species was used to determine toxicity. 

DNEL

Value

For workers

23300 x 6/8 x 6.7/10 / (1 x 3 x1x 1 x 1) =3902 mg/m3(837 ppm)

The derived worker DNEL of 837 ppm is very similar to the WEEL (Workplace Environmental Exposure Level) of 800 ppm set by the American Industrial Health Association (2011). The WEEL committee has been reviewing and setting exposure levels for fluorocarbons for many years. The WEEL Committee is composed of volunteers from industry, academia, government, and health/safety/environmental consultant organizations who provide a high level of education, professional certification, and experience in their respective disciplines.

As no local effects were observed in any of the available studies, no clinical effects or mortality was observed even with acute 4 hour exposures of 200,000 ppm (20%), no DNELs need to be derived for these effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
830 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to Derive DNELs (2010)
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
4 161 mg/m³
Explanation for the modification of the dose descriptor starting point:
Within the route to route extrapolation we have taken into account the following correction: a correction for the exposure duration of the study (6hr/day, 5days/week) to default worker exposure (24hr/day, 7 days/week)
AF for dose response relationship:
1
Justification:
The relevant and available studies are a 2-wk, 4-wk and 13-wk repeated dose toxicity study and a 2-generation reproductive toxicity study. These have respective NOECs of 5000, 10000, 5000 and 5000 ppm. For the DNEL derivation, the lowest NOEC was used and therefore no additional assessment factor is deemed necessary.
AF for differences in duration of exposure:
1
Justification:
HFO-1234ze will be poorly absorbed, undergoes minimal metabolism, and is rapidly cleared from the body. It will not bioaccumulate. The severity and incidence of effects related to the heart noted in the repeated dose toxicity studies did not increase with increasing exposure duration (based on results from 2-wk, 4-wk, 13-wk and a 2-generation reprotoxicity study). The NOECs in the respective studies were 5000, 10000, 5000 and 5000 ppm. As the 5000 ppm is used as start value for the DNEL derivation, it is considered appropriate to use an assessment factor of 1 in relation to the exposure duration.
AF for other interspecies differences:
1
Justification:
No interspecies factor is applied as the metabolic rate has been shown to be lower in man than in rat. This is further supported by the fact that the determined blood/air partition coefficient in humans is approximately half of the blood/air partition coefficient in rats. The results presented in the pharmacokinetic modeling approach also indicate that considerably higher exposure is required in humans to reach animal dosimetrics.
AF for intraspecies differences:
5
Justification:
HFO-1234ze can be considered as poorly absorbed, and should show minimal differences in toxicological properties between species. An assessment factor of 3 is considered by ECETOC in thier draft "Guidance on Assessment Factors to derive DNELs" sufficient to account for intraspecies differences in the worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the studies is high (all K1), and the most sensitive species was used to determine toxicity.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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 (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown (no further information necessary)

Additional information - General Population

The DNEL for consumers was derived in accordance to the ECETOC Guidance on Assessment Factors to Derive DNELs (2010).

In view of the toxicological and physicochemical properties of HFO-1234ze, the dermal exposure was considered as not relevant for consumers and DNEL derivation was limited to the exposure by inhalation. In view of the absence of acute toxicity far beyond the threshold criteria for classification, the derivation of an acute DNEL is not deemed as necessary. As no indication of local effects was observed for HFO-1234ze, the long term exposure DNEL was derived for systemic effects only.

The DNEL for long-term exposure - systemic effects for consumers is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC:23300 mg/m3(5000 ppm)

NOAEL 13 wk study – cardiac effects

Step 2) Modification of starting point

6/24

5/7

 

 

 

Correction of exposure duration in study (6 hrs/day, 5 days/week) to default consumer exposure (24 hrs/day, 7 days/week);

 

Step 3) Assessment factors

 

 

Interspecies

1

No interspecies factor is applied as the metabolic rate has been shown to be lower in man than in rat. This is further supported by the fact that the determined blood/air partition coefficient in humans is approximately half of the blood/air partition coefficient in rats. The results presented in the pharmacokinetic modeling approach also indicate that considerably higher exposure is required in humans to reach animal dosimetrics.

Intraspecies

5

HF1234ze can be considered as poorly adsorbed, and should show minimal differences in toxicological properties. An assessment factor of 5 is considered by ECETOC in their draft “Guidance on Assessment Factors to derive DNELs” sufficient to account for the intraspecies differences in the consumer population

Exposure duration

1

HFO-1234ze will be poorly absorbed, undergoes minimal metabolism, and is rapidly cleared from the body. It will not bioaccumulate. The severity and incidence of effects related to the heart noted in the repeated dose toxicity studies did not increase with increasing exposure duration (based on results from 2-wk, 4-wk, 13-wk and a 2-generation reprotoxicity study). The NOECs in the respective studies were 5000, 10000, 5000 and 5000 ppm. As the 5000 ppm is used as start value for the DNEL derivation, it is considered appropriate to use an assessment factor of 1 in relation to the exposure duration.

Dose response

1

The relevant and available studies are a 2-wk, 4-wk and 13-wk repeated dose toxicity study and a 2-generation reproductive toxicity study. These have respective NOECs of 5000, 10000, 5000 and 5000 ppm. For the DNEL derivation, the lowest NOEC was used and therefore no additional assessment factor is deemed necessary. 

Quality of database

1

 The quality of the studies is high (all K1), and the most sensitive species was used to determine toxicity.

DNEL

Value

For consumers

23300 x 6/24 x 5/7/ (1 x 5 x1x 1 x 1) = 830 mg/m3(180 ppm)

 

As no local effects were observed in any of the available studies, no clinical effects or mortality was observed even with acute 4 hour exposures of 200,000 ppm (20%), no DNELs need to be derived for these effects.