Difluoromethane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 035 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7.5

Dose descriptor starting point:

NOAEC

Value:

105 000 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

52 762.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

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).

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

already taken into consideration in the calculation of tle modified descriptor starting point.

AF for interspecies differences (allometric scaling):

2.5

Justification:

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

AF for other interspecies differences:

1

Justification:

no other interspecies differences

AF for intraspecies differences:

3

Justification:

3 was considered to address the intraspecies extrapolation (worker subpopulation). As no effects were observed at the highest tested concentration (50000 ppm v/v) an intraspecies assessment factor of 3 is considered as amply sufficient.

AF for the quality of the whole database:

1

Justification:

good quality of the whole database

AF for remaining uncertainties:

1

Justification:

no uncertainties remaining

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:

no hazard identified

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:

no hazard identified

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.

 

As the substance is a gas, oral and dermal routes of exposure are considered to be irrelevant, therefore no DNELs were derived for these routes.

 

As the substance is not classified for acute toxicity, according to the REACH “Guidance on information requirements and chemical safety assessment” (R.8.4.3.1), no acute / short-term exposure DNELs need to be derived.

 

For long-term exposure, a subchronic (13 weeks) toxicity study with rats is available. No adverse effects were observed at the highest concentration tested (50000 ppm (105000 mg/m³)).

 

As no local effects were observed in long-term exposure studies, no DNEL for local effects was derived.

 

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

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 105000 mg/m^3	The highest concentration tested in the 13 week inhalation study with rats; no adverse effects have been observed.
Step 2) Modification of starting point	6/8       6.7 m^3/10 m^3	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 m^3/10 m^3).
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.
Intraspecies	3	3 was considered to address the intraspecies extrapolation (worker subpopulation). As no effects were observed at the highest tested concentration (50000 ppm v/v) an intraspecies assessment factor of 3 is considered as amply sufficient.
Exposure duration	1	1 was considered to address the exposure duration extrapolation (from subchronic to chronic exposute). HFC-32 showed no adverse effects at the highest tested concentration (50000 ppm v/v) both in subacute and subchronic studies in rats. No dependence on exposure duration is observable. Thus, the assessment factor is not considered necessary.
Dose response	1
Quality of database	1
DNEL	Value
For workers	105000 x 6/8 x 6.7/10 / (2.5 x 3 x 1 x 1 x 1) = 7035 mg/m^3

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

750 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

105 000 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

18 750 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction of exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day) [1].

 

Correction ofdifferent exposure conditions (5 days/week in the subchronic study, 7 days/week of exposure for general population)

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

already taken into consideration in the calculation of the modified dose descriptor starting point

AF for interspecies differences (allometric scaling):

2.5

Justification:

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

AF for other interspecies differences:

1

Justification:

no other interspecies differences

AF for intraspecies differences:

10

Justification:

As the general population includes the elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 10 is proposed in the REACH Guidance (R.8.4.3.1).

AF for the quality of the whole database:

1

Justification:

good quality of the whole database

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

General Population - Hazard via dermal 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

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:

no hazard identified

Additional information - General Population

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.

 

As the substance is a gas, oral and dermal routes of exposure are considered to be irrelevant, therefore no DNELs were derived for these routes.

 

As the substance is not classified for acute toxicity, according to the REACH “Guidance on information requirements and chemical safety assessment” (R.8.4.3.1), no acute / short-term exposure DNELs need to be derived.

 

For long-term exposure, a sub-chronic (13 weeks) toxicity study with rats is available. No adverse effects were observed at the highest concentration tested (50000 ppm (105000 mg/m³)).

 

As no local effects were observed in long-term exposure studies, no DNEL for local effects was derived.

 

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

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 105000 mg/m^3	The highest concentration tested in the 90-d inhalation study with rats; no adverse effects have been observed.
Step 2) Modification of starting point	6/24 5/7	Correction of exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day)[1]. Correction of different exposure conditions (5 days/week in the subchronic study, 7 days/week of exposure for general population)
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.
Intraspecies	10	As the general population includes the elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 10 is proposed in the REACH Guidance (R.8.4.3.1).
Exposure duration	1	1 was considered to address the exposure duration extrapolation (from subchronic to chronic exposure). HFC-32 showed no adverse effects at the highest tested concentration (50000 ppm v/v) both in subacute and subchronic studies in rats. No dependence on exposure duration is observable. Thus the assessment factor is not considered necessary.
Dose response	1
Quality of database	1
DNEL	Value
For general population	105000 x 6/24 x 5/7 / (2.5 x 10 x 1 x 1 x 1) =750 mg/m^3

 

[1]Exposure duration for humans indirect exposed via the environment is assumed 24 hours per day, for consumers the exposure duration is assumed 1-24 hours per day (depending on the exposure scenario).