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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
72.4 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):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1 800 mg/m³
AF for dose response relationship:
1
Justification:
NOAEC used
AF for differences in duration of exposure:
1
Justification:
Chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Inhalation - no Allometric scaling required
AF for other interspecies differences:
2.5
Justification:
Toxicodynamics - Remaining Differences
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
96 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1 800 mg/m³
AF for dose response relationship:
1
Justification:
NOAEC identified
AF for interspecies differences (allometric scaling):
1
Justification:
inhalation - no allometric scaling required
AF for other interspecies differences:
2.5
Justification:
Remaining Differences - ECHA Guidance
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
150 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
300 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.6 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
100% absorption is assumed for both oral and dermal
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat study
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
5
Justification:
workers
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

DNELs for workers have been derived according to the following paradigm.Worker

A. Inhalation Route

 1. Inhalation Route, Systemic Effect (effect(s) somewhere other than lung)

 a) Long-term DNEL for workers, inhalation route, systemic effects:72.4 mg/m3

Dose descriptor: NOAEL 600 ppm (1800 mg/m3)

Basis for dose descriptor: NTP study with 14 week and 2 year exposures in rats and mice. The critical effects were observed in the two year mouse study. Animals were exposed to 0, 200, 600 and 1800 ppm. 

Rationale for selection of dose descriptor:  In the 2 year mouse study, the critical effects observed were significant reduction in survival in male mice, as well as significant urogenital non-neoplastic lesions in the kidney, bladder and prostate. In females, a significant increase in hepatocellular adenomas and carcinomas was seen at 1800 ppm. 

Modification factor: Time scaling is required to adjust for 6h/d exposure to 8h/d working condition. Exposures were for 5 days a week so no adjustment is needed.  In addition, worker ventilation rate needs to be accounted for.

1800 mg/m3* (6h/d / 8 h/d) * (6.7m3/10m3) = 905 mg/m3 

Assessment Factors     AF   Explanation

     Intraspecies:            5      ECHA Guidance value for workers

     Interspecies:            2.5   Inhalation – no allometric scaling required

     Duration:                 1      no adjustment – chronic study

     Total:                    12.5   (5)(2.5)(1) = 12.5

Calculation of DNEL: (905 mg/m3) / 12.5 =72.4 mg/m3

 

b) Acute DNEL for workers, inhalation route, systemic effects:241 mg/m3

Dose descriptor: NOAEL 600 ppm (1800 mg/m3)

Basis for dose descriptor: 14 week inhalation study with mice (NTP 1998). Animals were exposed to 0, 66, 200, 600, 1800 and 5000 ppm. 

Rationale for selection of dose descriptor:  Male and female mice exposed to 1,800 or 5,000 ppm THF vapour were observed to be in a state of narcosis (described as stupor) during exposure periods.

Modification factor: No time scaling required because effect is concentration driven. Exposures were for 5 days a week. In addition, worker ventilation rate needs to be accounted for. 

1800 mg/m3* 6.7m3/10m3= 1206 mg/m3

Assessment Factors     AF   Explanation

     Intraspecies:            5      ECHA Guidance value for workers

     Interspecies:            1      Concentration Driven, inhalation – no Allometric scaling required

     Duration:                 1      no adjustment required – long term exposure

     Total:                      5      (5)(1)(1) = 5

Calculation of DNEL: (1206 mg/m3) / 5 =241 mg/m3

 

2. Inhalation Route, Local Effect

 

a) Long-term DNEL for workers, inhalation route, local effects:

No evidence of local effects were observed following long term inhalation of THF in mice or rats following exposures for 2 years. However an IOEL value exists and to aid in risk assessment, the value has been adopted; 150 mg/m3

 

b) Acute DNEL for workers, inhalation route, local effects

No local effects were reported in the repeated dose NTP studies. However an IOEL value exists and to aid in risk assessment, the value has been adopted; 300 mg/m3

  

B. Dermal Route

 1. Dermal Route, Systemic Effect (effect(s) somewhere other than skin)

a)     Long-term DNEL for workers, dermal route, systemic effects:8.4 mg/kg

Dose descriptor: NOAEL 300 mg/kg body weight

Basis for dose descriptor: 2-generation drinking water study in Wistar rats with THF (BASF 1996). Aimals were exposed continuously to the test material at concentrations of 0, 1000, 3000, or 9000 ppm.   

Rationale for selection of dose descriptor:  Signs of general toxicity in parental animals as adverse effects on food and water consumption and on body weight gains. Progeny of high-dose parents displayed impaired body weight/body weight gains and delays in physiological development of the F2 offspring. 

Modification factor: It is necessary to adjust from 7 days per week to 5 days per week to account for exposure differences. In addition scaling from 24 hour exposure to 8 hour exposure for workers is appropriate. 100% absorption is assumed for oral and dermal expsorue

300 mg/kg * 7d/w / 5 d/wk * 24h/d / 8 h/d = 1260 mg/kg

Assessment Factors     AF   Explanation

     Intraspecies:            5      ECHA Guidance value

     Interspecies:            10    Allometric Scaling (4) & Remaining Difference (2.5)

     Duration:                 3      subchronic to chronic

     Total:                      150  (5)(10)(3) = 150

Calculation of DNEL: (1260 mg/kg) / 150 =8.4 mg/kg

 

b)    Acute DNEL for workers, dermal route, systemic effects

A value cannot be calculated due to the lack of a dose-response curve. It is expected that the value derived from long-term exposure will be protective.

  

2. Dermal Route, Local (skin) Effect

a)     Long-term DNEL for workers, dermal route, local effects:There are no repeated dose studies with dermal administration of the test product. Therefore no DNEL for long term dermal effects shall be derived.

 

b)    Acute DNEL for workers, dermal route, local effects:Acute dermal toxicity is observed as irritation and not lethality or other clinical effect. It is not appropriate to derive a DNEL for this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13 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
Modified dose descriptor starting point:
NOAEC
Value:
1 800 mg/m³
AF for dose response relationship:
1
Justification:
NOAEC identified
AF for differences in duration of exposure:
1
Justification:
Chronic Study
AF for interspecies differences (allometric scaling):
1
Justification:
Inhalation study - allometric scaling not required
AF for other interspecies differences:
2.5
Justification:
Remaining Differences - Toxicodynamics
AF for intraspecies differences:
10
Justification:
General Population
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
52 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
1 800 mg/m³
AF for dose response relationship:
1
Justification:
not required - NOAEC from repeated exposure study
AF for interspecies differences (allometric scaling):
1
Justification:
inhalation study
AF for other interspecies differences:
2.5
Justification:
Remaining Differences - ECHA Guidance
AF for intraspecies differences:
10
Justification:
General Population
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
75 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2
Dose descriptor:
other: IOELV
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
150 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2
Dose descriptor starting point:
other: IOELV

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
100% absorption is assumed for oral and dermal exposures.
AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat study
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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
Value:
300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat study
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

DNELs for the General Population have been derived according to the following paradigm.

General Population

A. Inhalation Route (aerosol/vapour of substance breathed in)

1. Inhalation Route, Systemic Effect (effect(s) somewhere other than lung)

a) Long-term DNEL for general population, inhalation route, systemic effects:13 mg/m3

Dose descriptor: NOAEL 600 ppm (1800 mg/m3)

Basis for dose descriptor: NTP study with 14 week and 2 year exposures in rats and mice. The critical effects were observed in the two year mouse study. Animals were exposed to 0, 200, 600 and 1800 ppm. 

Rationale for selection of dose descriptor:  In the 2 year mouse study, the critical effects observed were significant reduction in survival in male mice, as well as significant urogenital non-neoplastic lesions in the kidney, bladder and prostate. In females, a significant increase in hepatocellular adenomas and carcinomas was seen at 1800 ppm. 

Modification factor: Time scaling is required to adjust for 6h/d exposure to 24 h/d. Exposures were for 5 days a week so adjustment to 7 days per week is required. 

1800 mg/m3* (6 h/d / 24 h/d) * (5d/w / 7 d/w) = 321 mg/m3

 

Assessment Factors    AF      Explanation

     Intraspecies:         10       ECHA Guidance value

     Interspecies:         2.5     No Allometric Scaling, Remaining Differences

     Duration:              1         no adjustment – chronic study

     Total:                    25       (10)(2.5)(1) = 25

Calculation of DNEL: (321 mg/m3) / 25 = 13 mg/m3

 

b) Acute DNEL for general population, inhalation route, systemic effects:52 mg/m3

Dose descriptor: NOAEL 600 ppm (1800 mg/m3)

Basis for dose descriptor: 14 week inhalation study with mice (NTP 1998). Animals were exposed to 0, 66, 200, 600, 1800 and 5000 ppm. 

Rationale for selection of dose descriptor:  Male and female mice exposed to 1,800 or 5,000 ppm THF vapour were observed to be in a state of narcosis (described as stupor) during exposure periods.

Modification factor: No time scaling required because effect is concentration driven. Adjustment is required from 5 days a week to 7 days a week. 

 

1800 mg/m3* (5d/w / 7 d/w) = 1286 mg/m3

 

 

Assessment Factors       AF   Explanation

     Intraspecies:            10    ECHA Guidance value

     Interspecies:            2.5   No Allometric Scaling, No toxicodynamic consideration required as effects are concentration driven.

     Duration:                 1      no adjustment required – long term exposure

     Total:                       25    (10)(2.5)(1) = 25

Calculation of DNEL: (1286 mg/m3) / 25 =52 mg/m3

 

 

2. Inhalation Route, Local (lung) Effect

 

a) Long-term DNEL for general population, inhalation route, local effects:No evidence of local effects were observed following long term inhalation of THF in mice or rats following exposures for 2 years. However an IOEL value exists and to aid in risk assessment, the value has been divided by 2 to account for the intraspecies difference between workers (5) and the general population (10); 150 mg/m3/2 = 75 mg/m3

 

b) Acute DNEL for general population, inhalation route, local effects:No local effects were reported in the repeated dose NTP studies. However an IOEL value exists and to aid in risk assessment, the value has been adopted and divided by 2 to account for the intraspecies difference between workers (5) and the general population (10); 300 mg/m3/ 2 = 150 mg/m3

 

 

 

B. Dermal Route (Application of substance on skin)

 

1. Dermal Route, Systemic Effect (effect(s) somewhere other than skin)

 

a) Long-term DNEL for general population, dermal route, systemic effects:1.5 mg/kg

Dose descriptor: NOAEL 300 mg/kg body weight

Basis for dose descriptor: 2-generation drinking water study in Wistar rats with THF (BASF 1996). Aimals were exposed continuously to the test material at concentrations of 0, 1000, 3000, or 9000 ppm.   

Rationale for selection of dose descriptor:  Signs of general toxicity in parental animals as adverse effects on food and water consumption and on body weight gains. Progeny of high-dose parents displayed impaired body weight/body weight gains and delays in physiological development of the F2 offspring. 

Modification factor: Animals were exposed 24 hours per day, 7 days per week. No adjustment is required. 100% absorption is assumed for oral and dermal expsorue

 

Assessment Factors    AF      Explanation

     Intraspecies:         10       ECHA Guidance value for Gen. Pop.

     Interspecies:         10       Allometric Scaling (4) & Remaining Difference (2.5)

     Duration:              2         subchronic to chronic

     Total:                    200     (10)(10)(2) = 200

Calculation of DNEL: (300 mg/kg) / 200 =1.5 mg/kg

 

b) Acute DNEL for general population, dermal route, systemic effects:A value cannot be calculated due to the lack of a dose response curve. It is expected that the value derived from long term exposure will be protective.

 

 

2. Dermal Route, Local (skin) Effect

a)     Long-term DNEL for general population, dermal route, local effects: There are no repeated dose studies with dermal administration of the test product. Therefore no DNEL for long term dermal effects shall be derived. Additionally the long-term oral will provide sufficient protection as 100% absorption is presumed for both routes of exposure.

 

b)    Acute DNEL for general population, dermal route, local effects:Acute dermal toxicity is observed as irritation and not lethality or other clinical effect. It is not appropriate to derive a DNEL for this endpoint..

 

 

 

C. Oral Route (substance ingested, for indirect exposure assessment)

 

a) Long-term DNEL for general population, oral route, systemic effects:1.5 mg/kg

Dose descriptor: NOAEL 300 mg/kg body weight

Basis for dose descriptor: 2-generation drinking water study in Wistar rats with THF (BASF 1996). Aimals were exposed continuously to the test material at concentrations of 0, 1000, 3000, or 9000 ppm.   

Rationale for selection of dose descriptor:  Signs of general toxicity in parental animals as adverse effects on food and water consumption and on body weight gains. Progeny of high-dose parents displayed impaired body weight/body weight gains and delays in physiological development of the F2 offspring. 

Modification factor: Animals were exposed 24 hours per day, 7 days per week. No adjustment is required. 

 

Assessment Factors    AF      Explanation

     Intraspecies:         10       ECHA Guidance value for Gen. Pop.

     Interspecies:         10       Allometric Scaling (4) & Remaining Difference (2.5)

     Duration:              2         subchronic to chronic

     Total:                    200     (10)(10)(2) = 200

Calculation of DNEL: (300 mg/kg) / 200 =1.5 mg/kg