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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:
23.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC 2003, 2010
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
DNEL value:
140 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC 2003, 2010
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
DNEL value:
144.9 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified. The oral and dermal LD50 values for Terpenes and terpenoids, turpentine oil, alpha-pinene fraction oligomers both excced 2000 mg/kg bw, and no classification is necessary under EU Regulation 1272/2008. Hence no acute DNELs are required for this substance.

Irritation/Sensitisation

Terpenes and terpenoids, turpentine oil, alpha-pinene fraction oligomers is not irritating to skin or eye. A LLNA test on this substance (performed using exposure concentrations of 5%, 10% and 25% w/w) resulted in very slight erythema in the highest treatment group however the SI was 3 in all cases; under the conditions of the study, the test item was not a sensitiser.

Repeated dose toxicity

Information is available from two US National Toxicology Program (NTP) studies conducted on alpha pinene, in which female and male F344/N rats and B6C3F1 mice were exposed to concentrations ranging from 0 to 400 ppm by inhalation. Alpha pinene is structurally related to Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers, however its less complex structure and lower formula weight suggest it is should be more readily available than the oligomer. Hence results from these two sub-chronic inhalation studies have been used to predict the potential systemic toxicity of Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers (read-across using the analogue approach). In rats, organ weight effects but no toxicologically relevant histopathological alterations were apparent in animals exposed to up to 400 ppm alpha pinene for up to 14 weeks. Sub-chronic inhalation toxicity testing in mice revealed hyperplasia of the transitional epithelium of the urinary bladder with a NOAEC of 50 ppm in both sexes.

Genetic toxicity

In vivo and in vitro studies showed that both Terpenes and Terpenoids, turpentine oil, alpha-pinene fraction oligomers and Alpha pinene are not genotoxic. Reproductive / developmental toxicity Developmental toxicity testing has been proposed for Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers, however no reproductive toxicity testing is necessary as this is not a standard information requirement for a substance registered under annex IX of REACH.

Mode of Action Considerations

For studies relevant to the setting of DNELs, a threshold mode of action was assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point

The NOAEC for repeated dose toxicity may be converted from ppm to mg/m3 according to the following formula:

Y mg/m3 = (X ppm) * (molecular weight) / 24.45

In the case of alpha terpene, this is equivalent to (50) * (136.23) / 24.45

The equivalent NOAEC is therefore 278.6 mg/m3.

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and oral exposures, route-to-route extrapolations from the repeated dose inhalation NOAEC was performed. For the purposes of DNEL derivation, inhalation and dermal absorption have been assumed to be 50% with 100% uptake following ingestion.

Inhalation route:

The corrected inhalation NOAEC is derived as follows.

To convert the mouse inhalatory NOAEC into a human inhalatory NOAEC, correction is necessary for differences in the duration of exposure i.e. the NOAEC originates from a study where mice were exposed to the test substance for 6 hr/d, 5 d/wk while worker exposure is 8 hr/d, 5 d/wk; exposure of the general population involves exposure 24 hr/d on 7 d/wk. In addition, for workers a correction is needed to correct for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-hr exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-hr exposure period). Uptake after inhalation is assumed to be 50% for both the mouse and for humans.

For Workers, the corrected inhalation NOAEC is: 278.6 * (6/8) * (5/5) * (6.7/10) = 140.0 mg/m3

For the General population, the corrected inhalation NOAEC is: 278.6 * (6/24) * (5/7) = 49.7 mg/m3

Dermal route:

The corrected dermal NOAEL is derived as follows:

corrected dermal NOAEL = inhalatory NOAEC * sRV-mouse-6hr * (ABSinhl-mouse/ABSderm-human)

From Table R.8-17, sRV-mouse-6hr may be calculated thus :

Males: [(2.5/0.03) / 1000] * 6 = 0.50 m3/kg bw/6hr

Females: [(2.2/0.025) / 1000] * 6 = 0.53 m3/kg bw/6hr

A value of 0.52 m3/kg bw/6hr will be used.

Hence corrected dermal NOAEL = 278.6 * 0.52 * (50/50) = 144.9 mg/kg bw/d

Oral route:

The corrected oral NOAEL is derived as follows:

corrected oral NOAEL = inhalatory NOAEC * sRV-mouse-6hr * (ABSinhl-mouse/ABSoral-human)

sRV-mouse-6hr was calculated as described above.

Hence corrected oral NOAEL = 278.6 * 0.52 * (50/100) = 72.44 mg/kg bw/d

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010).

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical Report No. 110, ECETOC, Brussels, October 2010.

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

3

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

6

 

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

3

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

24

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC 2003, 2010
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
49.7 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC 2003, 2010
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
144.9 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC 2003, 2010
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
144.9 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified. The oral and dermal LD50 values for Terpenes and terpenoids, turpentine oil, alpha-pinene fraction oligomers both excced 2000 mg/kg bw, and no classification is necessary under EU Regulation 1272/2008. Hence no acute DNELs are required for this substance.

Irritation/Sensitisation

Terpenes and terpenoids, turpentine oil, alpha-pinene fraction oligomers is not irritating to skin or eye. A LLNA test on this substance (performed using exposure concentrations of 5%, 10% and 25% w/w) resulted in very slight erythema in the highest treatment group however the SI was 3 in all cases; under the conditions of the study, the test item was not a sensitiser.

Repeated dose toxicity

Information is available from two US National Toxicology Program (NTP) studies conducted on alpha pinene, in which female and male F344/N rats and B6C3F1 mice were exposed to concentrations ranging from 0 to 400 ppm by inhalation. Alpha pinene is structurally related to Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers, however its less complex structure and lower formula weight suggest it is should be more readily available than the oligomer. Hence results from these two sub-chronic inhalation studies have been used to predict the potential systemic toxicity of Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers (read-across using the analogue approach). In rats, organ weight effects but no toxicologically relevant histopathological alterations were apparent in animals exposed to up to 400 ppm alpha pinene for up to 14 weeks. Sub-chronic inhalation toxicity testing in mice revealed hyperplasia of the transitional epithelium of the urinary bladder with a NOAEC of 50 ppm in both sexes.

Genetic toxicity

In vivo and in vitro studies showed that both Terpenes and Terpenoids, turpentine oil, alpha-pinene fraction oligomers and Alpha pinene are not genotoxic. Reproductive / developmental toxicity Developmental toxicity testing has been proposed for Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers, however no reproductive toxicity testing is necessary as this is not a standard information requirement for a substance registered under annex IX of REACH.

Mode of Action Considerations

For studies relevant to the setting of DNELs, a threshold mode of action was assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point

The NOAEC for repeated dose toxicity may be converted from ppm to mg/m3 according to the following formula:

Y mg/m3 = (X ppm) * (molecular weight) / 24.45

In the case of alpha terpene, this is equivalent to (50) * (136.23) / 24.45

The equivalent NOAEC is therefore 278.6 mg/m3.

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and oral exposures, route-to-route extrapolations from the repeated dose inhalation NOAEC was performed. For the purposes of DNEL derivation, inhalation and dermal absorption have been assumed to be 50% with 100% uptake following ingestion.

Inhalation route:

The corrected inhalation NOAEC NOAEL is derived as follows.

To convert the mouse inhalatory NOAEC into a human inhalatory NOAEC, correction is necessary for differences in the duration of exposure i.e. the NOAEC originates from a study where mice were exposed to the test substance for 6 hr/d, 5 d/wk while worker exposure is 8 hr/d, 5 d/wk; exposure of the general population involves exposure 24 hr/d on 7 d/wk. In addition, for workers a correction is needed to correct for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-hr exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-hr exposure period). Uptake after inhalation is assumed to be 50% for both the mouse and for humans.

For Workers, the corrected inhalation NOAEC is: 278.6 * (6/8) * (5/5) * (6.7/10) = 140.0 mg/m3

For the General population, the corrected inhalation NOAEC is: 278.6 * (6/24) * (5/7) = 49.7 mg/m3

Dermal route:

The corrected dermal NOAEL is derived as follows:

corrected dermal NOAEL = inhalatory NOAEC * sRV-mouse-6hr * (ABSinhl-mouse/ABSderm-human)

From Table R.8-17, sRV-mouse-6hr may be calculated thus :

Males: [(2.5/0.03) / 1000] * 6 = 0.50 m3/kg bw/6hr

Females: [(2.2/0.025) / 1000] * 6 = 0.53 m3/kg bw/6hr

A value of 0.52 m3/kg bw/6hr will be used.

Hence corrected dermal NOAEL = 278.6 * 0.52 * (50/50) = 144.9 mg/kg bw/d

Oral route:

The corrected oral NOAEL is derived as follows:

corrected oral NOAEL = inhalatory NOAEC * sRV-mouse-6hr * (ABSinhl-mouse/ABSoral-human)

sRV-mouse-6hr was calculated as described above.

Hence corrected oral NOAEL = 278.6 * 0.52 * (50/100) = 72.44 mg/kg bw/d

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010).

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical Report No. 110, ECETOC, Brussels, October 2010.

 

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

10

  

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

40

  

Long-term DNEL Assessment Factors (Oral)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

40