Tributyl O-acetylcitrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.04 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):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

88.15 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOEL of 100 mg/kg bw from chronic oral study in rats is available (Sommer, 2005). The starting point (=NOEL) was modified to obtain inhalation NOEC: 100 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7m³/10 m³) = 88.15 mg/m³.

AF for dose response relationship:

1

Justification:

clear dose response

AF for differences in duration of exposure:

1

Justification:

chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

default in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

1

Justification:

default for a good quality database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 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):

50

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOEL of 100 mg/kg bw from chronic oral study in rats is available (Sommer, 2005). The starting point (=NOEL) was not modified for absorption. Oral and dermal absorption are considered to be the same and are set to 100%.

AF for dose response relationship:

1

Justification:

clear dose response

AF for differences in duration of exposure:

1

Justification:

chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default for rats

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

1

Justification:

default for a good quality data base

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNELs for acute toxicity are not considered since long-term DNEL is sufficient to ensure that these effects do not occur.

Skin irritation/corrosion: not irritating

Eye irritation/corrosion: slightly irritating

Sensitisation: not sensitising

Mutagenicity: all in vitro and in vivo mutagenicity tests demonstrated the abcence of mutagenic effects.

Carcinogenicity: Oral long term studies on rats showed no carcinogenic activity of ATBC. There is no evidence for carcinogenicity in epidemiology. In conclusion, there is no concern for carcinogenicity in humans.

Reproductive toxicity: No impairment of reproductive capability and fertility was found in rats exposed via the diet at a dose level of 100 mg/kg in a 2 generation reproduction toxicity study. Further developmental toxicity studies in mice and rats indicated that ATBC has no specific embryotoxic or teratogenic properties.

Long-term-exposure – systemic effects (dermal):

Relevant dose-descriptor for the endpoint concerned: Sommer (2005): NOEL of 100 mg/kg bw in rats exposed over 2 years at concentrations of 0, 100, 300 or 1000 mg/kg bw/d (nominal in diet)

Assessment factors relating to the extrapolation procedure:

Duration extrapolation: sufficient (chronic study; no additional assessment factor)

Interspecies differences: default value of 4 (rat → human)

Interspecies differences: default value of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 5 (workers)

Route to route extrapolation: default assessment factor of 1 (oral → dermal)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 4 * 2.5 * 5 * 1 = 50

DNEL / worker / long-term-exposure / systemic effects (dermal):

100 mg/kg bw/d÷50 = 2 mg/kg bw/d

Long-term-exposure – systemic effects (inhalation):

Relevant dose-descriptor for the endpoint concerned: Sommer (2005): NOEL of 100 mg/kg bw in rats exposed over 2 years at concentrations of 0, 100, 300 or 1000 mg/kg bw/d (nominal in diet)

Default physiological parameter for allometric scaling (rat; 8 h): 0.38 m3/kg bw

Default physiological parameter for allometric scaling (human; 8 h): 6.7 m3/person

Default value for respiratory volume (human; 8 h): 10 m3/person

NOECworker(8 h): 100 mg/kg bw/d ÷ 0.38 m3/kg bw * (6.7 m3/10 m3) * (50%/100%) = 88.15 mg/m3

Deafult assumption for absorption in case of route-to-route extrapolation: oral → inhalation (50%/100%).

Assessment factors relating to the extrapolation procedure:

Duration extrapolation: sufficient (chronic study; no additional assessment factor)

Interspecies differences: default value of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 5 (workers)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 2.5 * 5 = 12.5

DNEL / worker / long-term-exposure / systemic effects (inhalation): 88.15 mg/m3÷12.5 = 7.04 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.74 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):

25

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOEL of 100 mg/kg bw from chronic oral study in rats is available (Sommer, 2005). The starting point (=NOEL) was modified to obtain inhalation NOEC: 100 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 43.5 mg/m³.

AF for dose response relationship:

1

Justification:

clear dose response

AF for differences in duration of exposure:

1

Justification:

chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

default in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default for general population

AF for the quality of the whole database:

1

Justification:

default for a good quality database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 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:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOEL of 100 mg/kg bw from chronic oral study in rats is available (Sommer, 2005). The starting point (=NOEL) was not modified for absorption. Oral and dermal absorption are considered to be the same and are set to 100%.

AF for dose response relationship:

1

Justification:

clear dose response

AF for differences in duration of exposure:

1

Justification:

chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default in case of rats

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default for general population

AF for the quality of the whole database:

1

Justification:

default for a good quality database

AF for remaining uncertainties:

1

Justification:

No remaing uncertainties are 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:

DNEL (Derived No Effect Level)

Value:

1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

Not applicable (the routes of exposure are the same in animals and in humans)

AF for dose response relationship:

1

Justification:

clear dose response

AF for differences in duration of exposure:

1

Justification:

chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

default in case of rats

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default for general population

AF for the quality of the whole database:

1

Justification:

default for a good quality database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNELs for acute toxicity are not considered since long-term DNEL is sufficient to ensure that these effects do not occur.

Skin and eye irritation/corrosion: no data

Sensitisation: no data

Mutagenicity: all in vitro and in vivo mutagenicity tests demonstrated the abcence of mutagenic effects.

Carcinogenicity: Oral long term studies on rats showed no carcinogenic activity of ATBC. There is no evidence for carcinogenicity in epidemiology. In conclusion, there is no concern for carcinogenicity in humans.

Reproductive toxicity: No impairment of reproductive capability and fertility was found in rats exposed via the diet at a dose level of 100 mg/kg in a 2 generation reproduction toxicity study. Further developmental toxicity studies in mice and rats indicated that ATBC has no specific embryotoxic or teratogenic properties.

Long-term-exposure – systemic effects (dermal):

Relevant dose-descriptor for the endpoint concerned: Sommer (2005): NOEL of 100 mg/kg bw in rats exposed over 2 years at concentrations of 0, 100, 300 or 1000 mg/kg bw/d (nominal in diet)

Assessment factors relating to the extrapolation procedure:

Duration extrapolation: sufficient (chronic study; no additional assessment factor)

Interspecies differences: default value of 4 (rat → human)

Interspecies differences: default value of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 10 (general population)

Route to route extrapolation: default assessment factor of 1 (oral → dermal)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 4 * 2.5 * 10 * 1 = 100

DNEL / general population / long-term-exposure / systemic effects (dermal):

100 mg/kg bw/d ÷ 100 = 1 mg/kg bw/d

Long-term-exposure – systemic effects (inhalation):

Relevant dose-descriptor for the endpoint concerned: Sommer (2005): NOEL of 100 mg/kg bw in rats exposed over 2 years at concentrations of 0, 100, 300 or 1000 mg/kg bw/d (nominal in diet)

Default physiological parameter for allometric scaling (rat; 24 h): 1.15 m3/kg bw

Deafult assumption for absorption in case of route-to-route extrapolation: oral → inhalation (50%/100%).

Corrected NOEC(24 h): 100 mg/kg bw/d ÷ (1/sRV rats) x (ABS oral/ABS inhalation) = 100 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 43.5 mg/m³

Assessment factors relating to the extrapolation procedure:

Duration extrapolation: sufficient (chronic study; no additional assessment factor)

Interspecies differences: default value of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 10 (general population)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 2.5 * 10 = 25

DNEL / general population / long-term-exposure / systemic effects (inhalation):

43.5 mg/m3 ÷ 25 = 1.74 mg/m3

Long-term-exposure – systemic effects (oral):

Relevant dose-descriptor for the endpoint concerned: Sommer (2005): NOEL of 100 mg/kg bw in rats exposed over 2 years at concentrations of 0, 100, 300 or 1000 mg/kg bw/d (nominal in diet)

Assessment factors relating to the extrapolation procedure:

Duration extrapolation: sufficient (chronic study; no additional assessment factor)

Interspecies differences: default value of 4 (rat → human)

Interspecies differences: default value of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 10 (general population)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 4 * 2.5 * 10 = 100

DNEL / general population / long-term-exposure / systemic effects (oral):

100 mg/kg bw/d ÷ 100 = 1 mg/kg bw/d