Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.01 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:
100 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
50.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

The subchronic inhalation toxicity study conducted in rats by 6-hour nose-only exposure (Monsanto, 1986) was used as a starting point for the DNEL derivation. The systemic NOAEC of 100 mg/m³ was corrected for duration of exposure (6 to 8hrs; factor *6/8) and a correction for the inhalation volume of a worker was taken into account (*6.7/10):

corrected NOAEC = 100 mg/m³ * (6 h/d / 8 h/d) * (6.7 m³/d / 10 m³/d) = 50.3 mg/m³.

A corrected NOAEC of 50.3 mg/m³ is derived.

AF for dose response relationship:
1
Justification:
default, starting points is a NOAEL
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
already regarded by deriving a corrected NOAEC
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
default for worker
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

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:
0.622 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
Dose descriptor starting point:
NOAEL
Value:
14.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
62.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Despite the fact that a repeated dose toxicity study via the dermal route is available, the OECD 408 repeated dose study via the oral route was chosen as the starting point. The oral study is with 13 weeks of subchronic duration, whereas the dermal study is with 21 days only in the lower subacute range. This allows a better assessment of potential long-term effects of the substance, which could be missed in a study with shorter duration. Further, the oral study gives a definitive NOAEL value, whereas the dermal one only indicates NOAEL >= 2000 mg/kg bw/d, which does not only allow to calculate with a distinct value but also indicates that systemic exposure occurred. Last but not least, the present oral NOAEL is with 14.8 mg/kg bw/d the most sensitive value; even the 13 week inhalative NOAEL is with approx. 16.5 mg/kg bw/d (recalculated from exposure) higher than the oral one, and so, the most conservative approach was followed.

Using this dose descriptor starting point, all further calculations were performed with the DNEL calculator.

AF for dose response relationship:
1
Justification:
default, starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for allometric scaling (rat to human)
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

Local effects

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

The long-term DNELs relevant for workers were based on the key studies below.

A key study for oral repeated dose administration was performed in rats with hydrogenated terphenyl (Monsanto, 1981); the study was conducted according to OECD 408 and GLP testing guidelines, and was considered to be reliable, adequate and relevant.  Dosing was performed during 90 days via dietary mixture to 72 Sprague-Dawley CD rats (12/sex/group) at dose levels of 50, 200 and 2000 ppm in the diet for a period of approximately 14 weeks, corresponding with nominal doses of 3, 12 and 120 mg/kg body weight/day. Control animals (12/sex/group) received a standard laboratory diet. All rats survived; the mean body weights of the high-dose females were slightly lower than control throughout the treatment-period. The mean food consumption values of high-dose males and females were slightly lower than control during the first week of the study and were unremarkable for the remainder of the treatment-period. The high-dose males exhibited slight decrease in mean hemoglobin concentration, hematocrit and erythrocyte counts and a slight increase in mean platelet count. The high-dose males exhibited slight, statistically significant elevations in mean cholesterol and albumin level. The high-dose females exhibited a slight reduction in mean glucose levels. There was an increased incidence of a spontaneously occurring renal tubular lesions in high dose males when compared to control males. The lesion incidence in low and mild dose males was similar to that observed in controls. Females were essentially free of the lesion. The aetiology and toxicopathological significance of the increased incidence rate in high dose males was unclear. The NOAEL was determined at 200 ppm in the diet, corresponding to nominal 12 mg/kg body weight/day which was shown to be after analytical verification 14.8 mg/kg bw7day in males and 17.0 mg/kg bw/day in females.

Despite the fact that a repeated dose toxicity study via the dermal route is available, the above mentioned OECD 408 repeated dose study via the oral route was chosen as the starting point for DNEL derivation for the dermal route of exposure. The oral study is with 13 weeks of subchronic duration, whereas the dermal study is with 21 days only in the lower subacute range. This allows a better assessment of potential long-term effects of the substance, which could be missed in a study with shorter duration. Further, the oral study gives a definitive NOAEL value, whereas the dermal one only indicates NOAEL >= 2000 mg/kg bw/d, which does not only allow to calculate with a distinct value but also indicates that systemic exposure occurred. Last but not least, the present oral NOAEL is with 14.8 mg/kg bw/d the most sensitive value; even the 13 week inhalative NOAEL is with approx. 16.5 mg/kg bw/d (recalculated from exposure) higher than the oral one, and so, the most conservative approach was followed.

A key study for inhalation repeated dose administration was performed in rats with Therphenyl, hydrogenated (Monsanto, 1986). Therphenyl, hydrogenated when administered by whole-body inhalation exposure as an aerosol to 90 CD (Sprague-Dawley derived) rats (15/sex/group) for six hours per day, five days per week for thirteen weeks at target concentrations of 0, 10, 100 and 500 mg/m³ (groups I, II, III,IV). One Group I female and one Group II female died spontaneously during the study. The Group II female’s death was not considered treatment related. Increased incidences of chromodacryorrhea, excess lacrimation and rough coat were exhibited by all groups of treated males compared to control males. Increased incidences of dried brown material around the facial area were exhibited by all treated groups of females compared to control females. These findings were considered to be treatment related. The mean body weights were decreased approximately 8% for the Group IV males during the study compared to the control males. The differences between Group IV and control males were considered suggestive of a treatment related effect. Although some statistically significant differences were seen at study termination between clinical chemistry values for control and treated groups, values were generally within control ranges and the absence of supporting microscopic lesions or organ weight findings suggests these clinical chemistry results were insufficient to be considered toxicologically significant. The mean absolute and relative liver weights were increased for all groups of treated males compared to control males. The differences between treated and control males were statistically significant for all comparisons except for the absolute liver weights of Group II and III males. Postmortem findings, observed grossly and microscopically, either occurred in the treated and control animals with comparable incidence and severity or they occurred sporadically. These findings did not appear to be related to the test article. The systemic NOAEC was considered to be 100 mg/m³ or 0.1 mg/L air.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.358 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):
50
Dose descriptor starting point:
NOAEC
Value:
100 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
17.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

The subchronic inhalation toxicity study conducted in rats by 6-hour nose-only exposure (Monsanto, 1986) was used as a starting point for DNEL derivations.

The systemic NOAEC of 100 mg/m³ was corrected for duration of exposure (6 to 24hrs; factor *6/24) and a correction for exposure days per week (5 d/week to 7 d/week; factor: *5/7):

corrected NOAEC = 100 mg/m³ * (6 h/d / 24 h/d) * (5 d/week / 7 d/week) = 17.9 mg/m³.

A corrected NOAEC of 17.9 mg/m³ is derived.

AF for dose response relationship:
1
Justification:
default, starting point is a NOAEC
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
already regarded by deriving a corrected NOAEC
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

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:
0.222 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
Dose descriptor starting point:
NOAEL
Value:
14.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
44.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Despite the fact that a repeated dose toxicity study via the dermal route is available, the OECD 408 repeated dose study via the oral route was chosen as the starting point. The oral study is with 13 weeks of subchronic duration, whereas the dermal study is with 21 days only in the lower subacute range. This allows a better assessment of potential long-term effects of the substance, which could be missed in a study with shorter duration. Further, the oral study gives a definitive NOAEL value, whereas the dermal one only indicates NOAEL >= 2000 mg/kg bw/d, which does not only allow to calculate with a distinct value but also indicates that systemic exposure occurred. Last but not least, the present oral NOAEL is with 14.8 mg/kg bw/d the most sensitive value; even the 13 week inhalative NOAEL is with approx. 16.5 mg/kg bw/d (recalculated from exposure) higher than the oral one, and so, the most conservative approach was followed.

Using this dose descriptor starting point, all further calculations were performed with the DNEL calculator.

AF for dose response relationship:
1
Justification:
default, starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for allometric scaling (rat to human)
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
74 µg/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
Dose descriptor starting point:
NOAEL
Value:
14.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
14.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is necessary.

AF for dose response relationship:
1
Justification:
default, starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for allometric scaling (rat to human)
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The long-term DNELs were based on the key study below (oral and dermal DNEL) & on the key study described in the section for workers (inhalation DNEL).

 

A key study for oral repeated dose administration was performed in rats with hydrogenated terphenyl (Monsanto, 1981); the study was conducted according to OECD 408 and GLP testing guidelines, and was considered to be reliable, adequate and relevant.  Dosing was performed during 90 days via dietary mixture to 72 Sprague-Dawley CD rats (12/sex/group) at dose levels of 50, 200 and 2000 ppm in the diet for a period of approximately 14 weeks, corresponding with nominal doses of 3, 12 and 120 mg/kg body weight/day. Control animals (12/sex/group) received a standard laboratory diet. All rats survived; the mean body weights of the high-dose females were slightly lower than control throughout the treatment-period. The mean food consumption values of high-dose males and females were slightly lower than control during the first week of the study and were unremarkable for the remainder of the treatment-period. The high-dose males exhibited slight decrease in mean hemoglobin concentration, hematocrit and erythrocyte counts and a slight increase in mean platelet count. The high-dose males exhibited slight, statistically significant elevations in mean cholesterol and albumin level. The high-dose females exhibited a slight reduction in mean glucose levels. There was an increased incidence of a spontaneously occurring renal tubular lesions in high dose males when compared to control males. The lesion incidence in low and mild dose males was similar to that observed in controls. Females were essentially free of the lesion. The aetiology and toxicopathological significance of the increased incidence rate in high dose males was unclear. The NOAEL was determined at 200 ppm in the diet, corresponding to nominal 12 mg/kg body weight/day which was shown to be after analytical verification 14.8 mg/kg bw/day in males and 17.0 mg/kg bw/day in females.