N-1-naphthylaniline

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 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):

300

Dose descriptor starting point:

LOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

24.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to lack of repeated dose toxicity data by the inhalation route, a route to route extrapolation was performed. The LOAEL (oral) derived in the sub-chronic oral toxicity study in rats is converted into a LOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. For this purpose a default body weight of 70 kg and a respiratory volume of 10 m³/d are applied.

An oral absorption of 100% is expected for N-phenyl-1-naphthylamine since the substance is well absorbed after ingestion and readily excreted. Nevertheless, for the oral-to-inhalation extrapolation, following a worst-case assumption and to account for uncertainties an additional assessment factor of 2 was used to consider the different absorption properties of the respiratory tract and after oral intake in accordance with ECHA Guidance R.8.

Also, to account for differences in experimental and worker exposure conditions (rats: 7 d/week; workers: 5 d/week) a factor of 7/5 was applied as well.

LOAEC_corr = 5 mg/kg bw/d x 70 kg / 10 m³/d / 2 x (7 d/week / 5 d/week) = 24.5 mg/m³

AF for dose response relationship:

3

Justification:

default for extrapolation of the LOAEL to the NAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default for allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

GLP and guideline compliant study

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

125

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

5 583 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since no acute studies by inhalation are available, a route to route extrapolation is performed with data from oral application.

The following acute oral toxicity studies are available:

	MacEwen, J. D. and Vernot, E. H., 1974	Ciba-Geigy, 1987	Weil, 1974	Bayer, 1978
test animal	SD rats, male	rats, male and female	Wistar rats, male	Wistar rats, female
Dose levels	500, 1000, 2000, 4000 mg/kg	200, 2000 mg/kg	1000, 2000 and 4000 mg/kg bw	5000 mg/kg
LD50 combined	-	> 200 - < 2000 mg/kg	2380 mg/kg
LD50 males	1625 mg/kg	2000 mg/kg
LD50 females	-	> 200 - < 2000 mg/kg		> 5000 mg/kg
LD0 males	1000 mg/kg	200 mg/kg	1000 mg/kg bw
LD0 females	-	200 mg/kg		-
Pathology	no data	no effects noted at 200 mg/kg	livers mottled; stomachs transparent, free blood; kidneys and adrenals congested; intestines injected, free blood and distended; dose levels not specified.	no data

Identification of the point of departure:

The lowest, therefore most conservative no effect value is the LD0 of 200 mg/kg in both male and female rats based on the study by Ciba-Geigy. This value is considered suitable since no deaths and no systemic effects have been reported at this dose level. This value is considered to be the NOAEL.

 

DNEL derivation

The LD0 (=NOAEL) of 200 mg/kg body weight observed in male and female rats is the starting point for DNEL derivation. Following a rout to route extrapolation approach, this oral NOAEL needs to be transformed into an inhalatory NOAEC considering the respiratory volume of the rat.

The standard respiratory volume of the rat is 0.2 l/min. Considering a short term exposure of 15 min, the total respiratory volume of a rat during 15 minutes is 0.2 l/min x 15 min = 3 l = 0.003 m³. Based on the average rat body weight (0.25 kg) this translates into 0.012 m³/kg body weight.

The atmospheric concentration yielding a dose equivalent to 200 mg/kg orally after 15 min of breathing is therefore calculated as 200 mg/kg / 0.012 m³/kg = 16666 mg/m³. To correct this value for human workers, further modifications are required taking the increased respiratory volume of workers into account compared to humans in rest. This is achieved by multiplication with a factor of 0.67.

An oral absorption of 100% is expected for N-phenyl-1-naphthylamine since the substance is well absorbed after ingestion and readily excreted. Nevertheless, for the oral-to-inhalation extrapolation, following a worst-case assumption and to account for uncertainties an additional assessment factor of 2 was used to consider the different absorption properties of the respiratory tract and after oral intake in accordance with ECHA Guidance R.8.

16666 mg/m³x 0.67 / 2 = 5583 mg/m³. This value is considered the NOAEC_corr.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

The data base is considered sufficient and a worst case approach was followed, using the most sensitve result available.

AF for remaining uncertainties:

10

Justification:

uncertainties in regard of route to route extrapolation

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:

0.02 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):

300

Dose descriptor starting point:

LOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation is needed from the oral to the dermal route. Due to differences in experimental and worker exposure conditions (rats: 7 d/week; worker: 5 d/week) a factor of 7/5 is applied to the LOAEL.

Also, it is assumed that dermal absorption will not be higher than the oral absorption (100%). Hence, no additional assessment factor was used according to REACH Guidance R.8.

LOAEL_corr = 5 mg/kg bw/d x (7 d/week / 5 d/week) = 7 mg/kg bw/d

However, the dermal absorption of the pure substance and relevant in-use concentrations were determined in a dermal absorption study. The derived percentages are not used to derive the dermal DNEL. They are directly applied to the exposure estimates instead. Please refer to section 9 of the CSR.

AF for dose response relationship:

3

Justification:

default for extrapolation of the LOAEL to the NAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation from rat to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

GLP-compliant guideline study

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.67 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

LOAEL

Value:

2 000 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Available acute dermal toxicity study:

	Weil, 1974
test animal	male rabbits
Dose levels	2000 and 8000 mg/kg bw
LD50 males	> 5000 mg/kg. One animal died at 8000 mg/kg
LD0 males	2000 mg/kg bw
Pathology	Livers congested and mottled; spleens dark; kidneys khaki brown in color. Not specified at which dose level, therefore it is assumed to have occurred also at the 2000 mg/kg dose level

 

Identification of the point of departure:

The lowest applied dose level is 2000 mg/kg in male rabbits. Although no deaths occurred at this dose level, it is considered a LOAEL since it has to be assumed that histological findings were also recorded at this dose level. This LOAEL of 2000 mg/kg is used as starting point for DNEL calculations.

Additionally, the dermal absorption of the pure substance and relevant in-use concentrations were determined in a dermal absorption study. The derived percentages are not used to derive the dermal DNEL. They are directly applied to the exposure estimates instead. Please refer to section 9 of the CSR.

AF for dose response relationship:

1

Justification:

The dose response is considered unremarkable.

AF for interspecies differences (allometric scaling):

2.4

Justification:

extrapolation from rabbit to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

The data base is considered sufficient.

AF for remaining uncertainties:

10

Justification:

remaining uncertainties for using a LOAEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.015 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):

50

Dose descriptor starting point:

LOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

2.17 mg/m³

Explanation for the modification of the dose descriptor starting point:

As starting point the LOAEL resulting from a subchronic oral repeated dose toxicity study in rats (2016) is used.

Route-to-route extrapolation is needed from the oral to the inhalation route. In accordance with ECHA Guidance R.8 the LOAEL is divided by the respiratory volume accounting for 24 hours (1.15 mg/kg bw).

An oral absorption of 100% is expected for N-phenyl-1-naphthylamine since the substance is well absorbed after ingestion and readily excreted. Nevertheless, for the oral-to-inhalation extrapolation, following a worst-case assumption and to account for uncertainties an additional assessment factor of 2 was used to consider the different absorption properties of the respiratory tract and after oral intake in accordance with ECHA Guidance R.8.

LOAEC_corr = 5 mg/kg bw/d / 1.15 m³/kg bw / 2 = 2.17 mg/m³

AF for dose response relationship:

3

Justification:

default since the starting point is a LOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

GLP and guideline compliant study

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

33 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

250

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

8 333 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since no acute studies by inhalation are available, a route to route extrapolation is performed with data from oral application.

The following acute oral toxicity studies are available:

	MacEwen, J. D. and Vernot, E. H., 1974	Ciba-Geigy, 1987	Weil, 1974	Bayer, 1978
test animal	SD rats, male	rats, male and female	Wistar rats, male	Wistar rats, female
Dose levels	500, 1000, 2000, 4000 mg/kg	200, 2000 mg/kg	1000, 2000 and 4000 mg/kg bw	5000 mg/kg
LD50 combined	-	> 200 - < 2000 mg/kg	2380 mg/kg
LD50 males	1625 mg/kg	2000 mg/kg
LD50 females	-	> 200 - < 2000 mg/kg		> 5000 mg/kg
LD0 males	1000 mg/kg	200 mg/kg	1000 mg/kg bw
LD0 females	-	200 mg/kg		-
Pathology	no data	no effects noted at 200 mg/kg	livers mottled; stomachs transparent, free blood; kidneys and adrenals congested; intestines injected, free blood and distended; dose levels not specified.	no data

Identification of the point of departure:

The lowest, therefore most conservative no effect value is the LD0 of 200 mg/kg in both male and female rats based on the study by Ciba-Geigy. This value is considered suitable since no deaths and no systemic effects have been reported at this dose level. This value is considered to be the NOAEL.

 

DNEL derivation

The LD0 (=NOAEL) of 200 mg/kg body weight observed in male and female rats is the starting point for DNEL derivation. Following a route to route extrapolation approach, this oral NOAEL needs to be transformed into an inhalatory NOAEC considering the respiratory volume of the rat.

The standard respiratory volume of the rat is 0.2 l/min. Considering a short term exposure of 15 min, the total respiratory volume of a rat during 15 minutes is 0.2 l/min x 15 min = 3 l = 0.003 m³. Based on the average rat body weight (0.25 kg) this translates into 0.012 m³/kg body weight.

The atmospheric concentration yielding a dose equivalent to 200 mg/kg orally after 15 min of breathing is therefore calculated as 200 mg/kg / 0.012 m³/kg = 16666 mg/m³.

An oral absorption of 100% is expected for N-phenyl-1-naphthylamine since the substance is well absorbed after ingestion and readily excreted. Nevertheless, for the oral-to-inhalation extrapolation, following a worst-case assumption and to account for uncertainties an additional assessment factor of 2 was used to consider the different absorption properties of the respiratory tract and after oral intake in accordance with ECHA Guidance R.8.

16666 mg/m³ /2 = 8333 mg/m³. This value is considered the NOAEC_corr.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

The data base is considered sufficient and a worst case approach was followed, using the most sensitve result available.

AF for remaining uncertainties:

10

Justification:

uncertainties in regard of route to route extrapolation

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:

0.008 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):

600

Dose descriptor starting point:

LOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As starting point the LOAEL resulting from a subchronic oral repeated dose toxicity study in rats (2016) is used.

Route-to-route extrapolation is needed from the oral to the dermal route. In accordance with ECHA Guidance R.8 it is assumed that dermal absorption will not exceed the oral absorption (100%). Hence, no additional assessment factor was used according to REACH Guidance R.8.

However, the dermal absorption of the pure substance and relevant in-use concentrations were determined in a dermal absorption study. The derived percentages are not used to derive the dermal DNEL.They are directly applied to the exposure estimates instead.

AF for dose response relationship:

3

Justification:

default as the starting point for the DNEL derivation is a LOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation from rat to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

GLP-compliant guideline study

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

LOAEL

Value:

2 000 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Available acute dermal toxicity study:

	Weil, 1974
test animal	male rabbits
Dose levels	2000 and 8000 mg/kg bw
LD50 males	> 5000 mg/kg. One animal died at 8000 mg/kg
LD0 males	2000 mg/kg bw
Pathology	Livers congested and mottled; spleens dark; kidneys khaki brown in color. Not specified at which dose level, therefore it is assumed to have occurred also at the 2000 mg/kg dose level

 

Identification of the point of departure:

The lowest applied dose level is 2000 mg/kg in male rabbits. Although no deaths occurred at this dose level, it is considered a LOAEL since it has to be assumed that histological findings were also recorded at this dose level. This LOAEL of 2000 mg/kg is used as starting point for DNEL calculations.

However, the dermal absorption of the pure substance and relevant in-use concentrations were determined in a dermal absorption study. The derived percentages are not used to derive the dermal DNEL. They are directly applied to the exposure estimates instead.

AF for dose response relationship:

1

Justification:

The dose response is considered unremarkable.

AF for interspecies differences (allometric scaling):

2.4

Justification:

extrapolation from rabbit to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

The data base is considered sufficient.

AF for remaining uncertainties:

10

Justification:

remaining uncertainties for using a LOAEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 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):

600

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As starting point the LOAEL obtained in an subchronic oral toxicity study in rats (2016) is used. No modification of the dose descriptor starting point is necessary.

AF for dose response relationship:

3

Justification:

default as the starting point for the DNEL derivation is a LOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation from rat to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

GLP-compliant guideline study

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/kg bw/day

Most sensitive endpoint:

acute 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:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The following acute oral toxicity studies are available:

	MacEwen, J. D. and Vernot, E. H., 1974	Ciba-Geigy, 1987	Weil, 1974	Bayer, 1978
test animal	SD rats, male	rats, male and female	Wistar rats, male	Wistar rats, female
Dose levels	500, 1000, 2000, 4000 mg/kg	200, 2000 mg/kg	1000, 2000 and 4000 mg/kg bw	5000 mg/kg
LD50 combined	-	> 200 - < 2000 mg/kg	2380 mg/kg
LD50 males	1625 mg/kg	2000 mg/kg
LD50 females	-	> 200 - < 2000 mg/kg		> 5000 mg/kg
LD0 males	1000 mg/kg	200 mg/kg	1000 mg/kg bw
LD0 females	-	200 mg/kg		-
Pathology	no data	no effects noted at 200 mg/kg	livers mottled; stomachs transparent, free blood; kidneys and adrenals congested; intestines injected, free blood and distended; dose levels not specified.	no data

Identification of the point of departure:

The lowest, therefore most conservative no effect value is the LD0 of 200 mg/kg in both male and female rats based on the study by Ciba-Geigy. This value is considered suitable since no deaths and no systemic effects have been reported at this dose level. This value is considered to be the NOAEL.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human (default)

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

10

Justification:

standard factor for the general population

AF for the quality of the whole database:

1

Justification:

The data base is considered sufficient and a worst case approach was followed, using the most sensitve result available.

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified