Benzenamine, N-phenyl-, reaction products with 2,4,4-trimethylpentene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.31 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:

other: LOAEL in F0 generation of OECD 443, NOAEL in F1 adult generation of OECD 443

Value:

18 mg/kg bw/day

Value:

15.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/80%   0.38 m3/kg bw   6.7 m3/10 m3	Ratio of oral to inhalation absorption   Respiratory volume of a rat, corrected for 8 h exposure   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest
Modified dose-descriptor	NOAEC corrected = 18 * (39/80) * (1/0.38) * (6.7/10) = 15.5 mg/m3

for details on absorption estimation, please refer to IUCLID section 7.1 (toxicokinetics)

AF for dose response relationship:

2

Justification:

point of departure for DNEL derivation was LOAEL in F0 generation of OECD 443 and NOAEL in adult F1 rats of same study. The effects in the F0 generation were limited and weak, therefore an assessment factor of 2 was chosen since the POD did not correspond to a NOAEL in all animals, but only very mild toxicity was observed in some of the animals.

AF for differences in duration of exposure:

2

Justification:

Treatment period was 17-19 weeks in OECD 443 for F0 generation and 18 weeks in OECD 443 for F1 generation. This is very closely corresponding to the 12 weeks standard exposure time of a subchronic toxicity study (OECD 408), for which a factor of 2 is the recommended assessment factor for duration of exposure in ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

1

Justification:

not required (according to ECHA guidance document R.8)

AF for other interspecies differences:

2.5

Justification:

default factor for interspecies differences (according to ECHA guidance document R.8)

AF for intraspecies differences:

5

Justification:

default factor for intraspecies differences (according to ECHA guidance document R.8)

AF for the quality of the whole database:

1

Justification:

GLP and Guideline study

AF for remaining uncertainties:

1

Justification:

covered by interspecies factor

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:

0.44 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:

other: LOAEL in F0 generation of OECD 443, NOAEL in F1 adult generation of OECD 443

Value:

18 mg/kg bw/day

Value:

87.75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/8%	Ratio of oral to dermal absorption
Modified dose-descriptor	NOAEC corrected = 18 * (39/8) = 87.75 mg/kg bw/d

for details on absorption estimation, please refer to IUCLID section 7.1 (toxicokinetics)

AF for dose response relationship:

2

Justification:

point of departure for DNEL derivation was LOAEL in F0 generation of OECD 443 and NOAEL in adult F1 rats of same study. The effects in the F0 generation were limited and weak, therefore an assessment factor of 2 was chosen since the POD did not correspond to a NOAEL in all animals, but only very mild toxicity was observed in some of the animals.

AF for differences in duration of exposure:

2

Justification:

Treatment period was 17-19 weeks in OECD 443 for F0 generation and 18 weeks in OECD 443 for F1 generation. This is very closely corresponding to the 12 weeks standard exposure time of a subchronic toxicity study (OECD 408), for which a factor of 2 is the recommended assessment factor for duration of exposure in ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

default (according to ECHA Guidance R.8)

AF for other interspecies differences:

2.5

Justification:

default factor for interspecies differences (according to ECHA guidance document R.8)

AF for intraspecies differences:

5

Justification:

default factor for intraspecies differences (according to ECHA guidance document R.8)

AF for the quality of the whole database:

1

Justification:

Guideline and GLP study

AF for remaining uncertainties:

1

Justification:

not required

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

DNEL inhalation, long-term, systemic (worker):

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/80%   0.38 m3/kg bw   6.7 m3/10 m3	Ratio of oral to inhalation absorption   Respiratory volume of a rat, corrected for 8 h exposure   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest
Modified dose-descriptor	NOAEC corrected = 18 * (39/80) * (1/0.38) * (6.7/10) = 15.5 mg/m3
Step 3) Assessment factors
Allometric scaling	1	not required (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	5	Accounting for differences in worker population
Exposure duration	2	OECD 443 with 18 weeks treatment as starting point
Dose response	2	LOAEL in F0 parental animals is used as starting point, but is considered NOAEL in F1 adult rats
Quality of database	1	Guideline and GLP study
DNEL	Value
	15.5 / (1 x 2.5 x 5 x 2 x 2 x 1) = 0.31 mg/m3

 

 

DNEL dermal, long-term, systemic (worker):

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/8%	Ratio of oral to dermal absorption
Modified dose-descriptor	NOAEC corrected = 18 * (39/8) = 87.75 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Default allometric scaling factor for rat to human (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	5	Accounting for differences in worker population
Exposure duration	2	OECD 443 with 18 weeks treatment as starting point
Dose response	2	LOAEL in F0 parental animals is used as starting point, but is considered NOAEL in F1 adult rats
Quality of database	1	Guideline and GLP study
DNEL	Value
	87.75 / (4 x 2.5 x 5 x 2 x 2 x 1) = 0.44 mg/kg bw/d

 

 

General Population - 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):

100

Dose descriptor starting point:

other: LOAEL in F0 generation of OECD 443, NOAEL in F1 adult generation of OECD 443

Value:

18 mg/kg bw/day

Value:

7.63 mg/m³

Explanation for the modification of the dose descriptor starting point:

Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/80%   1.15 m3/kg bw	Ratio of oral to inhalation absorption (default according to ECHA guidance R.8) Respiratory volume of a rat, corrected for 24 h exposure
Modified dose-descriptor	NOAEC corrected = 18 * (39/80) * (1/1.15) = 7.63 mg/m3

for details on absorption estimation, please refer to IUCLID section 7.1 (toxicokinetics)

AF for dose response relationship:

2

Justification:

point of departure for DNEL derivation was LOAEL in F0 generation of OECD 443 and NOAEL in adult F1 rats of same study. The effects in the F0 generation were limited and weak, therefore an assessment factor of 2 was chosen since the POD did not correspond to a NOAEL in all animals, but only very mild toxicity was observed in some of the animals.

AF for differences in duration of exposure:

2

Justification:

Treatment period was 17-19 weeks in OECD 443 for F0 generation and 18 weeks in OECD 443 for F1 generation. This is very closely corresponding to the 12 weeks standard exposure time of a subchronic toxicity study (OECD 408), for which a factor of 2 is the recommended assessment factor for duration of exposure in ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

1

Justification:

not required (according to ECHA guidance document R.8)

AF for other interspecies differences:

2.5

Justification:

default factor for interspecies differences (according to ECHA guidance document R.8)

AF for intraspecies differences:

10

Justification:

default factor for intraspecies differences (according to ECHA guidance document R.8)

AF for the quality of the whole database:

1

Justification:

Guideline and GLP study

AF for remaining uncertainties:

1

Justification:

not required

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:

0.22 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):

400

Dose descriptor starting point:

other: LOAEL in F0 generation of OECD 443, NOAEL in F1 adult generation of OECD 443

Value:

18 mg/kg bw/day

Value:

87.75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/8%	Ratio of oral to dermal absorption
Modified dose-descriptor	NOAEC corrected = 18 * (39/8) = 87.75 mg/kg bw/d

for details on absorption estimation, please refer to IUCLID section 7.1 (toxicokinetics)

AF for dose response relationship:

2

Justification:

point of departure for DNEL derivation was LOAEL in F0 generation of OECD 443 and NOAEL in adult F1 rats of same study. The effects in the F0 generation were limited and weak, therefore an assessment factor of 2 was chosen since the POD did not correspond to a NOAEL in all animals, but only very mild toxicity was observed in some of the animals.

AF for differences in duration of exposure:

2

Justification:

Treatment period was 17-19 weeks in OECD 443 for F0 generation and 18 weeks in OECD 443 for F1 generation. This is very closely corresponding to the 12 weeks standard exposure time of a subchronic toxicity study (OECD 408), for which a factor of 2 is the recommended assessment factor for duration of exposure in ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

default (according to ECHA Guidance R.8)

AF for other interspecies differences:

2.5

Justification:

default factor for interspecies differences (according to ECHA guidance document R.8)

AF for intraspecies differences:

10

Justification:

default factor for intraspecies differences (according to ECHA guidance document R.8)

AF for the quality of the whole database:

1

Justification:

Guideline and GLP study

AF for remaining uncertainties:

1

Justification:

not required

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:

0.05 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):

400

Dose descriptor starting point:

other: LOAEL in F0 generation of OECD 443, NOAEL in F1 adult generation of OECD 443

Value:

18 mg/kg bw/day

Value:

18 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/39%	No differences in oral absorption expected between rats and humans Substance was administered in feed
Modified dose-descriptor	NOAEC corrected = 18 * (39/39) = 18 mg/kg bw/d

for details on absorption estimation, please refer to IUCLID section 7.1 (toxicokinetics)

AF for dose response relationship:

2

Justification:

point of departure for DNEL derivation was LOAEL in F0 generation of OECD 443 and NOAEL in adult F1 rats of same study. The effects in the F0 generation were limited and weak, therefore an assessment factor of 2 was chosen since the POD did not correspond to a NOAEL in all animals, but only very mild toxicity was observed in some of the animals.

AF for differences in duration of exposure:

2

Justification:

Treatment period was 17-19 weeks in OECD 443 for F0 generation and 18 weeks in OECD 443 for F1 generation. This is very closely corresponding to the 12 weeks standard exposure time of a subchronic toxicity study (OECD 408), for which a factor of 2 is the recommended assessment factor for duration of exposure in ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

default (according to ECHA Guidance R.8)

AF for other interspecies differences:

2.5

Justification:

default (according to ECHA Guidance R.8)

AF for intraspecies differences:

10

Justification:

default (according to ECHA Guidance R.8)

AF for the quality of the whole database:

1

Justification:

Guideline and GLP study

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:

no hazard identified

Additional information - General Population

DNEL inhalation, long-term, systemic (general population):

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/80%   1.15 m3/kg bw	Ratio of oral to inhalation absorption (default according to ECHA guidance R.8) Respiratory volume of a rat, corrected for 24 h exposure
Modified dose-descriptor	NOAEC corrected = 18 * (39/80) * (1/1.15) = 7.63 mg/m3
Step 3) Assessment factors
Allometric scaling	1	not required (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	10	Accounting for differences in general population
Exposure duration	2	OECD 443 with 18 weeks treatment as starting point
Dose response	2	LOAEL in F0 parental animals is used as starting point, but is considered NOAEL in F1 adult rats
Quality of database	1	Guideline and GLP study
DNEL	Value
	7.63 / (1 x 2.5 x 10 x 2 x 2 x 1) = 0.08 mg/m3

 

DNEL dermal, long-term, systemic (general population):

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/8%	Ratio of oral to dermal absorption
Modified dose-descriptor	NOAEC corrected = 18 * (39/8) = 87.75 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Default allometric scaling factor for rat to human (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	10	Accounting for differences in general population
Exposure duration	2	OECD 443 with 18 weeks treatment as starting point
Dose response	2	LOAEL in F0 parental animals is used as starting point, but is considered NOAEL in F1 adult rats
Quality of database	1	Guideline and GLP study
DNEL	Value
	87.75 / (4 x 2.5 x 10 x 2 x 2 x 1) = 0.22 mg/kg bw/d

 

DNEL oral, long-term, systemic (general population):

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL/NOAEL: 18 mg/kg bw/day	as determined in OECD 443 study in rats (based on increased ALP and decreased albumin in F1 animals)
Step 2) Modification of starting point	39%/39%	No differences in oral absorption expected between rats and humans Substance was administered in feed
Modified dose-descriptor	NOAEC corrected = 18 * (39/39) = 18 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Default allometric scaling factor for rat to human (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	10	Accounting for differences in general population
Exposure duration	2	OECD 443 with 18 weeks treatment as starting point
Dose response	2	LOAEL in F0 parental animals is used as starting point, but is considered NOAEL in F1 adult rats
Quality of database	1	Guideline and GLP study
DNEL	Value
	18 / (4 x 2.5 x 10 x 2 x 2 x 1) = 0.05 mg/kg bw/d