N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.87 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.95

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEC

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.265 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.12 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Local effects

Long term exposure

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Most sensitive endpoint:

sensitisation (skin)

Additional information - workers

Acute/short-term local effects/ Long-term exposure local effects

The test substance 77PD showed a practically non-irritating potential to rabbit skin (Bayer AG 1990). The even very low skin irritation potential is confirmed by another skin irritation study (Monsanto Co. 1973). No eye irritating effects were noted in a GLP and OECD guideline study (Bayer AG 1990). An earlier eye irritation study revealed slight and transient eye irritating effects of 77PD (Monsanto Co. 1973).

There are several animal data for the sensitizing potential of 77PD from different data sources available; but the data are limited in documentation and also have some deficiencies concerning the study design and are not comparable with current guideline studies. However, in a weight of evidence approach the data indicate a rather moderate skin sensitizing potential of 77PD. This is in line with the available limited human data, which also indicate a rather moderate skin sensitizing potential.

Acute/short-term exposure systemic effects:

The acute oral toxicity of 77PD is moderate, indicated by an oral LD50 value of 730 mg/kg bw in Sprague-Dawley rats (Monsanto Co. 1973); based on this finding 77PD should be classified as harmful if swallowed. The acute dermal toxicity of 77PD is low, indicated by a dermal LD50 value of > 3160 mg/kg bw in rabbits after single application (Monsanto Co. 1973). Due to the moderate acute oral toxicity and the very low acute dermal toxicity of 77PD a limit exposure peaks to a factor of 8 is suggested. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic dermal: 0.265 mg/kg bw/day x 8 = 2.12 mg/kg bw/day

DNEL short-term systemic inhalation: 1.87 mg/m³ x 8 = 14.95 mg/m³

DNEL long-term exposure systemic

The data from the subchronic feeding study in rats (Monsanto Co. 1989) discussed under chapter repeated dose toxicity) are used for DNEL calculation. The derivated LOAEL of 250 ppm (15.9 mg/kg bw/day) based on slight reduction of body weight and body weight gain. This is in line with the effects seen in the subacute and the chronic feeding study as well as the generation study; which consistently showed effects on body weight and body weight gain.

Worker DNEL long-term systemic for oral route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected LOAEL 15.9 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic study): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 60

=>Worker DNEL long-term for oral route-systemic: 0.265 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

Worker DNEL long-term sytemic for dermal route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Differences in absorption Abs (oral-rat) / Abs (dermal-human): 1

=> Corrected LOAEL 15.9 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 60

=>Worker DNEL long-term for dermal route-systemic: 0.265 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

Worker DNEL long-term systemic for inhalation route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Respiratory volume rat (sRV) (worker (8 h): 1/0.38): 2.632

Differences in respiratory volume (default factor "light activity worker"): 0.67

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1*

Corrected LOAEC: 28 mg/m³

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 15

=>Worker DNEL long-term for inhalation route-systemic: 1.87 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

DNEL fertility

The effect of 77PD on fertility was evaluated in an early three-generation study (Monsanto Co. 1980). Rats were treated with 77PD concentrations of 30, 100 and 300 ppm in the diet for three successive generations. No adverse effects on foetal survival or on mating or fertility indices were indicated. Parental toxicity was indicated by reduced body weights and effects on liver and kidney weights. However the body weights of mid- and high dose pups as well as the survival during lactation were reduced; because of the limited documentation the relevance of these findings are unclear. Based on the data from this study a NOAEL fertility of 300 mg/kg (ca. 22.5 mg/kg bw/day, highest dose tested) is suggested. The NOAEL for parental toxicity is 100 ppm (ca. 7.5 mg/kg bw/day) and based on body weight changes and reduction in kidney and liver weights observed at 300 ppm (ca. 22.5 mg/kg bw/day). The NOAEL values observed for fertility and parental toxicity are above or in the range of the NOAEL and LOAEL values observed in the repeated dose toxicity studies; in addition parental toxicity observed is comparable to the effects seen in the repeated dose toxicity studies. It was considered that the systemic DNEL of 77PD covers fertility and also the parental toxicity. No additional DNEL fertility was calculated.

DNEL developmental toxicity

The developmental toxicity of the test substance 77PD was evaluated in a teratology study in rats (Monsanto Co. 1986). No relevant differences were observed in number of viable foetuses, number of implantations, post-implantation loss, number of corpora lutea and foetal sex distribution in treated animals compared to control. However, the mean foetal body weight value at 25 mg/kg/day was significantly higher than the control but was attributed to inherent biological variation. Malformations that were observed in the treated groups occurred in low incidence and were not considered treatment related. No meaningful differences were noted between the incidence of developmental variations seen in the treated groups and those in the control group. Based on the findings from this study a NOAEL developmental 150 mg/kg bw and day (highest dose tested) and a NOAEL maternal toxicity of 25 mg/kg bw and day are suggested. It was considered that the systemic DNEL of 77PD covers developmental toxicity and also the maternal toxicity. No additional DNEL fertility was calculated.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.461 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.69 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEC

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.133 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.06 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Local effects

Long term exposure

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.133 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.06 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

LOAEL

Additional information - General Population

Acute/short-term local effects/ Long-term exposure local effects

The test substance 77PD showed a practically non-irritating potential to rabbit skin (Bayer AG 1990). The even very low skin irritation potential is confirmed by another skin irritation study (Monsanto Co. 1973). No eye irritating effects were noted in a GLP and OECD guideline study (Bayer AG 1990). An earlier eye irritation study revealed slight and transient eye irritating effects of 77PD (Monsanto Co. 1973).

There are several animal data for the sensitizing potential of 77PD from different data sources available; but the data are limited in documentation and also have some deficiencies concerning the study design and are not comparable with current guideline studies. However, in a weight of evidence approach the data indicate a rather moderate skin sensitizing potential of 77PD. This is in line with the available limited human data, which also indicate a rather moderate skin sensitizing potential.

Acute/short-term exposure systemic effects

The acute oral toxicity of 77PD is moderate, indicated by an oral LD50 value of 730 mg/kg bw in Sprague-Dawley rats (Monsanto Co. 1973); based on this finding 77PD should be classified as harmful if swallowed. The acute dermal toxicity of 77PD is low, indicated by a dermal LD50 value of > 3160 mg/kg bw in rabbits after single application (Monsanto Co. 1973). Due to the moderate acute oral toxicity and the very low acute dermal toxicity of 77PD a limit exposure peaks to a factor of 8 is suggested. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic oral: 0.1325 mg/kg bw/day x 8 = 1.06 mg/kg bw/day

DNEL short-term systemic dermal: 0.1325 mg/kg bw/day x 8 = 1.06 mg/kg bw/day

DNEL short-term systemic inhalation: 0.461 mg/m³ x 8 = 3.69 mg/m³

General public long-term exposure systemic

General public long-term systemic for oral route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected LOAEL 15.9 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 120

=> General Public long-term for oral route-systemic: 0.133 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

General public long-term systemic for dermal route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Differences in absorption Abs (oral-rat) / Abs (dermal-human): 1

=> Corrected LOAEL 15.9 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 120

=>General public long-term for dermal route-systemic: 0.133 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

General public long-term systemic for inhalation route

Start point: LOAEL 15.9 mg/kg bw/day (subchronic feeding study in rats with 77PD, Monsanto 1989).

Respiratory volume rat (sRV) general public 1/1.15: 0.87

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1

=> Corrected LOAEC: 13.8 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 3***

Overall factor (product of individual factors): 30

=>General Public DNEL long-term for inhalation route-systemic: 0.461 mg/m3

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

**LOAEL based on effects (slight reduction of body weight and body weight gain) seen in subacute, subchronic and chronic rat feeding studies, in the same dose range

*** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

DNEL fertility

The effect of 77PD on fertility was evaluated in an early three-generation study (Monsanto Co. 1980). Rats were treated with 77PD concentrations of 30, 100 and 300 ppm in the diet for three successive generations. No adverse effects on foetal survival or on mating or fertility indices were indicated. Parental toxicity was indicated by reduced body weights and effects on liver and kidney weights. However the body weights of mid- and high dose pups as well as the survival during lactation were reduced; because of the limited documentation the relevance of these findings are unclear. Based on the data from this study a NOAEL fertility of 300 mg/kg (ca. 22.5 mg/kg bw/day, highest dose tested) is suggested. The NOAEL for parental toxicity is 100 ppm (ca. 7.5 mg/kg bw/day) and based on body weight changes and reduction in kidney and liver weights observed at 300 ppm (ca. 22.5 mg/kg bw/day). The NOAEL values observed for fertility and parental toxicity are above or in the range of the NOAEL and LOAEL values observed in the repeated dose toxicity studies; in addition parental toxicity observed is comparable to the effects seen in the repeated dose toxicity studies. It was considered that the systemic DNEL of 77PD covers fertility and also the parental toxicity. No additional DNEL fertility was calculated.

DNEL developmental toxicity

The developmental toxicity of the test substance 77PD was evaluated in a teratology study in rats (Monsanto Co. 1986). No relevant differences were observed in number of viable foetuses, number of implantations, post-implantation loss, number of corpora lutea and foetal sex distribution in treated animals compared to control. However, the mean foetal body weight value at 25 mg/kg/day was significantly higher than the control but was attributed to inherent biological variation. Malformations that were observed in the treated groups occurred in low incidence and were not considered treatment related. No meaningful differences were noted between the incidence of developmental variations seen in the treated groups and those in the control group. Based on the findings from this study a NOAEL developmental 150 mg/kg bw and day (highest dose tested) and a NOAEL maternal toxicity of 25 mg/kg bw and day are suggested. It was considered that the systemic DNEL of 77PD covers developmental toxicity and also the maternal toxicity. No additional DNEL fertility was calculated.