N,N'-diphenyl-p-phenylenediamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.41 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

7.05 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC corrected inhalative = 8 * (50/100) * (1/0.38) * (6.7/10) = 7.05 mg/m³

AF for dose response relationship:

1

Justification:

Default assessment factor for NOAEL as starting point (ECHA Guidance, Chapter R.8, 2012)

AF for differences in duration of exposure:

1

Justification:

The available information indicate that adverse effects of DPPD are restricted to pregnancy. In the OECD 421 study, the entire pregnancy period in the rat is covered, and therefore, an assessment factor for exposure duration is not considered necessary.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to ECHA Guidance, Chapter R.8, 2012.

AF for other interspecies differences:

1

Justification:

A mechanism of the prolonged gestation period caused by DPPD has been investigated in the literature:
Marois (Bull. Acad. Natl. Med;1982(3):581-95, 1998) found that a single application of PGF2α on the 21st day of gestation re-establishes the normal onset of parturition in rats that had previously been treated with DPPD from day 14 of gestation onwards. Fujita et al. (Experentia 38(12), 1472, 1982) found that DPPD inhibited the synthesis of PGE in rabbit kidney medulla slices. Yohko et al. (J. Pharm. PHarmacol, 1984, 36:195-197) that this inhibition could be reversed by addition of arachidonic acid.
These results indicate that prolongation of the gestation period of DPPD is mediated by an inhibition of PGF2α and/or PGE2.

PGF2α and PGE2 are known to be critical modulators of parturition in rats and mice by induction of luteolysis (PGF2α) and cervix ripening (PGE2), respectively, prior to birth. While the effects in mediated by PGE2 in this context are comparable in rats and humans, a significant interspecies difference exists regarding the influence of PGF2α: In humans and guinea pigs, luteolysis is not a key event to initiate parturition. Birth can begin without a prior decrease in progesterone levels. For mice and rats, this process is, however, critical (Welsh et al., J. PHysiol. 569.3(2005) 903-912).
In conclusion, human relevance of this mode of action can thus not be excluded: The DPPD effects mediated by interference with PGE2 may in principle also be relevant to humans; however, interference with PGF2α represents a second crucial modulator in rats, which is irrelevant in humans. It is therefore likely that the rat represents a quantitative and qualitative worst case compared to humans. Therefore, the default assessment factors (acc. to ECHA GD R8) have been modified into a substance specific assessment factor of 1 considering the intrinsic hazard properties of DPPD.

AF for intraspecies differences:

5

Justification:

A default factor of 5 for workers according to ECHA Guidance, Chapter R.8, 2012.

AF for the quality of the whole database:

1

Justification:

GLP Guideline Study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

0.4 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to R8 ECHA 2012 in general, it can be assumed that dermal absorption will not be higher than oral absorption, and thus no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation

AF for dose response relationship:

1

Justification:

Default assessment factor for NOAEL as starting point (ECHA Guidance, Chapter R.8, 2012)

AF for differences in duration of exposure:

1

Justification:

The available information indicate that adverse effects of DPPD are restricted to pregnancy. In the OECD 421 study, the entire pregnancy period in the rat is covered, and therefore, an assessment factor for exposure duration is not considered necessary.

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor for allometric scaling according to ECHA Guidance, Chapter R.8, 2012

AF for other interspecies differences:

1

Justification:

A mechanism of the prolonged gestation period caused by DPPD has been investigated in the literature:
Marois (Bull. Acad. Natl. Med;1982(3):581-95, 1998) found that a single application of PGF2α on the 21st day of gestation re-establishes the normal onset of parturition in rats that had previously been treated with DPPD from day 14 of gestation onwards. Fujita et al. (Experentia 38(12), 1472, 1982) found that DPPD inhibited the synthesis of PGE in rabbit kidney medulla slices. Yohko et al. (J. Pharm. PHarmacol, 1984, 36:195-197) that this inhibition could be reversed by addition of arachidonic acid.
These results indicate that prolongation of the gestation period of DPPD is mediated by an inhibition of PGF2α and/or PGE2.

PGF2α and PGE2 are known to be critical modulators of parturition in rats and mice by induction of luteolysis (PGF2α) and cervix ripening (PGE2), respectively, prior to birth. While the effects in mediated by PGE2 in this context are comparable in rats and humans, a significant interspecies difference exists regarding the influence of PGF2α: In humans and guinea pigs, luteolysis is not a key event to initiate parturition. Birth can begin without a prior decrease in progesterone levels. For mice and rats, this process is, however, critical (Welsh et al., J. PHysiol. 569.3(2005) 903-912).
In conclusion, human relevance of this mode of action can thus not be excluded: The DPPD effects mediated by interference with PGE2 may in principle also be relevant to humans; however, interference with PGF2α represents a second crucial modulator in rats, which is irrelevant in humans. It is therefore likely that the rat represents a quantitative and qualitative worst case compared to humans. Therefore, the default assessment factors (acc. to ECHA GD R8) have been modified into a substance specific assessment factor of 1 considering the intrinsic hazard properties of DPPD.

AF for intraspecies differences:

5

Justification:

A default factor of 5 for workers according to ECHA Guidance, Chapter R.8, 2012.

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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

Several repeated dose studies are available based on which a DNEL could be derived:

In a 28-day study in rats according to OECD 407 (Matsumoto et al., 2013), DPPD was administered via gavage at 100, 300 and 1000 mg/kg bw/d. The only relevant findings were significantly reduced food consumpation during week 4 in the males of the 300 mg/k group and during weeks 3 and 4 in the males of the 1000 mg/kg group. However, this was not accompanied by any effects on body weight or body weight gain. In addition, total bilirubin was significantly increased in the males of all treatment groups at the end of the treatment period. This increase had reversed at the end of the recovery period. No histopathological correlates were found in the liver, and bilirubin or urobilirubinogen levels in urine did not increase. Therefore, the NOAEL in this study is 1000 mg/kg bw/d.

In a long-term feeding study, Hasegawa et al. (1989) treated rats with DPPD via the diet (0.5 or 2% of DPPD) for 104 weeks. A LOAEL of 0.5% was observed in this study (corresponding to 194 mg/kg for males and to to 259 mg/kg for females), based on haematological alterations (in females), changes in clinical biochemistry parameters, organ weight effects and histopathological findings. This study is less well documented than the one by Matsumoto et al. (2013) and is therefore evaluated as supporting evidence only.

The most sensitive endpoint for DNEL derivation is fertility, as is demonstrated in a screening study for reproductive / developmental toxicity (Matsumoto et al., 2013) according to OECD TG 421. DPPD was applied to rats at 8, 50 and 300 mg/kg bw/d by gavage. Gestation times were significantly elongated in females in the 50 and 300 mg/kg group. From gestation day 22 onwards, severe clinical signs (pale skin, piloerection, hypothermia), mortality, dystocia were observed in females in the 300 mg/kg group. Several offspring parameters were dose-dependently decreased, especially in the 300 mg/kg group: no. of pups born, delivery index, no. of live pups, birth index and live birth index. None of these changes was statistically significant.

The NOAEL with regard to maternal toxicity was 50 mg/kg in this study (based on mortality and clinical signs in the highest dose group), and the NOAEL with regard to reproductive toxicity was 8 mg/kg (elongated gestation times at higher doses).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected