Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

The potential of a substance to cause long-term systemic effects can be judged based on the results of repeated dose toxicity testing. In August 2013 ECHA published a final review report “Evaluation of new scientific evidence concerning DINP and DIDP”. For repeated dose toxicity ECHA considered hepatic effects as the endpoint for DNEL derivation. These were considered the most sensitive endpoint and considered appropriate for risk assessment of the substances. The liver effects seen in rodent studies have been evaluated by multiple bodies and been determined not to be relevant or of questionable relevance to human risk assessment (Pugh et al 2000, Hasmall et al 1999, Corton et al 2013, EPL 1999, Berry 2012), and comments to this effect have been submitted to ECHA. However, given the use of hepatic effects in the recent ECHA evaluation consideration of appropriate NOAELs and assessment factors (AF) for the endpoint is provided along with derivation of a reference DNEL for liver effects.The most appropriate endpoint for derivation of DNELs is the rat oral NOAEL of 32 mg/kg-bw/day assumed from pooling data on the same endpoint from two chronic dietary feeding studies in F344 rats. These studies are entered as robust study summaries in the dossier and are deemed suitable for pooled analysis based on availability of individual animal data, similar population and exposures. The Moore et al. 98 study report and the Lington et al. 97 publication/ ExxonMobil 86 study reporteach had sufficient power to detect significant increases in the incidence of spongiosis hepatis (Table 1). While other effects were noted at higher doses (e.g.,hepatic neoplasms, increased mortality, organ weight changes), the effect commonly used to derive a point of depature in DINP risk assessments is incidence of spongiosis hepatis(Phthalate 2001;Agency 2013). Given its history of use, it was selected as the health endpoint of interest for BMD modeling.There is a histology methodology difference among the studies that may have led to differences in the number of spongiosis hepatis cases observed, but these have been adjusted for using standard probability theory prior to pooled analysis.The resulting NOAEL is conservative by nature since the mechanism of toxicity, peroxisome proliferation via PPARα, is not relevant to humans. 

Greater detail can be found the commentaries attached in IUCLID section 7 (Toxicological Information) or 13 (Assessment Reports) of the dossier provided to ECHA during the reevaluation process and titled: “RA Weight of Evidence DINP and DIDP JW Bridges Nov 26 2012”, “Comments on the ECHA Draft Review Report on Di-isononyl Phthalate (DINP) and Di-isodecyl Phthalate (DIDP) ”, and “Application of Chemical Specific Adjustment Factors DINP DIDP”.

Table 1. Overview of Original Reported Spongiosis Hepatis Incidence from Study 1 and Study 2

Study 1

Study 2

Dose (mg/kg/day)

n

Incidence of Spongiosis Hepatis

Fraction of Spongiosis Hepatis

Dose (mg/kg/day)

n

Incidence of Spongiosis Hepatis

Fraction of Spongiosis Hepatis

0

81

22

0.272

0

55

6

0.109

15

80

24

0.300

 

 

29

50

6

0.120

 

88

50

3

0.060

152

80

51**

0.638

 

307

80

62**

0.775

 

 

359

55

18**

0.327

 

733

55

26**

0.473

** P≤0.01 compared to control by Fisher’s Exact test

After statistically adjusting for the number of slides examined per liver per study, based on standard probability theory and the same method used by Babich and Green (2000), the resulting dose response for spongiosis hepatis is used for BMD modeling (Table 2).  

 

Table 2. Data used in BMD Calculation for Pooled F344 Chronic Studies

Study 1

Study 2

Dose (mg/kg/day)

n

Observedn4with spongiosis hepatis

Observedp4for spongiosis hepatis

Dose (mg/kg/day)

n

Observedn1with spongiosis hepatis

Observedp1

Calculatedp4

Calculatedn4with Spongiosis Hepatis

0

61

20

0.33

0

41

5

0.12

0.41

16.8

15

55

18

0.33

 

 

29

35

4

0.11

0.38

13.3

 

88

39

2

0.05

0.19

7.4

152

50

33

0.66

 

307

51

42

0.82

 

 

359

36

12

0.33

0.80

28.8

 

733

32

18

0.56

0.96

30.7

 

Dose response was evaluated using eight different models for dichotomous data. Data was modeling including and excluding the 88 mg/kg/day dose group from Study 2. Table 3 shows every model indicated poor goodness-of-fit for the models (P values less than 0.10), with the scaled residual of interest also being the scaled residual furthest from the BMR curve in 7 of 8 models.

Table 3. Descriptive Characteristics for BMD Models Including All Doses

Model Name

P-value

Scaled Residual of Interest

Scaled Residual Furthest from BMR curve

AIC

BMD

BMDL

BMDU

BMD Uncertainty

Gamma

0.0151

-2.992

-2.992

466.7

92.4

49.9

N.C.

N.C.

Logistic

0.0155

-3.308

-3.308

466.5

67.9

56.9

N.C.

N.C.

LogLogistic

0.0349

-2.775

-2.775

464.6

101.4

66.2

N.C.

N.C.

LogProbit

0.0377

-2.731

-2.731

464.4

103.6

69.2

N.C.

N.C.

Multistage

0.0048

-3.233

-3.233

467.4

69.1

38.4

N.C.

N.C.

Probit

0.0077

-3.296

-3.296

467.8

72.4

61.0

N.C.

N.C.

Weibull

0.0104

-3.199

-3.199

467.7

78.5

43.0

N.C.

N.C.

Quantal-Linear

0.0072

0.047

-3.797

468.6

44.1

33.9

N.C.

N.C.

Given the poor model fits and relatively large scale residuals the results were reanalyzed following exclusion of the 88 mg/kg/day group from the analysis (Table 4). Other analyses have considered the 88 mg/kg/day group an outlier(Babich and Osterhout 2010).

Table 4. Descriptive Characteristics for BMD Models Excluding 88 mg/kg/day dose

Model Name

P-value

Scaled Residual of Interest

Scaled Residual Furthest from BMR curve

AIC

BMD

BMDL

BMDU

BMD Uncertainty

Gamma

0.8191

-0.262

-0.677

415.494

47.3

31.8

101

69.2

Logistic

0.647

-0.24

1.025

415.117

66.9

55.2

84.0

28.8

Log Logistic

0.8748

-0.012

-0.779

415.157

60.0

23.2

113

89.8

Log Probit

0.9126

0.03

-0.727

414.917

58.9

23.4

111

87.6

Multistage

0.8028

-0.262

0.642

414.789

41.9

31.7

74.6

48.0

Probit

0.3713

-0.297

-1.472

416.611

72.6

60.5

90.5

30.0

Weibull

0.8128

-0.306

-0.707

415.532

44.0

31.8

90.8

59.1

Quantal-Linear

0.903

-0.332

-0.722

413.541

41.9

31.7

57.6

25.9

 

For all the models the absolute scaled residual was less than two 2, further confirming adequate model fits. The obtained BMD values ranged from 41.9 to 72.6 mg/kg/day, with corresponding BMDLs ranging from 23.2 to 60.5. The model with the lowest AIC value and narrowest 95% confidence interval was the Quantal-Linear model with a BMD of 41.9 and BMDL of 31.7. Given the similarity of multiple models, a BMDL of 32 mg/kg-day is a reasonable approximation. This value is close to the 29 mg/kg/day exposure from Study 2, which found incidence of spongiosis hepatis lower than controls. The comparison of modeled and observed data suggest close agreement, if not a conservative estimate, of the dose expected to cause a 10% increase in spongiosis hepatis incidence.In all cases, calculations were based on default assumptions as defined in the REACH guidance document. 

 

 

Study

Doses (mg/kg/day)

NOAEL or BMDL10

LOAEL or BMD10

DINP ExxonMobil Chronic Rat Male

15

152

307

15

152

DINP Aristech Chronic Rat Male

29

88

358

733

88

358

DINP Pooled Analysis Rat Male

All doses noted above included in analysis

32

73

 

The following reference DNELs are conservative by nature and are protective of all effects.

Uncertainty

Adjustment Factor

Justification

Chronic studies

1

No adjustment necessary

Interspecies differences

4

Used species specific allometric scaling factors (REACH guidance)  Studies in-vivo primate studies and in-vitro culture studies with human hepatocytes indicate humans are refractory to these liver effects (Pugh et al 2000, Hasmall et al 1999).  No additional dynamic factor is considered necessary for the interspecies adjustment since humans are considered refractory to the hepatic effects (see detailed commentaries attached in IUCLID section 13)

Intraspecies differences

5

Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 5 is considered appropriate for the general population. This value is between those approximate associated with the 95thpercentile (6) and the 90thpercentile (4) on the basis of intraspecies human variability in the database of Hattis et al 2002.

Overall Adjustment Factor

20

 

 

Study

NOAEL or BMDL10

(mg/kg bw/day)

AF

Reference DNEL

(mg/kg bw/day)

DINP ExxonMobil Chronic Rat Male

15

20

0.75

 

DINP Aristech Chronic Rat Male

88

20

4.4

 

DINP Pooled Analysis Rat Male

32

20

1.6

 

 

Multiple documents evaluating the appropriate Adjustment Factor usage for DINP/DIDP have been attached in IUCLID section 13 (titles provided above). These evaluations generated Adjustment Factors from 3.13 (derived using chemical specific adjustment factor derivation guidance) to 20 (applying ECHA guidance and justification provided above for not including the 2.5 toxicdynamic factor for the interspecies AF). Using the identified NOAELs or BMDL10 values above with these Adjustment Factors give a reference DNEL range of 0.75 mg/kg bw/day to 4.4 mg/kg bw/day. This value is considered protective of potential human health effects.

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL.

 

The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

  • Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

 

  • Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

 

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor.

 

In order to retain the scientific credibility in its DNEL setting process, the DINP REACH Consortium will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

WORKERS

Inhalation

Due to its extremely low vapour pressure, DINP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. At 20ºC, DINP has a vapour pressure of 6E10-5 Pa and a calculated saturated vapour concentration of 10 µg/m3

At high temperatures and mechanical pressures, aerosol formation is observed with DINP like with other phthalates. Exposure to aerosol is therefore possible in any situation where pure DINP is heated or materials containing DINP are heated under influence of mechanical pressure. Exposure to DINP aerosol is likely to result in limited absorption through the lungs and is more likely to result in oral absorption due to mucocilliary clearance. The protective value used to calculate and inhalation DNEL is derived from the oral NOAEL 32 mg/kg/day as opposed to the data presented in the 2-week repeated dose study with aerosolized DIDP in which the limit dose was tested and no systemic effects were reported. 

Dose descriptor

rat oral NOAEL = 32 mg/kg/day

Assumptions

100% oral absorption regardless of species

100% inhalation absorption regardless of species

Modification of dose descriptor calculation B.3 in ECHA Guidance R.8

 

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

inhalatory NOAEC= 32 * (1/0.38) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 56.4 mg/m3

Assessment factors – Based on ECETOC guidance document #86

Uncertainty

AF

Justification

workers

3

default workers

Overall AF

3

 

DNELworker inhalation= 56.4 mg/m3/ 3

                                             = 18.8 mg/m3



Dermal

DINP, like other high molecular weight phthalates, has a very low dermal penetration rate (2-4%). While a repeated dose dermal study is available for DINP, it is not suitable for DNEL calculation due to several study limitations;it is an old study (1969) performed prior to GLP, a small number of animals were used (n=4 per group where 2 were abraded and 2 were not), there was an in-house infection in which animals in the control and treated groups died and the others required pharmacological intervention, an incomplete histopathological analysis was performed (only liver, kidney, and skin were examined).

 

A dermal DNEL will be calculated from route to route extrapolation from the rat oral NOAEL of 32 mg/kg/day. This value is expected to be protective since there are clear dose responses via the oral route of exposure and it is highly unlikely that enough material could be applied to animals, since the dermal penetration rate is so low (2%), to observe similar effects.

Dose descriptor 

rat oral NOAEL = 32 mg/kg/day.

Assumptions

100% oral absorption regardless of species

2% dermal absorption regardless of species

Modification of dose descriptor

Route-to-route extrapolation (calculation B.5 in ECHA Guidance R.8):

dermal NOAEL = oral NOAEL * (ABS oral / ABS dermal)

dermal NOAEL = 32 mg/kg/day * (100/2)

dermal NOAEL = 1600 mg/kg/day

Assessment factors – Based on ECETOC guidance document #86

Uncertainty

AF

Justification

Allometric scaling

4

default for the rat

Intraspecies differences

3

default AF for workers

Overall AF

12

 


DNELworker dermal   = 1600 mg/kg bwt/d / 12

= 133.3 mg/kg bwt/d

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The potential of a substance to cause long-term systemic effects can be judged based on the results of repeated dose toxicity testing. In August 2013 ECHA published a final review report “Evaluation of new scientific evidence concerning DINP and DIDP”. For repeated dose toxicity ECHA considered hepatic effects as the endpoint for DNEL derivation. These were considered the most sensitive endpoint and considered appropriate for risk assessment of the substances. The liver effects seen in rodent studies have been evaluated by multiple bodies and been determined not to be relevant or of questionable relevance to human risk assessment (Pugh et al 2000, Hasmall et al 1999, Corton et al 2013, EPL 1999, Berry 2012), and comments to this effect have been submitted to ECHA. However, given the use of hepatic effects in the recent ECHA evaluation consideration of appropriate NOAELs and assessment factors (AF) for the endpoint is provided along with derivation of a reference DNEL for liver effects. The DNEL derivation approach outlined below disagrees with that of ECHA in the re-evaluation. The basis for this different view is outlined below. Greater detail can be found in the commentaries attached in IUCLID section 7 (Toxicological Information) or 13 (Assessment Reports) titled: “RA Weight of Evidence DINP and DIDP JW Bridges Nov 26 2012”, “Comments on the ECHA Draft Review Report on Di-isononyl Phthalate (DINP) and Di-isodecyl Phthalate (DIDP) ”, and “Application of Chemical Specific Adjustment Factors DINP DIDP”.

For the ECHA assessment a NOAEL of 15 mg/kg bw/day based on spongiosis hepatis in male rats was selected to derive the overall DNEL (see IUCLID section 7.5.1 for summary of ExxonMobil 1986 chronic exposure study). In this approach ECHA chose not to use the Aristech (1998) study detailed in this registration dossier that has a NOAEL of 88 mg/kg bw/day, nor an alternative lower NOAEL of 29 mg/kg day/day dose group from the Aristech study, and disregarding an alternative approach pooling data from both Aristech and ExxonMobil studies to derive a BMDL10 of 32 mg/kg bw/day:

Study

Doses (mg/kg/day)

NOAEL or BMDL10

LOAEL or BMD10

DINP ExxonMobil Chronic Rat Male

15

152

307

15

152

DINP Aristech Chronic Rat Male

29

88

358

733

88

358

DINP Pooled Analysis Rat Male

All doses noted above included in analysis

32

42

 

Similar to the reevaluation, DNELs have been derived using all three studies above. The following reference DNELs are conservative by nature and are protective of all effects.

 

Uncertainty

Adjustment Factor

 Justification

Chronic studies

1

No adjustment necessary

Interspecies differences

4

Used species specific allometric scaling factors (REACH guidance)  Studies in-vivo primate studies and in-vitro culture studies with human hepatocytes indicate humans are refractory to these liver effects (Pugh et al 2000, Hasmall et al 1999).  No additional dynamic factor is considered necessary for the interspecies adjustment since humans are considered refractory to the hepatic effects (see detailed commentaries attached in IUCLID section 13)

Intraspecies differences

5

Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 5 is considered appropriate for the general population. This value is between those approximate associated with the 95thpercentile (6) and the 90thpercentile (4) on the basis of intraspecies human variability in the database of Hattis et al 2002.

Overall Adjustment Factor

20

 

 

 

Study

NOAEL or BMDL10

(mg/kg bw/day)

AF

Reference DNEL

(mg/kg bw/day)

DINP ExxonMobil Chronic Rat Male

15

20

0.75

 

DINP Aristech Chronic Rat Male

88

20

4.4

 

DINP Pooled Analysis Rat Male

32

20

1.6

 

 

Multiple documents evaluating the appropriate Adjustment Factor usage for DINP/DIDP were produced in response to the ECHA RA report, which have been attached in IUCLID section 13 (titles provided above). These evaluations generated Adjustment Factors from 3.13 (derived using chemical specific adjustment factor derivation guidance) to 20 (applying ECHA guidance and justification provided above for not including the 2.5 toxicodynamic factor for the interspecies AF). Using the identified NOAELs or BMDL10 values above with these Adjustment Factors give a reference DNEL range of 0.75 mg/kg bw/day to 4.4 mg/kg bw/day. This value is considered protective of potential human health effects.