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

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). DIUP is not classified for acute toxicity; oral, dermal or inhalation. It does not present an acute hazard following skin and exposure via the oral route is not relevant for workers. 

 

Irritation

DIUP is not classified as an irritant and does not require the derivation of a DNEL for this endpoint. 

 

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity testing. The following DNELs are conservative by nature and are protective of all perceived adverse effects.  

For DIUP, the following NOAEC, presented in the IUCLID dossier, is deemed to be substantially protective of all potential adverse effects. 

 

Oral:
subchronic effects for DIDP: rat NOAEL = 150 mg/kg bw/d

 

Dermal

DIUP, like other high molecular weight phthalates, is anticipated to have a very low dermal penetration rate (2-4%). A dermal DNEL does not need to be calculated for long-term systemic effects since the route to route extrapolation from a well documented repeated dose oral study will result in a modified dose-descriptor that is well in excess of the limit dose used in testing. 

 

Inhalation

Due to its extremely low vapour pressure, DIUP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. An inhalationDNEL does not need to be calculated for long-term systemic effects since the route to route extrapolation from a well documented repeated dose oral study will result in a modified dose-descriptor that is well in excess of the limit dose used in testing.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term systemic effects

 

The potential of a substance to cause long-term systemic effects can be judged based on the results of repeated dose toxicity testing. Read across to DIDP is used in the IUCLID dossier for repeat dose toxicity. In August 2013 ECHA published a final review report “Evaluation of new scientific evidence concerning DINP and DIDP”. The entirety of this report is attached in the section 13 of the current dossier. In the report ECHA used repeated dose toxicity and reproductive toxicity for DNEL derivation. 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 the commentaries attached in section 13 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”.

For the ECHA assessment three studies Cho et al. 2008, 2010 (LOAEL of 22 mg/kg bw/day), BASF 1969b as cited in EC 2003b (NOAEL of 60 mg/kg bw/day) and Hazleton 1960b as cited in EC 2003b (NOAEL of 15 mg/kg bw/day) were combined in a WoE approach to derive the overall DNEL. In this approach ECHA chose not to use the ExxonMobil study detailed in this registration dossier that has a NOAEL of 150 mg/kg bw/d. Exclusion of the ExxonMobil study is not warranted and should be considered in any WoE approach for DNEL derivation. Additionally, though each DNEL was derived separately and were based on hepatic effects they were not the same hepatic effect. Similar to the reevaluation, DNELs were derived for each of these three studies used in the ECHA risk assessment as well as the ExxonMobil DIDP study. In addition a reference DNEL for women of child bearing age can be derived using the developmental toxicity NOAEL of 33 mg/kg bw/day. The following reference DNELs are conservative by nature and are protective of all effects.

 Table 41: Studies considered for reference DNEL derivation

Study

Doses (mg/kg/day)

NOAEL

LOAEL

Comments

DIDP BASF 90 d rat M

55

100

200

400

200

400

Dose-related increase of relative liver weights which were significant at all dose levels. Changes in absolute liver weights were only significant at 400 mg/kg/day. No histological lesions noted - lag in body weight gain in treatment groups

DIDP BASF 90 d F

60

120

250

500

120

250

Dose-related increase of relative liver weights which were significant at 120 mg/kg/day and higher. Changes in absolute liver weights were only significant at 250 & 500 mg/kg/day.

DIDP EM 90 d M

28

170

 

586

170

586

Absolute and relative liver weights were significantly increased at the high dose no histological changes

DIDP EM 90 d F

35

211

 

686

211

686

Absolute and relative liver weights were significantly increased at the high dose; no histological changes

DIDP 90 d dog M

15

77

 

307

15

77

Liver weight increase accompanied by swollen and vacuolated hepatocytes at higher doses

DIDP 90 d dog F

16

88

 

320

16

88

Liver weight increase accompanied by swollen and vacuolated hepatocytes at higher doses

DIDP Cho 2y rat M

22

111

 

479

111

479

Significant decrease in the overall survival and body weight with a significant increase in relative liver and kidney weights at 470 mg/kg/day; no accompanying histology. Significant increase in spongiosis hepatis at all dose levels however, this is compaired to 0 incidence in controls which is very unusual

DIDP Cho 2y rat F

23

128

 

620

128

620

Significant decrease in the overall survival and body weight with a significant increase in relative liver and kidney weights at 620 mg/kg/day; no accompanying histology. No spongiosis hepatis observed.

Table 42 Assessment factors for DNEL derivation

Uncertainty

AF

Justification

Subchronic study

2

subchronic to chronic extrapolation (REACH Guidance)

Interspecies differences

Rat 4, Dog 1.4

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 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 AF

40

 

Application of assessment factors to studies considered for reference DNEL derivation:

Dog 90 d study (Hazleton 1968b), NOAEL 15 mg/kg/day

-Interspecies factor:

AS (correction for differences in metabolic rate dog): 1.4

remaining differences: 1

-Intraspecies factor general population: 5

-Exposure duration 90 day - chronic: 2

-Issues related to dose-response: 1

-Quality of whole database: 1

-Total factor: 14

DNEL: 1.07 mg/kg/day

 

Rat 90 d study (BASF 1969), NOAEL 200 mg/kg/day

-Interspecies factor:

AS (correction for differences in metabolic rate rat): 4

remaining differences: 1

-Intraspecies factor general population: 5

-Exposure duration 90 day - chronic: 2

-Issues related to dose-response: 1

-Quality of whole database: 1

-Total factor: 40

DNEL: 5.0 mg/kg/day

 

Rat 2y study (Cho et al 2008, 2010), NOAEL 128 mg/kg/day

-Interspecies factor:

AS (correction for differences in metabolic rate rat): 4

remaining differences: 1

-Intraspecies factor general population: 5

-Exposure duration 90 day - chronic: 1

-Issues related to dose-response: 1

-Quality of whole database: 1

Total factor: 20

DNEL: 6.4 mg/kg/day

Rat 90 d study (ExxonMobil), NOAEL 150 mg/kg/day

-Interspecies factor:

AS (correction for differences in metabolic rate rat): 4

remaining differences: 1

-Intraspecies factor general population: 5

-Exposure duration 90 day - chronic: 2

-Issues related to dose-response: 1

-Quality of whole database: 1

Total factor: 40

DNEL: 3.75 mg/kg/day

 

Multiple documents evaluating the appropriate AF usage for DINP/DIDP were produced in response to the ECHA RA report, which have been attached in section 13 (titles provided above). Given the use of read across to the registered substance, similar arguments are applicable to the registered substance. These evaluations generated AFs from 3.13, following the chemical specific adjustment factor derivation guidance, to 40, applying ECHA guidance and justification provided above for not including the 2.5 toxicdynamic factor for the interspecies AF. Using the selected NOAEL of 150 mg/kg/d these AFs give a reference DNEL range of 3.75 mg/kg bw/day to 47.9 mg/kg bw/day. DNELs can also be derived using the repeated dose toxicity data from other studies conducted with DIDP and similar justification for AFs as provided in the table above. This gives a range of DNELs from 1.07 mg/kg/d – 6.4 mg/kg/d. The derived reference DNEL falls in the middle of this range. Additionally the lowest reference DNEL (1.07 mg/kg/d) was derived using a NOAEL from a study with a small N and insufficient animals to run statistics. This and other factors outlined in the commentaries make the study inappropriate for risk assessment. Removal of this DNEL gives a DNEL range of 3.75-6.4 mg/kg/d of which the derived reference DNEL is the most conservative. Based on this assessment the evaluation of AFs that indicate lower AFs, and thus higher DNELs, are scientifically justified. This value is considered protective of potential human health effects.

Additional References

Berry, C. (2012). Evaluation of the significance of changes found in studies on DINP (Di-isononyl phthalate) and DIDP (Di-isodecyl phthalate) in the rat.  Expert report for European Council for Plasticisers and Intermediates, Brussels, Belgium.

Corton JC, Cunningham ML, Hummer BT, Lau C, Meek B, Peters JM, Popp JA, Rhomberg L, Seed J, Klaunig JE. Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol. 2014 Jan;44(1):1-49.

European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) (2003). Technical Report No. 86 Derivation of Assessment Factors for Human Health Risk Assessment.

Experimental Pathology Laboratories, Inc. (EPL) (1999) Histopathology peer review and pathology working group review of selected lesions of the liver and spleen in male and female F344 rats exposed to di(isononyl) phthalate. Pathology working group review. Pathology report. Experimental Pathology Laboratories, Inc., Research Triangle park, NC 27709. August 24, 1999.

Hasmall, S. C., James, N. H., Macdonald, N., West, D., Chevalier, S., Cosulich, S. C., & Roberts, R. A. (1999). Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate (DINP): a comparison of rat and human hepatocytes in vitro. Archives of toxicology, 73(8-9), 451-456.

Hattis, D., Baird, S., and Goble, R. 2002 A straw man proposal for a quantitative definition of the RfD.Drug Chem Toxico25: 403-436.

Pugh, G., Isenberg, J. S., Kamendulis, L. M., Ackley, D. C., Clare, L. J., Brown, R.... & Klaunig, J. E. (2000). Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. Toxicological Sciences, 56(1), 181-188.