1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Guidance Document #86

Dose descriptor starting point:

NOAEC

Value:

32 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

56.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

See "Additional Information".

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

Default for workers

Justification:

N/A

Justification:

N/A

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:

133.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Guidance Document #86

Dose descriptor starting point:

NOAEL

Value:

32 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See "Additional Information".

Justification:

N/A

Justification:

N/A

Justification:

Default for rat

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

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

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 95^thpercentile (6) and the 90^thpercentile (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

DNEL_{worker 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

DNEL_{worker dermal}   = 1600 mg/kg bwt/d / 12

= 133.3 mg/kg bwt/d

 

European Commission (2014): Phthalates entry 52 – Commission conclusions on the review clause and next steps (2014)

Between September 2009 and December 2010 the European Commission (EC) asked ECHA to review the available scientific information published online and in registration dossiers for DINP, DIDP and DNOP, to assess whether there was sufficient evidence to justify the re-examination of entry 52 of Annex XVII to REACH, which restricts the use of the three phthalates in toys and childcare articles which can be placed in the mouth by children. ECHA assessed the uses of DINP, DIDP and DNOP as well as their risks to the general population and to children via toys, childcare articles and other sources. The main ECHA conclusions, which incorporated comments from the ECHA Risk Assessment Committee and interested parties, were released by ECHA in 2013 (report attached in Section 13.2). The conclusions stated that, based on the scientific information for DINP and DIDP, no unacceptable risks of exposure could becharacterisedexceptfrom the mouthing of toys and childcare articles containing either phthalate, which cannot be excluded if the existing restriction were lifted, on the basis of the calculated Risk Characterisation Ratios (1.3 to 2.0). Therefore, there was insufficient evidence to justify a re-examination of the existing restriction (entry 52 in Annex XVII to REACH) on DINP and DIDP in toys and childcare articles which can be placed in the mouth by children. Based on this, ECHA concluded that no additional risk management measures are required to reduce the exposure of children and adults to DINP and DIDP, provided that the existing measures are maintained.

ECHA Risk Assessment Committee (RAC) (2018): Opinion proposing harmonised classification and labelling at EU level of 1,2-Benzenedicarboxylic acid, di-C8-10-branched alkylesters, C9- rich; [1] di-“isononyl” phthalate; [2] [DINP] EC Number: 271-090-9 [1] 249-079-5 [2] CAS Number: 68515-48-0 [1] 28553-12-0 [2]

In 2018, ECHA RAC published their opinion on the proposed harmonised classification and labelling (CLH) of DINP1 (CAS 68515-48-0) and DINP 2 (28553-12-0) as Repr. 1B, H360Df in a CLH dossier submitted by Denmark in 2017. To support their proposal, the dossier submitter (DS) summarised effects of DINP exposure reported in studies on fertility in animals and humans, developmental toxicity in various strains of rat and human epidemiological studies, and concluded that these findings were consistent with effects reported for other phthalates (DIBP, DBP, BBP, DCHP, DPP, DnHP, DEHP). On review of this information, ECHA RAC noted that several adequately designed studies with DINP reported no significantly increased malformations or other signs of developmental toxicity (Waterman et al., 1999; Gray et al., 2000; Boberg et al., 2011; Clewell et al., 2013). In addition, ECHA RAC noted that the similarity between effects of DINP and other phthalates classified as toxic to reproduction does not reflect the complete data set. In support of these outcomes were comments provided during public consultation from industry stakeholders, national authorities, downstream-users, manufacturers and member state component authorities, which regarded ‘no classification’ to be more appropriate overall. This view was based on criticisms such as: the CLH proposal did not adhere to CLP criteria, most studies sited by the DS had already been assessed by regulators and did not justify classification (EU RAR, 2003), and the referenced effects on fertility for lower molecular weight and classified phthalates (DBP, BBP, DEH and DIBP) are not comparable to DINP. In light of these comments and the data provided, ECHA RAC concluded that the evidence was too inconsistent to justify the classification of DINP. Therefore, no classification for DINP for either effects on sexual function, fertility or for developmental toxicity was warranted.

LITERATURE RELATED TO DINP TOXICITY PUBLISHED BETWEEN 2014 TO 2022:

Scientific literature relevant to the toxicity of DINP that was published between 2014 and 2022 has been included in the dossier. In one study, a quantitative weight of evidence (QWoE) method was used to critically evaluate scientific literature related to the effects of DINP on developmental and fertility endpoints to determine whether the reported adverse effects fulfil the requirements for CLP classification of these chemicals as reproductive toxicants (Dekant and Bridges 2016). Thirteen papers (including Boberg et al., 2011; Clewell et al., 2013a, 2013b; Exxon, 1996a, 1996b; Hellwig et al., 1997; Li et al., 2015 reported in this dossier) were scored. The overall weight of evidence indicated these papers provided insufficient evidence (i.e adverse effects) to support the allocation of a CLP reproductive classification category for DINP, which corresponds to ECHA RAC’s conclusions that DINP does not require CLP classification for reproductive toxicity (ECHA RAC, 2014; ECHA RAC, 2018). In another study, a three-day uterotrophic assay using a method similar to the OECD 440 test guideline was performed in which groups of six immature female Wistar rats were dosed orally by gavage with 0 (control), 0 (vehicle control; corn oil), 276 or 1380 mg/kg day DINP, once daily for three days (Sedha et al., 2015). Apart from a significant, dose-related reduction in weight gain, DINP did not affect relative uterine wet weight at either dose level. Using a similar dose regime, the authors then performed a 20-day pubertal female assay from post-natal day 21 to PND 41. The results from this assay showed that DINP did not cause any effects of toxicological relevance. In another study, van den Driesche et al.(2020) exposed pregnant Wistar rats to corn oil (vehicle control), DINP (125 or 750 mg/kg/day) or DBP (positive control; 750 mg/kg/day) during the male masculinisation programming window (MPW) (embryonic days 15.5 to 18.5) to assess and compare the effects of DINP and DBP exposure on the male rat reproductive tract. DINP was shown not to have any adverse effect on the parameters investigated, which contrasted to that for DBP, which induced significant changes of toxicological relevance.

Overall, the outcomes of these studies support the data and conclusions already presented in the dossier in that DINP does not require CLP classification for reproductive toxicity, DINP has no estrogenic effect of toxicological relevance, and that DINP has no adverse or anti-androgenic effects to the developing male rat foetus.

Other studies on DINP toxicity that were published between 2014 and 2022 have been included in the dossier but were not summarised here. This is because these papers were given a Klimisch Score of 3 due to various methodological deficiencies or a Klimisch Score of 4 due to insufficient characterisation of the test material used (i.e no CAS number, purity and or supplier information). An explanation on substance identification and CAS numbers is given in the Substance Identity Profile attached in Section 1.2. In addition, information on the test material used in key toxicity studies reported in the dossier is documented in Section 13.2 (see ‘Test material information in key toxicology studies_DINP.pdf’).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEC

Value:

15 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See "Additional Information".

Justification:

N/A

Justification:

N/A

Justification:

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)

Justification:

N/A

Justification:

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.

Justification:

N/A

Justification:

N/A

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:

0.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See "Additional Information".

Justification:

N/A

Justification:

N/A

Justification:

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)

Justification:

N/A

Justification:

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.

Justification:

N/A

Justification:

N/A

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

See "Additional 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:

0.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See "Additional Information".

Justification:

N/A

Justification:

N/A

Justification:

sed 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)

Justification:

N/A

Justification:

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.

Justification:

N/A

Justification:

N/A

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

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 95^thpercentile (6) and the 90^thpercentile (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.

European Commission (2014): Phthalates entry 52 – Commission conclusions on the review clause and next steps

Between September 2009 and December 2010 the European Commission (EC) asked ECHA to review the available scientific information published online and in registration dossiers for DINP, DIDP and DNOP, to assess whether there was sufficient evidence to justify the re-examination of entry 52 of Annex XVII to REACH, which restricts the use of the three phthalates in toys and childcare articles which can be placed in the mouth by children. ECHA assessed the uses of DINP, DIDP and DNOP as well as their risks to the general population and to children via toys, childcare articles and other sources. The main ECHA conclusions, which incorporated comments from the ECHA Risk Assessment Committee and interested parties, were released by ECHA in 2013 (attached in Section 13.2). The conclusions stated that, based on the scientific information for DINP and DIDP, no unacceptable risks of exposure could becharacterisedexceptfrom the mouthing of toys and childcare articles containing either phthalate, which cannot be excluded if the existing restriction were lifted, on the basis of the calculated Risk Characterisation Ratios (1.3 to 2.0). Therefore, there was insufficient evidence to justify a re-examination of the existing restriction (entry 52 in Annex XVII to REACH) on DINP and DIDP in toys and childcare articles which can be placed in the mouth by children. Based on this, ECHA concluded that no additional risk management measures are required to reduce the exposure of children and adults to DINP and DIDP, provided that the existing measures are maintained.

ECHA Risk Assessment Committee (RAC) (2018): Opinion proposing harmonised classification and labelling at EU level of 1,2-Benzenedicarboxylic acid, di-C8-10-branched alkylesters, C9- rich; [1] di-“isononyl” phthalate; [2] [DINP] EC Number: 271-090-9 [1] 249-079-5 [2] CAS Number: 68515-48-0 [1] 28553-12-0 [2]

In 2018, ECHA RAC published their opinion (attached in Section 13.2) on the proposed harmonised classification and labelling (CLH) of DINP1 (CAS 68515-48-0) and DINP 2 (28553-12-0) as Repr. 1B, H360Df in a CLH dossier submitted by Denmark in 2017. To support their proposal, the dossier submitter (DS) summarised effects of DINP exposure reported in studies on fertility in animals and humans, developmental toxicity in various strains of rat and human epidemiological studies, and concluded that these findings were consistent with effects reported for other phthalates (DIBP, DBP, BBP, DCHP, DPP, DnHP, DEHP). On review of this information, ECHA RAC noted that several adequately designed studies with DINP reported no significantly increased malformations or other signs of developmental toxicity (Waterman et al., 1999; Gray et al., 2000; Boberg et al., 2011; Clewell et al., 2013). In addition, ECHA RAC noted that the similarity between effects of DINP and other phthalates classified as toxic to reproduction does not reflect the complete data set. In support of these outcomes were comments provided during public consultation from industry stakeholders, national authorities, downstream-users, manufacturers and member state component authorities, which regarded ‘no classification’ to be more appropriate overall. This view was based on criticisms such as: the CLH proposal did not adhere to CLP criteria, most studies sited by the DS had already been assessed by regulators and did not justify classification (EU RAR, 2003), and the referenced effects on fertility for lower molecular weight and classified phthalates (DBP, BBP, DEH and DIBP) are not comparable to DINP. In light of these comments and the data provided, ECHA RAC concluded that the evidence was too inconsistent to justify the classification of DINP. Therefore, no classification for DINP for either effects on sexual function, fertility or for developmental toxicity was warranted.

LITERATURE RELATED TO DINP TOXICITY PUBLISHED BETWEEN 2014 TO 2022:

Scientific literature relevant to the toxicity of DINP that was published between 2014 and 2022 has been included in the dossier. In one study, a quantitative weight of evidence (QWoE) method was used to critically evaluate scientific literature related to the effects of DINP on developmental and fertility endpoints to determine whether the reported adverse effects fulfil the requirements for CLP classification of these chemicals as reproductive toxicants (Dekant and Bridges 2016). Thirteen papers (including Boberg et al., 2011; Clewell et al., 2013a, 2013b; Exxon, 1996a, 1996b; Hellwig et al., 1997; Li et al., 2015 reported in this dossier) were scored. The overall weight of evidence indicated these papers provided insufficient evidence (i.e adverse effects) to support the allocation of a CLP reproductive classification category for DINP, which corresponds to ECHA RAC’s conclusions that DINP does not require CLP classification for reproductive toxicity (ECHA RAC, 2014; ECHA RAC, 2018). In another study, a three-day uterotrophic assay using a method similar to the OECD 440 test guideline was performed in which groups of six immature female Wistar rats were dosed orally by gavage with 0 (control), 0 (vehicle control; corn oil), 276 or 1380 mg/kg day DINP, once daily for three days (Sedha et al., 2015). Apart from a significant, dose-related reduction in weight gain, DINP did not affect relative uterine wet weight at either dose level. Using a similar dose regime, the authors then performed a 20-day pubertal female assay from post-natal day 21 to PND 41. The results from this assay showed that DINP did not cause any effects of toxicological relevance. In another study, van den Driesche et al. (2020) exposed pregnant Wistar rats to corn oil (vehicle control), DINP (125 or 750 mg/kg/day) or DBP (positive control; 750 mg/kg/day) during the male masculinisation programming window (MPW) (embryonic days 15.5 to 18.5) to assess and compare the effects of DINP and DBP exposure on the male rat reproductive tract. DINP was shown not to have any adverse effect on the parameters investigated, which contrasted to that for DBP, which induced significant changes of toxicological relevance.

Overall, the outcomes of these studies support the data and conclusions already presented in the dossier in that DINP does not require CLP classification for reproductive toxicity, DINP has no estrogenic effect of toxicological relevance, and that DINP has no adverse or anti-androgenic effects to the developing male rat foetus.

Other studies on DINP toxicity that were published between 2014 and 2022 have been included in the dossier but were not summarised here. This is because these papers were given a Klimisch Score of 3 due to various methodological deficiencies or a Klimisch Score of 4 due to insufficient characterisation of the test material used (i.e no CAS number, purity and or supplier information). An explanation on substance identification and CAS numbers is given in the Substance Identity Profile attached in Section 1.2. In addition, information on the test material used in key toxicity studies reported in the dossier is documented in Section 13.2 (see ‘Test material information in key toxicology studies_DINP.pdf’).