Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.001 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
Modified dose descriptor starting point:
T25
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.002 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
Modified dose descriptor starting point:
T25
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

There are no IOELV levels documented; hence assessment of applicable DNEL / DMEL has to be undertaken for the substance.

Workers

Derivation of specific DNELs for workers for the registered substance is deemed not applicable as although values are available, the classification of the substance as a Category 2 Carcinogen effectively renders any additional DNEL redundant. As it is considered that no DNEL can be derived for non-threshold mutagens/carcinogens, it is assumed that a no-effect-level cannot be established for these substances (either because there is no threshold or the threshold level cannot be determined). In such cases, and assuming that there are data allowing it, the registrant is required to develop a DMEL(derived minimal effect level), a reference risk level which is considered to be of very low concern. DMEL derived in accordance with the guidance should be seen as a tolerable level of effects and it should be noted that it is not a level where no potential effects can be foreseen. If a DMEL is not derived, the registrant should find other means for assessing/judging "...the likelihood that effects are avoided when implementing the exposure scenario" (Annex I, section 6.5).

The data available within the Carcinogenicity studies available on the registered substance indicated that it is difficult to derive both aBMD(L)10 and T25 value from the data available. However with use of the relevant guidance, it is possible to determine a T25 value, based on the data presented. Evaluation of the T25 values from Carcinogenicity studies in the rat, mouse has therefore been undertaken. The results of these evaluation provides the following results:

 

NTP 80 14 (1980) Bioassay of 4 4 oxydianiline for possible carcinogenicity - Results

 

The T25 dose descriptor in the Rat is therefore 4.90 mg/kg/day based on occurrence of hepatocellular carcinoma or neoplastic nodules.

 

The T25 dose descriptor in the Mouse is therefore 12.4 x 10E-03 mg/kg/day based on occurrence of Harderian Gland adenomas.

 

An evaluation of the potential potency of the carcinogenic effects was then taken, using the reference source: Guidelines For Setting Specific Concentration Limits For Carcinogens In Annex I Of Directive 67/548/EEC - Inclusion Of Potency Considerations - Commission Working Group On The Classification And Labelling Of Dangerous Substance.s

This document details that T25 values can be used to place substances classified as a carcinogen into arbitrarily selected ranges that define potency. As such, it is possible to identify carcinogens of high and low potency. For the purpose of assigning specific concentration limits, it is proposed that:

 

Carcinogens of high potency:T25 value < 1 mg/kg bodyweight/day

 

Carcinogens of medium potency:1 mg/kg bodyweight/day < T25 value < 100 mg/kg

bodyweight/day

 

Carcinogens of low potency:T25 value > 100 mg/kg bodyweight/day.

 

Based on this guidance, it is deemed appropriate, on a worst case basis, to assign the lowest T25 value for the purposes of calculation of the DMEL for the substance as a potential Carcinogen of high potency; this being theT25 dose descriptor in the Mouse at 12.4 x 10E-03 mg/kg/day. However, as this value is calculated from harderian gland adenomas, a further evaluation of the appropriate value was undertaken. Whilst harderian gland’s are known to exist within rodents, the existence within humans is still debatable. As such, it was concluded that calculation of DMEL using a T25 value derived from a biological endpoint that may not exist inhumans was not appropriate. As such, other endpoints were evaluated. Ashepatocellular adenoma and carcinoma occurred in both species evaluated within the NTP studies, there is strong indication that liver is the target organ for tumours and hepatocellular adenoma and carcinoma are endpoints considered relevant for humans.

 

As such, it was therefore considered appropriate to utilise the T25 lowest value for these endpoints, which was determined to be 4.90 mg/kg/day based on occurrence of hepatocellular carcinoma or neoplastic nodules.

 

It is this value that has been used to derive the DMELs presented within this dossier.

 

Derivation of T25 value is determined by the following calculations, utilising the reference source Guidelines For Setting Specific Concentration Limits For Carcinogens In Annex I Of Directive 67/548/EEC - Inclusion Of Potency Considerations - Commission Working Group On The Classification And Labelling Of Dangerous Substances

Derivation of DMEL’s based on T25 – ORAL TOXICITY

 

The following derivations are taken from Guidance DocumentCHAPTER R.8 - DOSE [CONCENTRATION]-RESPONSE REGARDING HUMAN HEALTH, issued by ECHA.

 

NTP 80 14 (1980) Bioassay of 4 4 oxydianiline for possible carcinogenicity.

 

Results in the Rat, 400 ppm - Hepatocellular carcinoma or neoplastic nodule::

 

 

"Linearised" approach

Relevant Dose descriptor

T25 (rat, oral)4.90mg/kg/day

 

Step 2:

Modification of the relevant dose descriptor

 

 

"Linearised" approach

For this scenario (workers, oral exposure) there is no need for a modification factor

1

Corrected Dose Descriptor

Corrected T25 4.90 mg/kg/day

 

Step 3:

Application of assessment factors to get the DMEL

 

"Linearised" approach

Interspecies extrapolation

For the "linearity" approach only the allometric scaling factor of 4 is applied (fromTable R. 8-3 Allometric scaling factors for different species as compared to humans)

4

Intraspecies extrapolation (see notes below)

Not applied

Nature of the carcinogenic process (see notes below)

Not applied

Point of comparison (see notes below)

Not applied

2.5 in cases where the T25 is used instead of the BMDL10 (EFSA draft 07.04.2006) (see notes below)

Not applied

High to low dose extrapolation

For 10-5risk: 25,000 (linearity, 1:100,000)

For 10-6Risk: 250,000 (linearity, 1:1.000.000)

Calculation of DMEL

(corrected T25 divided by overall assessment factor)

4.90 mg/kg/day/ (4 * 25,000) = 4.9 x 10E-05 mg/kg/d

4.90 mg/kg/day/ (4 * 250,000) = 4.9 x 10E-06 mg/kg/d

DMEL (based on T25)

associated with a lifetime cancer

risk of very low concern

4.90 x 10E-05 mg/kg/d(linearity, 1:100,000)

 

4.90 x 10E-06 mg/kg/d(linearity, 1:1.000.000)

 

 

 

Derivation of DMEL’s based on T25 –DERMAL TOXICITY

 

The following derivations are taken from Guidance DocumentCHAPTER R.8 - DOSE [CONCENTRATION]-RESPONSE REGARDING HUMAN HEALTH, issued by ECHA.

Calculations are based on the most Relevant Dose Descriptor. In order to calculate this, the following is taken from Figure R. 8-3 Modification of the starting point, taken from the above.

For workers (in case of 8 hour exposure / day)

 

T25dermal species = T25 oral species / AF * ABS oral species /ABSdermal human *  2.8 

Where:

ABS: Absorption.

ABS oral species: There is no current absorption data for the substance, based on the studies obtained. As such, and on a worse case basis, it is therefore assumed that 100% absorption can occur from the oral route.

 

ABSdermal human: On the basis of the toxicokinetics study on the substance, a value of 7% absorbance in the dermal penetration study was observed. It is well documented within the literature that rat skin is considered to be more sensitive than human skin. As such, it is deemed appropriate to apply the value of 7% as the possible maximum human dermal absorption as a worst case scenario. 

 

AF = Assessment Factor

Assessment Factor (AF) (refer to table R8-7; Pg 46), and AS = 4 (from table 8-3)

Therefore the calculation can be described as:

 

NTP 80 14 (1980) Bioassay of 4 4 oxydianiline for possible carcinogenicity.

 

Results in the Rat, 400 ppm - Hepatocellular carcinoma or neoplastic nodule::

 

 

 

"Linearised" approach

Relevant Dose descriptor

T25 (rat, oral)4.90 mg/kg/day

 

Step 2:

Modification of the relevant dose descriptor

 

 

"Linearised" approach

Route-specific bioavailability:

ABS oral species /ABSdermal human

 

100 / 7

Assessment Factor (AF) (refer to table R8-7; Pg 46), where AS = 7 (from table 8-3)

= 1 / AF

AF = 4

1 / 4

Differences between occupational and lifetime exposure conditions

7/5 * 52 /48 * 75 / 40 = 2.8

2.8

Calculation of modified dose descriptor

 

T 25 of 4.90 mg/kg/day multiplied by1/4 * 100/7 * 2.8

=49.0 mg/kg/d

Corrected Dose Descriptor

Corrected T25 49.0mg/kg/d

 

Step 3:

Application of assessment factors to get the DMEL

 

"Linearised" approach

Interspecies extrapolation

(fromTable R. 8-3 Allometric scaling factors for different species as compared to humans)

Not applicable; applied above

Intraspecies extrapolation (see notes below)

Not applied

Nature of the carcinogenic process (see notes below)

Not applied

Point of comparison (see notes below)

Not applied

2.5 in cases where the T25 is used instead of the BMDL10 (EFSA draft 07.04.2006) (see notes below)

Not applied

High to low dose extrapolation

For 10-5risk: 25,000 (linearity, 1:100,000)

For 10-6Risk: 250,000 (linearity, 1:1.000.000)

Calculation of DMEL

(corrected T25 divided by overall assessment factor)

49.0 mg/kg/d  / (25,000) = 1.96 x 10E-03mg/m3

49.0 mg/kg/d/ (250,000) = 1.96 x 10E-04mg/m3

DMEL (based on T25)

associated with a lifetime cancer

risk of very low concern

1.96 x 10E-03mg/kg/d(linearity, 1:100,000)

 

1.96 x 10E-04mg/kg/d (linearity, 1:1.000.000)

 

 

 

It should be noted that the above DMEL calculations take account of the Carcinogenicity risk associated with the substance, and are presented as worst case. However, note that there are other acute and local effects noted with dermal application (skin sensitisation and minor irritation). As such,application of stringent Risk Management Mearures (RMM) will be in place in order to protect the workers for these intrinsic hazards which would occur at higher concentration levels than the carcinogenicity effects. This, in associated with the fact that absorption via the dermal route is predicted to be very low in humans based on experimental data indicates that the DMEL for this endpoint is essentially redundant.

 

Derivation of DMEL’s based on T25 –INHALATION TOXICITY

 

The following derivations are taken from Guidance DocumentCHAPTER R.8 - DOSE [CONCENTRATION]-RESPONSE REGARDING HUMAN HEALTH, issued by ECHA.

Calculations are based on the most Relevant Dose Descriptor. In order to calculate this, the following is taken from Figure R. 8-3 Modification of the starting point, taken from the above.

For workers (in case of 8 hour exposure / day)

Corrected inhalatory T25 = Oral T25 * 1/sRVrat* ABSoral-rat/ ABSinh-human* sRVhuman /wRV

Where::

ABS: Absorption. It is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. Notethat if data on the starting route (oral) are available these should be used, but for the end route (inhalation), the worst case inhalation absorption should still be assumed (i.e. 100%). Note that this does not apply if there is a first pass effect, if there is non-resorption, or for bolus effects.

However, in the case of 4,4’-ODA, the particle size has been assessed. The Particle Size Distribution was determined to be 3% < 100 µm. As such, it is surmised that there is negligible exposure via inhalation, as there are not sufficient particles of respirable size. In addition, the low water solubility indicates that absorption within the alveoli of the lungs would be limited. Therefore, the ABS ratio is set at 1.

 

sRV: standard Respiratory Volume :– 6.7 m3 (8h) Human ; 0.38 m3/kg/bw (rat)

 

wRV: worker Respiratory Volume:- 10 m3 (8h) 

 

Therefore the calculation can be described as:

 

Results in the Mouse:

 

The following equation scaling factor is applied:

 

Equation 1:

 

T25 inhalation species = T25 oral species / AF * ABS oral species /ABSinhalation human * hBW human / Respiratory Volume human * 2.8 

 

NTP 80 14 (1980) Bioassay of 4 4 oxydianiline for possible carcinogenicity.

 

Results in the Rat, 400 ppm - Hepatocellular carcinoma or neoplastic nodule:

 

 

"Linearised" approach

Relevant Dose descriptor

T25 (rat, oral) 4.90 mg/kg/day

 

Step 2:

Modification of the relevant dose descriptor

 

 

"Linearised" approach

Route-specific bioavailability:

1 (based on negligible respirable particles)

Adjustment of route of exposure:

from rat (oral) in mg/kg/d to rat inhalation (0.8l/min/kg, 8h): 0.384 m³/kg/8h

1/0.384

Activity-driven differences:

At rest / light activity: 6.7 /10 in line with the „10 m³“ approach

6.7 / 10

 

Differences between occupational and lifetime exposure conditions

7/5 * 52 /48 * 75 / 40 = 2.8

2.8

Calculation of modified dose descriptor

 

T 25 of 4.90 mg/kg/d multiplied by

1 * 1/0.384 * 6.7/10 * 2.8

= 23.9 mg/m³

Corrected Dose Descriptor

Corrected T25 23.9 mg/m3

 

Step 3:

Application of assessment factors to get the DMEL

 

"Linearised" approach

Interspecies extrapolation

(fromTable R. 8-3 Allometric scaling factors for different species as compared to humans)

Not applicable when setting an inhalation DMEL

Intraspecies extrapolation (see notes below)

Not applied

Nature of the carcinogenic process (see notes below)

Not applied

Point of comparison (see notes below)

Not applied

2.5 in cases where the T25 is used instead of the BMDL10 (EFSA draft 07.04.2006) (see notes below)

Not applied

High to low dose extrapolation

For 10-5risk: 25,000 (linearity, 1:100,000)

For 10-6Risk: 250,000 (linearity, 1:1.000.000)

Calculation of DMEL

(corrected T25 divided by overall assessment factor)

23.9 mg/m3  / (25,000) = 9.56 x 10E-04mg/m3

23.9 mg/m3/ (250,000) = 9.56 x 10E-05mg/m3

DMEL (based on T25)

associated with a lifetime cancer

risk of very low concern

 

9.56 x 10E-04mg/m3 (linearity, 1:100,000)

 

9.56 x 10E-05mg/m3 (linearity, 1:1.000.000)

 

 

 

The justification for these derivations is taken from Pages 41 thru 43 of the above guidance andAPPENDIX R. 8-7 Derivation of a DMEL for Non-Threshold Carcinogens: Comparison of the “linearised” and the “large assessment factor” approach. Here,thefollowing assessment factors are considered:

·        interspecies differences

·        intraspecies differences

·        differences in duration of exposure

·        issues related to dose-response

·        quality of whole database

 

Interspecies differences

For systemic non-threshold effects, only an assessment factor for differences in metabolic rate (allometric scaling) is to be applied. However, this assessment factor is not needed for non-threshold effects;

·        that are induced locally at the ports of entry, or

·        when a respiratory study is used as starting point for deriving a DMEL in air for humans.

 

It should be noted that it is the dose unit (original or transformed), and not the (experimental) route of application, that triggers the necessity for a species-specific factor for allometric scaling. By this follows, for instance, that an AS factor is needed also in chronic studies once the concentration (e.g., ppm in food) is transformed into a body burden or dose (mg/kg/day), which is then used in the risk assessment. The above implies that, in contrast to threshold effects, as a default there will be no assessment factor for remaining uncertainty (i.e. in the absence of substance-specific information) for both systemic and local non-threshold effects. The reason for this approach is that the linear model used for high to low dose extrapolation (see part onhigh to low dose extrapolationbelow), which is over about four orders of magnitude, is considered sufficiently conservative to also cover these differences in interspecies sensitivity.

 

Intraspecies differences

In contrast to threshold effects, no assessment factor is to be applied for this extrapolation step for non-threshold effects. The reason for this approach is that the linear model used for high to low dose extrapolation (see part onhigh to low dose extrapolationbelow), which is over about four orders of magnitude, is considered sufficiently conservative to also cover these differences in intraspecies sensitivity.

Differences in duration of exposure

 In contrast to threshold effects, no assessment factor is to be applied for this extrapolation step for non-threshold effects. The reason for this is that a correction for durations of exposure (and/or observation) is already performed in deriving the dose descriptors before use. It is noted, though, that if human exposure is not for lifetime or far from continuous during lifetime, correction of the DMEL may be needed according to the correction described in this approach.

Issues related to dose-response

The dose descriptor for non-threshold effects is, by definition, a dose level representing an observable and significant response. This is different from the situation encountered by threshold effects, where dose descriptors representing a true no-effect level are to be established and which inherently has some specific uncertainty.

Uncertainties related to the observable region of dose response curve for non-threshold effects are described in APPENDIX R. 8-6 of the guidance for genotoxic carcinogens. The dose descriptors T25, BMD10, and BMDL10 have in increasing order incorporated uncertainty in their estimate. As indicated, preference is given to the T25, unless dose response curves have an exceptional supra- or sublinear shape. There is no separate assessment factor to account for this.

Another related issue concerning the dose response that is relevant specifically for non-threshold effects is high to low dose extrapolation. This is separately dealt with below.

Quality of whole database

An assessment factor on the quality of the whole database should, if justified, be applied to compensate for the potential remaining uncertainties in the derived DMEL.

Special consideration should be given to the situation that alternative data are used, e.g. use of (Q)SAR, read across or chemical categories or the use of subchronic studies for deriving some surrogate dose descriptor (see Section R.8.5.3 of the guidance). The situation of absence of substance-specific carcinogenicity data will quite frequently be encountered, also because the use of alternative data is stimulated under REACH and preferred above performing additional animal studies.

However, using these data in a semi-quantitative way (in cases where this is considered possible) might be associated with some additional uncertainty in the dose descriptor derived. Though this should be accounted for, there is no standard recipe for this, and expert judgement is critically demanded here.

The default assessment factor to be applied for good/standard quality of the database, taking into account completeness and consistency, is 1. A larger database AF should be justified on a case-by-case basis when data do not meet the mentioned qualification.

High to low dose risk extrapolation factor

The preceding steps (correction of the starting point, and application of assessment factors) have resulted in relevant (i.e. with regard to route and absorption) human equivalent lifetime daily doses HT25 ('Human T25'), and occasionally HBMD10 ('Human BMD10'), assumed to represent human daily exposures associated with tumour incidences of 25%, and 10%, respectively. Thishigh to low doseextrapolation step is to arrive at the DMEL, i.e. an exposure level that is considered to represent a risk level where the likelihood that effects (cancer) are avoided is appropriately high and of very low concern, acknowledging the fact that for non-threshold carcinogens a dose level without any residual cancer risk cannot be identified.

This risk level of very low concern has to be decided on a policy level. Although there is no EU legislation setting the 'tolerable' risk level for carcinogens in the society, cancer risk levels have been set and used in different contexts (See APPENDIX R. 8-14 of the guidance for various values previously applied within and outside the EU). Based on these experiences, cancer risk levels of 10-5 and 10-6 could be seen as indicative tolerable risks levels when setting DMELs for workers and the general population, respectively. Furthermore, the Carcinogens and Mutagens Directive (2004/37/EC) requires effective risk management to prevent workers exposure to carcinogenic and mutagenic chemicals. Where it is not technically possible to prevent exposure then, by implementing the concept of the principles of good occupational hygiene practice, it should be reduced to as low a level as technically possible. Namely, through substitution, reduction of exposure, use in closed systems etc.

In the EU, risk assessments of industrial chemicals carried out under Regulation 793/93 certain genotoxic carcinogens have been assessed. The Technical Meeting of MS representatives under Regulation 793/93 agreed that a conclusion of concern should be drawn for all genotoxic carcinogens and the magnitude of the risk for each exposure scenario described as far as possible. In some cases quantitative risk estimates were included to assist in describing the risk. It can be deduced from some of these reports that the cut-off between concern and low concern or residual risk is in the region of 10-5and10-6. The decision point for 'acceptable'lifetime(i.e., a working life of 40 years) cancer risk levels used for workers are generally around “10-5but higher or lower levels have been considered to be tolerable under certain circumstances. 

The DMELs presented in this evaluation closely mirror these requirements, and as such can be considered as appropriate for application. These have been calculated using the linear approach specifiedwithin the Guidance DocumentCHAPTER R.8 - DOSE [CONCENTRATION]-RESPONSE REGARDING HUMAN HEALTH, issued by ECHA.

 

This document incorporates an assessment ofHigh to Low dose extrapolation and incorporates for 10-5 risk: 25,000 (linearity, 1:100,000) for workers. It is this value that has been applied within this assessment.

Finally, it should also be noted that for the purposes of this chemical safety assessment, there is no assigned risk of exposure. The substance is imported in a polymeric form, in which the substance acts as a monomer. Hence exposure to the “neat” substance will not occur.

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
Most sensitive endpoint:
carcinogenicity
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

Additional information - General Population

There is no assigned risk of exposure. The substance is imported in a polymeric form, in which the substance acts as a monomer. This polymer is not available to consumers or the general public, and is used only within the industrial environment. Hence exposure to the “neat” substance will not occur.