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Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Derivation of corrected starting points, overall assessment factors and DNELs for workers:

Oral exposure for workers is not considered to be a relevant exposure pathway. Hence DNELs for oral exposure of workers are not derived.

For dermal exposure (short-term and long-term) a qualitative assessment is needed and derivation of DNEL is not possible, because of the corrosive and skin sensitizing properties of the substance. According to Technical Guidance Document “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (published by European Chemicals Agency in May 2008 ) Appendix R. 8-10 and with respect to the GPMT study (Hüls, 1984) the potency categorisation came to the result “extreme” sensitizer (intradermal induction 0.1% intracutan; 16/20 positive; 80%sensitisation) and the substance is classified as R 43: "May cause sensitisation by skin contact" (according to DSD/DPD) and Sub-category Skin Sens. 1 A: H317 "May cause an allergic skin reaction" (according to EU GHS). In addition the substance is a strong base (pH ≥ 11.5) and is classified as R34:"Corrosive" (according to DSD/DPD) and Skin Corr. 1A : H314 "Causes severe skin burns" (according to EU GHS).

Furthermore a qualitative assessment is needed for inhalation exposure (short-term and long-term) and derivation of DNEL is not possible because of the corrosive properties of the substance and the expected corrosive/irritant properties to respiratory tract after inhalation of the substance. As the substance is corrosive the caustic properties are considered to represent the primary effect. A qualitative assessment covers both local and systemic effects after inhalation exposure.

Sub-category

This discussion is contained in the discussion part of section 5.11.2 of the Chemical Safety Report (CSR) and summarized in the table in section 5.11.2 of the CSR.

 



 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD.
AF for differences in duration of exposure:
2
Justification:
The assessment factor suggested by the ECHA TGD for exposure duration from subchronic to chronic is 2.
AF for interspecies differences (allometric scaling):
4
Justification:
The allometric scaling factor for rats as compared to human is 4 for systemic effects (see also section R 8.4.3.1 of TGD)
AF for other interspecies differences:
2.5
Justification:
A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
For intraspecies variability, the default assessment factor for the general population for local effects is 10.
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD.
AF for remaining uncertainties:
1
Justification:
No further assessment factors are considered necessary.
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

Derivation of corrected starting points, overall assessment factors and DNELs for general population (consumers):

The use of the substance trimethylhexane-1,6-diamine is restricted only to industrial and professional applications. Hence there is no need to derive DNELs for general population (consumers).

An indirect exposure of man via the environment might occur through ingestion of foodstuff or drinking water. Therefore, a systemic oral long-term DNEL for general population is derived and will be used to assess any possible risk that could result from indirect oral exposure of man via the environment .

Derivation of corrected dose descriptors (correct starting point), selection of assessment factors and calculation of relevant/critical DNEL´s according to Technical Guidance Document “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” published by European Chemicals Agency in May 2008 (in the following described as “TGD”)

1) Conversion of an rat NOAELoral; rep. dosefrom 90 day rat oral repeated dose toxicity study into an corrected NOAELoral; rep. dose (derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this chapter):

 

For general population:

assumptions:

- absorptionrat= absorptionhuman)

- frequency of exposure of rat (7d/wk) = frequency of exposure of general population (7d/wk)

corrected NOAELoral; rep.dose   = rat NOAELoral; rep. dose* (exp. cond.rat/ exp. cond.human)

= rat NOAELoral; rep. dose* (7d/wk / 7 d/wk) * (ABSrat/ ABShuman)

= 10 mg/kg bw day * 1 * 1

= 10 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

Description  Factor
Interspecies: factor for allometric scaling (systemic)   4
Interspecies: remaining differences (systemic) 2.5

Intraspecies (systemic)  

10

Exposure duration (systemic;subchronic to chronic)

2

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

200

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

DNELoral; rep. dose = corrected NOAELoral; rep.dose / overall AF = 10 mg/kg bw day / 200 = 0.05 mg/kg bw day



 

2a)Conversion of a rat NOAELoral; developfrom developmental toxicity study into an correctedNOAELoral; develop (derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this chapter):

For general population:

assumptions:

- absorptionrat= absorptionhuman

-frequency of exposurerat = frequency of exposurehuman(7d/week)

-lowest rat NOAELoral; developused (maternal toxicity)

corrected NOAELoral; develop   =        rat NOAELoral; develop* (exp. cond.rat/ exp. cond.human)

=        rat NOAELoral; develop* (ABSrat/ ABShuman)

=        10 mg/kg bw day * 1

=        10 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD): 

Description  Factor
Interspecies: factor for allometric scaling (systemic)   4
Interspecies: remaining differences (systemic) 2.5

Intraspecies (systemic)  

20***

Exposure duration (systemic)

 

1 ****

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

200

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

*** According to TGD Appendix R 8-12: Pregnant women have to be considered as a more vulnerable population. When deciding on assessment factors for the DNELdevelopcalculation the developing offspring should be the focus of attention. Therefore intraspecies factor of 10 for general population is enhanced 2-fold resulting in an assessment factor of 20.

****The exposure duration within this study has to be considered to be a chronic exposure for the unborn foetus, which is the focus of attention in this study and regarding the derivation of the DNELdevelop. Thus extrapolation of duration of exposure is not needed and assessment factor is set on 1.
  

DNELoral; develop= corrected NOAELoral; develop/ overall AF =10 mg/kg bw day / 200 = 0.05 mg/kg bw da

             

 

 

2b) Conversion of a rabbit NOAELoral; developfrom developmental toxicity study into an corrected NOAELoral; develop (derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this chapter):

For general population:

assumptions:

- absorptionrabbit= absorptionhuman

- frequency of exposurerabbit = frequency of exposurehuman(permanent)

- lowest rabbit NOAELoral; developused (maternal toxicity)

corrected NOAELoral; develop   = rabbit NOAELoral; develop* (exp. cond.rabbit/ exp. cond.human)

=        rabbit NOAELoral; develop* (ABSrabbit/ ABShuman)

=        44 mg/kg bw day * 1

=        44 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

Description  Factor
Interspecies: factor for allometric scaling (systemic)   2.4
Interspecies: remaining differences (systemic) 2.5

Intraspecies (systemic)  

20***

Exposure duration (systemic)

 

1 ****

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

120

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

*** According to TGD Appendix R 8-12: Pregnant women have to be considered as a more vulnerable population. When deciding on assessment factors for the DNELdevelopcalculation the developing offspring should be the focus of attention. Therefore intraspecies factor of 10 for general population is enhanced 2-fold resulting in an assessment factor of 20.

****The exposure duration within this study has to be considered to be a chronic exposure for the unborn foetus, which is the focus of attention in this study and regarding the derivation of the DNELdevelop. Thus extrapolation of duration of exposure is not needed and assessment factor is set on 1.

 

DNELoral; develop=corrected NOAELoral; develop/ overall AF = 44 mg/kg bw day / 120 = 0.37 mg/kg bw day

Conclusion: Because the DNELoral; developderived from the rats is lower and hence more conservative than the DNELoral; developderived from the rabbits, the DNELoral; developderived from the rats (0.05 mg/kg bw) is relevant for further calculations.

3) Conversion of an rat NOAELoral; fertility; male/femaleinto an corrected NOAELoral; fertility;male/female (derived from example A.1; Appendix R 8-2 of TGD):

For general population:

assumptions:

- absorptionrat= absorptionhuman

- frequency of exposure of rat (7d/wk) = frequency of exposure of general population (7d/wk)

corrected NOAELoral; fertility; male/female  = rat NOAELoral;fertility; male/female* (exp. cond.rat/ exp. cond.human)

= rat NOAELoral;fertility; male/female* (7d/wk / 7 d/wk) * (ABSrat/ABShuman)

=  10 mg/kg bw day * 1 * 1

=  10 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

Description  Factor
Interspecies: factor for allometric scaling (systemic)   4
Interspecies: remaining differences (systemic) 2.5

Intraspecies (systemic)  

10

Exposure duration (systemic; chronic)

 

1 ***

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

100

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

***Reproductive study covers two generations (duration: 287 days), which is considered to be a chronic study. Hence the Assessment Factor is 1.

DNELoral; fertility=corrected NOAELoral; fertility/ overall AF = 10 mg/kg bw day / 100 = 0.1 mg/kg bw day

Overall conclusions:

The derived DNELoral; rep. dose(0.05 mg/kg bw day) covers also effects regarding developmental toxicity and fertility after oral exposure (see derived DNELs for this endpoints)

The relevant DNELs are derived in the discussion part of section 5.11.2 of the Chemical Safety Report (CSR) and summarized in the table in section 5.11.2 of the CSR.