Propylidynetrimethanol, ethoxylated, esters... - Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

252

Modified dose descriptor starting point:

NOAEL

DNELs are derived from systemic NOAELs and if available local NOAELs. DNELs for sensitisation were not derived due to much uncertainties in the derivation (see sectionskin sensitisation DNELs)

Systemic DNELs:

Dermal:

For dermal toxicity a read across is performed to a structural similar acrylate (TMPTA CAS: 15625-89-5). Dermal studies are performed for this substance. The most critical record for dermal systemic effects of TMPTA are seen in a NTP study:

Subacute, rats/mice, 14/28 days (16 days, 5days/week), NTP protocol: NOAEL, (systemic, mice):≥200 mg/kg bw,NOAEL (local, mice): 25mg/kg bw (Publication: 14/28 day NTP, Battelle Columbus Laboratories, 2005)

Oral:

As for oral toxicity no adequate study for TMPeoTA is available a read across to another acrylate with comparable structure elements is performed. A reliable combined 28-Day Repeated Dose Oral toxicity study was performed with 1,6-Hexamethylene Diacrylate (HDDA, CAS 13048-33-4)(ReachCentrum, 2010, Stump D.G.). Thisstudy leads to aNOAEL (systemic) of 250 mg/kg bw/d. In conclusion a NOAEL of 250mg/kg bw/d is also assumed to be suitable to derive an oral and inhalation DNEL for TMPeoTA. But as this read across is performed to a substance containing two functional groups instead of three a decrease of 1/3 of the NOAEL is assumed reflecting these circumstances.

Values used for systemic DNEL derivation:

- mice, subacute, dermal,NOAEL, (f/m, systemic, mice): ≥200 mg/kg bw(Publication: 14/28 day NTP, Battelle Columbus Laboratories, 2005)

- rats, combined 28-day repeated dose oral, OECD 422, read acrossNOAEL (systemic, rat)250 mg/kg bw, read across adaptation ->166.7 mg/kg bw(ReachCentrum, 2010, Stump D.G.)

Skin sensitisation DNELs ("acute / short term exposure local effects" and "long-term exposure local effects"):

It is very difficult to derive a quantitative sensitisation DNELs based on the available test systems, as most of these test, as well as the human patch test, were not designed to derive a threshold for sensitisation. This was also addressed in the guideance document Chapter R.8: Characterisation of dose [concentration]-response for human health May 2008.APPENDIX R. 8-10concludes that GMPT and the Buehler test data are only allow a qualitative assessment and that LLNA and human data may be only allow (in some case) the derivation in a more quantitative manner.

A few LLNA studies conducted with TMPeoTA (different batches) show skin sensitisation. But only two of the studies determined a threshold for sensitisation. These two studies were conducted according to the protocol for the non radioactive version of the LLNA (BASF, 2002, Gamer A.O. (a) and BASF, 2004, Gamer A.O. (d)).

Therefore based on the data available, no quantitative derivation of a local DNEL can be calculated due to the following uncertainties:

-The LLNA method used was modified to avoid use of radioactive material. This modified method does not allow a judgement on the potency of the sensitizer. No EC3 value can be derived.

-Dermal penetration is a prerequisite step for sensitization. Based on calculations made using the OECD toolbox (DermWin), penetration is expected to be low.

Thus the first step of the general approach given in APPENDIX R. 8-10is followed and aqualitative approach (by using potency categorisation) to define the risk management measures (RMMs) (see sectionqualitative approach for sensitisation) is performed. The second step of the approach can not be fulfilled as it is not possible to derive reliable DNELs for sensitisation.

Instead, based on the qualitative information that the substance is a skin sensitiser, the applicant strongly suggests establishing adequate risk management measures for all uses.

Qualitative approach for sensitisation:

A qualitative assessment based on information available on skin sensitisation is given below:

- Based on a Buehler test (BASF, 2004, Gamer A.O.) according to Table R. 8-25 the substance is a moderate sensitizer.

- Based on results obtained when using the non-radioactive LLNA(BASF, 2002, Gamer A.O. (a) and BASF, 2004, Gamer A.O. (d))no categorisation based on potency according to Table R. 8-23 is possible. Nevertheless the test result obtained indicates that the substance has a sensitising potential.

Based on all the integrated information there is the concern that TMPeoTA is a moderate skin sensitiser. Therefore the applicant strongly suggests implementing risk management measure controlling the local dermal exposure (seeRisk management measure addressing the classification of the substance).

Risk management measure addressing the classification of the substance:

The substance is classified as irritant to eye and skin sensitiser therefore working with this substance requires a stringent use of appropriate chemical resistant gloves, protective clothing and suitable eye protection if any skin/eye contact is foreseen. Workers should receive a task specific training on how to use the protective equipment and the correct use of it needs to be supervised. Besides that, workers should be warned to avoid skin and eye contact, to wash off any skin contamination immediately and to report skin/eye problems that may develop. Taking these measures into account, the intensity of exposure is considered to be very low.

Assessment of available DNELs:

The lowest derived DNELs are derived from systemic effects, representing the most critical effect. These DNELs were used for risk assessment.

No further DNELs were derived due to increased uncertainties during derivation.

General information:

If no DNEL is derived, then the study design of the tests conducted does in general not allow the derivation of threshold values due to the study design e.g. when a limit test was conducted. Further information about the categorisation of e.g. regarding acute effects, can be obtained from the classification of the substance. If acute local or systemic thresholds or local effects values are recorded these values are used to derive adequate DNEL, otherwise this justification applies.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

420

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

120