6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

27.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

2 067 mg/m³

Explanation for the modification of the dose descriptor starting point:

no inhalation toxicity data available

AF for dose response relationship:

1

Justification:

default AF; clear NOAEC

AF for differences in duration of exposure:

2

Justification:

default AF for 90 day to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

inhalation, no allometric scaling

AF for other interspecies differences:

2.5

Justification:

default for remaining differences

AF for intraspecies differences:

5

Justification:

default AF for workers

AF for the quality of the whole database:

3

Justification:

Single, non-GLP study, pre-dates OECD guidelines and has limitations in design and reporting

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

3.5 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

1 058 mg/kg bw/day

AF for dose response relationship:

1

Justification:

default AF; clear NOAEL

AF for differences in duration of exposure:

2

Justification:

default AF for 90 day to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

differences in metabolic rate (rat to human)

AF for other interspecies differences:

2.5

Justification:

default for remaining differences

AF for intraspecies differences:

5

Justification:

default AF for workers

AF for the quality of the whole database:

3

Justification:

Single, non-GLP study, pre-dates OECD guidelines and has limitations in design and reporting.

AF for remaining uncertainties:

1

Justification:

non

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

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 (TGD Guidance Appendix R.8-8). HCA is not classified for acute oral or dermal toxicity. No data are available for the inhalation route. No acute DNELs for systemic effects are required, but skin sensitisation is considered as HCA should be classified as a Category 1B sensitiser.

Local effects

Sensitisation

In case of skin sensitisation, the first step is a qualitative approach to assessing and controlling the risks, with information on the potency can be used in qualitative risk characterisation and for recommendation of appropriate RMMs and OCs. HCA should be classified as Category 1B sensitiser and therefore according to current guidance is ‘Moderate hazard’ (ECHA Guidance on information requirements and chemical safety assessment: Part E: Risk Characterisation; Version 2.0 November 2012) on the basis that exposure to these moderate skin sensitising substances should be well-controlled.

It is not possible to set a DNEL as no meaningful EC3 value can be derived (insufficient dose response date) from the available study (Török-Bathó, 2011).

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for HCA and DNELs cannot therefore be determined. HCA is not classified as a skin or eye irritant and is not corrosive.

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 and reproductive (fertility, developmental) testing.

Oral:
sub-chronic effects: rat 16 wk NOAEL = 1058 mg/kg bw/d

It is clear that a systemic NOAEL (oral route) has been established as 1058 mg/kg bw/d (mean value for male and female rats) and this could be used to extrapolate a systemic DNEL following inhalation and dermal exposure. 

Dermal

Dose descriptor 

In sub-chronic studies the NOAEL for systemic effects was 1058 mg/kg bw/d in the rat and this value is used to derive the systemic DNEL long term for dermal exposure.

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human dermal NOAEL (mg/kg bw/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.5).

It is assumed that uptake of HCA after ingestion is 100% and after dermal exposure, is 100%.

_correctedDermal NOAEL = NOAEL_oralx [ABS_oral-rat/ABS_dermal-human]

_correctedDermal NOAEL = 1058 x [100/100] = 1058 mg/kg bwt/d

Assessment factors

Uncertainty	ECHA AFs	Justification
Interspecies differences	4 2.5	differences in metabolic rate remaining differences
Intraspecies differences	5	default AF for workers
Differences in duration of exposure	2	default AF for 90 day to chronic
Dose response and endpoint specific/ severity issues	1	default AF; clear NOAEL
Quality of database	3	Single, non-GLP study, pre-dates OECD guidelines and has limitations in design and reporting.
Overall AF	300

 

DNEL_{l-t dermal}     = 1058 mg/kg bw/d / 300

= 3.5 mg/kg bw/d

 

Inhalation

Dose descriptor 

In sub-chronic studies the NOAEL for systemic effects was 1058 mg/kg bw/d in the rat and this value is used to derive the systemic DNEL long term for inhalation exposure.

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human inhalation NOAEC (mg/m³) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.3).

It is assumed that uptake of HCA after ingestion is 100% and after inhalation exposure, is 100%.

NOAEC_inhalation  =Oral NOAEL x [1/ sRV_rat^[1]] x [ABS_oral-rat/ABS_inhal-human] x [sRV_human/wRV]

NOAEC_inhalation =1058 x [1/0.343] x [100/100] x [6.7/10]

                                       = 2067 mg/m³

Assessment factors

Uncertainty	ECHA AFs	Justification
Interspecies differences	1 2.5	No difference in metabolic rate (inhalation) remaining differences
Intraspecies differences	5	default AF for workers
Differences in duration of exposure	2	default AF for 90 day to chronic
Dose response and endpoint specific/ severity issues	1	default AF; clear NOAEC
Quality of database	3	Single, non-GLP study, pre-dates OECD guidelines and has limitations in design and reporting.
Overall AF	75

 

DNEL_{l-t inhal}     =  2067 mg/m³/ 75

=  27.5 mg/m³

 

Dermal & inhalation

No information is available to characterise the repeated local effects of HCA on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate.

 

 

^[1]  8 hour value calculated from TGD Table R.8-17 values (as per guidance Appx R.8-2, example B.4) – sRV for rat (mean male/female) is 1.43 L/min/kg bw = 0.343 m³/kg bw for 8 hours (same duration of exposure as worker)

General Population - Hazard via inhalation route

Systemic effects

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

Acute/short term exposure

DNEL related information

Additional information - General Population

No exposure anticipated