Reaction mass of m-terphenyl and o-terphenyl

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.645 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

123.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 100 mg/kg bw/day was modified into a corrected inhalatory NOAEC as follows:

corr. NOAEC = NOAEL * ((1/0.38 m³/kg/d)*(50%/100%)* 6.7m³(8h)/10m³(8h)) * (7days/5 days) = 100 * 2.63 * 0.5 * 0.67 *1.4 = 123.35 mg/m³

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 hours exposure of workers).

In the absence of substance-specific data on absorption for both the starting route and the end route (the route to which the extrapolation is being made), worst case assumptions have to be made. Worst case in this context will be obtained assuming a limited absorption for the starting route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL a maximum absorption should thereafter be assumed for the end route, leading to a low external NOAEL. It is proposed, thus, 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.

For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity).

The exposure conditions have been different, as for inhalation exposure of workers 5 days are taken into account. The NOAEL obtained in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test has been derived from the following exposure conditions: 7 days. Therefore, the NOAEL of 100 mg/kg bw has to be modified to correct these exposure condition differences as well by applying a factor of 1.4.

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

6

Justification:

Default for extrapolation from a subacute to a chronic duration

AF for interspecies differences (allometric scaling):

1

Justification:

Default; in case of route-to-route extrapolation from an oral NOAEL to an corrected inhalation NOAEC no factor for allometric scaling needs to be applied

AF for other interspecies differences:

2.5

Justification:

Default; If no substance-specific data are available, the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).

AF for intraspecies differences:

5

Justification:

Default

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are identified

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:

0.467 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation. However, the exposure conditions are different, as for dermal exposure of workers 5 days are taken into account. The NOAEL obtained in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test has been derived from the following exposure conditions: 7 days. Therefore, the NOAEL of 100 mg/kg bw has to be modified to correct these exposure condition differences by applying a factor of 1.4:

corr. NOAEC = NOAEL * (7days/5days) = NOAEL * 1.4 = 100 mg/kg bw/day * 1.4 = 140 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

6

Justification:

Default for extrapolation from a subacute to a chronic duration

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor for allometric scaling (rat to human)

AF for other interspecies differences:

2.5

Justification:

Default; If no substance-specific data are available, the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).

AF for intraspecies differences:

5

Justification:

Default

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are identified

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 calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

Reaction Mass of m-terphenyl and o-terphenyl is not expected to be acutely toxic by the oral, dermal or inhalatory route of exposure based on data available for the closely related analogue terphenyl (LD50 value is 2604 mg/kg bw/day, Environmental Health Laboratories, Monsanto Company, Report No 810011; Company Study No ML-80 -502; LD50 > 5000 mg/kg bw/day, Environmental Health Laboratory, Monsanto Company, Report No. 810012; Company Study No ML-80 -502 and LC50 > 3.8 mg/L air, Environmental Health Laboratory; Monsanto Company, Report No. MSL-5610; Company Study No ML-83 -239). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (0.018 Pa at 25 °C) (Tremain, 2018b). The substance is non-volatile and therefore no risk of irritation or sensitisation of respiratory tract exists. The substance is expected to be not irritating and not sensitising to skin based on data available for the closely related analogue terphenyl (Environmental Health Laboratory, Monsanto Company, 1981; Report No. 810013; Company Study No ML-80 -502; Haley at al, 1959) and biphenyl and biphenyl-2-ol (Dreist and Kolb, 1993; Anderson, 1984 and 1986). Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived for workers.

For the long-term exposure – systemic effects (inhalation and dermal DNEL), the NOAEL of 100 mg/kg bw/day (corresponding to 123.35 mg/m³) established for Reaction mass of m-terphenyl and o-terphenyl in the combined repeated dose toxicity study and reproductive / developmental toxicity screening test in the CD Rat by Oral Gavage Administration(Envigo CRS Limited, 2018; Report No. TP77DF) were used as the starting points.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No-Observed-Effect-Level could not be established from the relevant studies.

Modification of the starting point:

From all available data on the target and read-across substances it is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived only for workers as no consumer uses are intended.

Bioavailability (absorption):

There is no substance-specific experimental information available on absorption by the different routes of exposure. Absorption rates for oral, dermal and inhalation routes are assessed based on the physico-chemical properties of the substance and on the effects observed in treated animals in the available studies.

Oral absorption:

Molecular weight of 230.31 g/mol, the Log Pow values in the range of 3.01 - 5.94 and low water solubility (0.0001 g/L at 20 °C) are supportive for a limited absorption by oral route of exposure. However, the effects observed in animal studies: the oral combined repeated dose toxicity study and the reproductive / developmental toxicity screening study (Envigo, 2018, Report No TP77DF) point to an absorption by oral route of exposure. The oral absorption is set to 100 % (worst-case) for the purposes of hazard assessment (DNEL derivation). The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

Moderate dermal absorption potential is expected for the target substance. The molecular weight of 230.31 g/mol and Log Pow values in the range of 3.01 to 5.04 are favourable for dermal absorption and the low water solubility (0.0001 g/L at 20 °C) further support the possibility for dermal absorption and the substance' transfer through the outer skin layer. Taking into account effects of the closely related structural analogues in animals studies, no signs of systemic toxicity were noted in animals treated dermally for 24 hours in the acute dermal study in rats (Environmental Health Laboratory, Monsanto Company, Report No 810012; Company Study No ML-80 -502). The dermal absorption is set to 100 % (worst-Case) for the purpose of hazard assessment (DNEL derivation). Dermal absorption in rats and in humans is assumed to be the same.

Inhalation absorption

Absorption by inhalation is considered to be negligible since the substance may be not available for inhalation as a vapour due to its vapour pressure of 0.018 Pa at 25 °C (ECHA guidance R.7C, Table R.7.12-2). Absorption by inhalation is expected not to be higher than absorption by oral route. Therefore, 100 % absorption as worst case is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

A correction for differences between routes of exposure is necessary since there is only a dose descriptor for the oral route of exposure in experimental animals as for a given human exposure route (see also below). The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m3/kg for 8 hours exposure of workers). A factor of 0.5 was included for the assumption the 50 % (instead of 100 %) absorption is assumed for oral absorption and 100 % for inhalation.

Exposure conditions:

Modification of the starting point for exposure conditions was also necessary and a correction for differences in the respiratory volumes of workers under normal conditions (6.7 m³) and by light activity (10 m³) has been accounted.

Moreover, the exposure conditions have been different, as for inhalation and dermal exposure of workers only 5 days are taken into account. The NOAEL obtained in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test has been derived from the following exposure conditions: 7 days. Therefore, the NOAEL of 100 mg/kg bw has to be modified to correct these exposure condition differences by applying a factor of 1.4 (= 7days/5days).

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAELs from the combined repeated dose toxicity study and reproductive / developmental toxicity screening test in the CD Rat by Oral Gavage Administration(Envigo CRS Limited, 2018; Report No. TP77DF)

to derive the dermal long-term DNELs.

No allometric scaling factor was applied in case of inhalation NOAEC using for the derivation of inhalation long-term DNEL.

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all exposure routes.

Extrapolation of duration:

A default factor of 6 was applied for extrapolation from a subacute to a chronic duration

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied (there was a clear dose response).

Calculation of DNELs:

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 100 mg/kg bw/day was corrected for differences in breathing volume, absorption rates in rat and humans and in exposure conditions, :

Corrected inhalation NOAEC = oral NOAEL * ((1/0.38 m³/kg/d)*(50%/100%)* 6.7m³(8h)/10m³(8h)) * (7days/5days)= 100 * 2.63 * 0.5 * 0.67 * 1.4 = 123.35 mg/m³

DNEL = 123.35 mg/m³/(2.5 x 5 x 6 x 1 x 1) = 1.645 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (subactue study), 1 – dose response, 1 – quality of data base. The total AF amounts to 75.

Long-term exposure – systemic effects (dermal DNEL):

For the oral rat NOAEL of 100 mg/kg bw no modification was necessary for differences in absorption rates because dermal absorption is considered to be the same in animals and in humans. However, the exposure conditions

have been different, as for dermal exposure of workers only 5 days are taken into account. The NOAEL obtained in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test has been derived from the following exposure conditions: 7 days. Therefore, the NOAEL of 100 mg/kg bw has to be modified to correct these exposure condition differences:

Corrected dermal NOAEL = oral NOAEL * (7days/5days) = 100 * 1.4 = 140 mg/kg bw/day

Additionally, an exposure duration of 23 hours in the dermal developmental study was sufficient to ensure that amount of the substance that could be dermally absorbed during 8 -h working shift by workers is not underestimated:

DNEL = 140 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 0.467 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (subacute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

Selected DNELs

DNEL systemic inhalation = 1.645 mg/m³

DNEL systemic dermal (long-term) = 0.467 mg/kg bw

 

 

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:

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

Calculation of Consumer DNELs is not relevant, since no uses for consumers are intended.