7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.18 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):

25

Modified dose descriptor starting point:

NOAEC

Value:

4.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

The critical endpoint determined in a subchronic oral exposure toxicity study was identified as 5 mg/kg bw/day based on degenerative effects on the nasal epithelium. Oral exposure resulted in apparent systemic effects that would normally be attributable to inhalation exposure and consequently the use of the study data for determing a protective DNEL for inhalation exposure is considered valid

AF for dose response relationship:

1

Justification:

The NOAEL determined in an oral subchronic exposure study in rats was related to the identified target organ, nasal epithelium. Effects in the high dose and intermediate dose groups showed a degree of dose dependency that did not extend to the lowest dose administered

AF for differences in duration of exposure:

2

Justification:

Extrapolation from a subchronic, 90-day, exposure study for derivation of a chronic exposure DNEL

AF for interspecies differences (allometric scaling):

1

Justification:

default value (4 for rats) from ECHA guidance is not included in the overall AF since it is not applicable for route-to route extrapolation calculations for inhalation exposure

AF for other interspecies differences:

2.5

Justification:

default value used for conservative calculation of DNEL

AF for intraspecies differences:

5

Justification:

default value

AF for the quality of the whole database:

1

Justification:

No additional assessment factor is needed based on the quality of the data presented. The available studies are considered reliable, valid and of sufficient quality to address the data requirements at the appropriate tonnage band. The overall quality of the database was reviewed after confirming the appropriate NOAEL had been identified as the starting point for route-to-route extrapolation. The nasal epithelial changes identified were considered the critical endpoint in the database and interpretation of inhalation or oral systemic or local exposure is not likely to be affected by data from other studies. Since the derivation of the nasal effects was not established unequivocally, it is assumed that a systemic mode of action is worst case. The database has some identified gaps in relation to ddermal absorption, metabolism and fertility/ reproductive effects. The systemic nature of any nasal change, and the protective nature of the derived inhalation DNEL are unaffected by any possible fertility effects at much high doses (reproductive toxicity parameters assessed indicate no effects on fertility/ reproductive performance at doses equivalent to 100-fold the selected NOAEL). Since the database was sufficintly robust to support the conservative NOAEL, no adjustment for quality of the database is considered appropriate.

AF for remaining uncertainties:

1

Justification:

default value for reliable database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.18 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

other: based on read across from long term systemic inhalation starting point

AF for dose response relationship:

1

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for differences in duration of exposure:

2

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for interspecies differences (allometric scaling):

1

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for other interspecies differences:

2.5

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for intraspecies differences:

5

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for the quality of the whole database:

1

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

AF for remaining uncertainties:

1

Justification:

refer to justification for longterm systemic inhalation DNEL derivation

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:

0.05 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No indication of adverse effects following topical exposure. The key study for NOAEL derivation was administered by oral cannula but resulted in possible systemic exposure of nasal epithelium. The endpoint is a valid starting point for subchronic exposure and route-to-route extrapolation is justified in the absence of topical application data.

AF for dose response relationship:

1

Justification:

The NOAEL determined in an oral subchronic exposure study in rats was related to the identified target organ, nasal epithelium. Effects in the high dose and intermediate dose groups showed a degree of dose dependency that did not extend to the lowest dose administered. The starting point was based on an established NOAEL.

AF for differences in duration of exposure:

2

Justification:

Extrapolation from a subchronic, 90-day, exposure study to for derivation of a chronic exposure DNEL

AF for interspecies differences (allometric scaling):

4

Justification:

The highly specific tissue effect observed in nasal epithelium appears (from comparison with other substances eliciting similar effects) to be under metabolic control (influenced by P450 levels and epoxide hydrolase) following hepatic metabolism. Therefore the default adjustment for interspecies differences in toxicokinetics is considered appropriate.

AF for other interspecies differences:

2.5

Justification:

default value used for conservative calculation of DNEL

AF for intraspecies differences:

5

Justification:

default value

AF for the quality of the whole database:

1

Justification:

No additional assessment factor is needed based on the quality of the data presented. The available studies are considered reliable, valid and of sufficient quality to address the data requirements at the appropriate tonnage band. The overall quality of the database was reviewed after confirming the appropriate NOAEL had been identified as the starting point for route-to-route extrapolation. The nasal epithelial changes identified were considered the critical endpoint in the database and interpretation of topical or oral systemic or local exposure is not likely to be affected by data from other studies. Since the derivation of the nasal effects was not established unequivocally, it is assumed that a systemic mode of action is worst case. The database has some identified gaps in relation to dermal absorption, metabolism and fertility/ reproductive effects. The systemic nature of any nasal change, and the protective nature of the derived dermal DNEL are unaffected by any possible fertility effects at much high doses (reproductive toxicity parameters assessed indicate no effects on fertility/ reproductive performance at doses equivalent to 100-fold the selected NOAEL). Dermal absorption is likely to be low, irritation screens do not indicate any marked dermal changes following exposure and a high default value of 50% dermal absorption has been assumed in DNEL calculations. Since the database was sufficiently robust to support the conservative NOAEL, no adjustment for quality of the database is considered appropriate.

AF for remaining uncertainties:

1

Justification:

default value for reliable database

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

 

Due to the nature of the nasal effects observed in the subchronic oral exposure study and the lack of a clear mode of action - the effects could equally have arisen from secondary systemic exposure following oral administration or by local inhalation exposure - the quantitative assessment of systemic inhalation long term exposure was calculated by route-to-route extrapolation using the oral toxicity study endpoints. Other studies did not provided any indication of acute adverse effects, mucus membrane irritation or significant target organ toxicity. Due to a very low vapour pressure, no long term inhalation exposure assessments were considered necessary.

The orally dosed 90 -day study in rats resulted in a NOAEL of 5 mg/kg bw/day and did identify a systemic effect in nasal epithelium, suggesting that effects observed in the target organ following oral dosing could potentially be elicited by systemic exposure. Since the cause of the nasal effects was not clearly attributable to a particular route and was indicated to arise systemically, the long term systemic inhalation DNEL was conservatively calculated to provide protection for other possible exposure scenarios.   The long term systemic inhalation DNEL is also considered equally protective for long term local effects since the same effect is identified as the key response in the subchronic exposure study and its progression would appear to be the same whether exposure is via oral or inhalation routes, or systemic or resulting from localised inhalatory effects. The quantitative assessment of systemic effects resulted in a DNEL that is considered equally applicable to long term local effects. DNELs were calculated using the oral NOAEL as the starting point correcting for route-to-route extrapolation and using the default values provided in the ECHA guidance to determine the overall assessment factor as detailed above.

The argument for nasal epithelial change arising by systemic exposure following oral dosing (resulting in the observed nasal effects critical to NOAEL setting) is supported by the effects on liver and kidneys observed in the high dose group, suggesting some oral absorption of the material and systemic exposure of key organs.

It has been postulated that possible inhalation of volatile metabolites could occur following urinary excretion resulting in nasal irritation if the rats could inhale sufficient toxic vapour from urine-saturated bedding or urinary deposits on cage bars/tray liners. But no data are available to suggest highly volatile metabolites exist, or that they could be excreted via urine in appreciable quantities. QSAR alerts do not suggest highly volatile metabolites are likely to be present. In the absence of robust metabolism data and with no metabolite identification information, this postulate must be discounted and it is assumed for the purpose of safety assessments that the NOAEL is based on systemic toxic effects following oral administration.

The critical endpoint in this repeated dose oral toxicity study was nasal epithelial degeneration, an apparent systemic adverse effect observed in the high dose group predominantly but extending also to the intermediate dose group at much lower incidence and severity. The cause of the epithelial damage was not definitively ascertained despite peer review of the terminal and post-recovery findings. The induction of epithelial basal cell degeneration is normally attributable to inhalation of toxic fumes but for 7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate the vapour pressure is low and vapours, particularly from the material formulated in corn oil, are considered highly unlikely to be the source of the nasal effects.

However a systemic cause has been proposed for similar nasal effects observed following administration of epoxides where hepatic metabolism of epoxy groups can result in dihydrodiol formation and hydrolysis of the ester groups. Systemic nasal toxicity has been observed where the generation of reactive epoxide metabolites occurs in nasal epithelium following hepatic metabolism and mediation by cytochrome P450 isozymes. The expression of nasal toxicity is influenced by relative levels of P450, epoxide hydrolase and glutathione. The effects observed in the subchronic oral toxicity study (including hepatic enzyme induction, liver enlargement and persistent nasal epithelial degeneration) are therefore considered likely to have resulted from an administration-route-independent, systemic exposure rather than inhalation of the test substance or exposure to reactive metabolites present or excreted in exhaled air or via volatiles released from the test substance or secondary exposure to highly volatile metabolites. While the precise mechanisms were not evaluated in the current study, the nature of the nasal effects and similarity of response when compared to other epoxy materials is strongly indicative of a systemic exposure hazard under metabolic influence.

 

Since no data are available relating to the likely extent of dermal absorption, a default value (50%, equivalent to the oral absorption default value) assumes that absorption by the dermal route would be equivalent to that following oral exposure. It is assumed therefore that any nasal effects arising from systemic exposure would also be comparable for the oral and dermal routes and expression of the critical effect would be equally reliant on the metabolism of the product and subsequent systemic distribution. Once the skin has been bypassed the systemic exposure is equal in the worst case for oral or dermally exposed test models and therefore use of the oral study and the NOAEL of 5 mg/kg bw/day as the starting point for route-to-route extrapolation for derivation of a dermal DNEL is justified.

The specific nasal epithelial effect does not have an identified mode of toxic action, the extent of the epithelial damage is unquantified, but it does appear that the toxic effect is highly tissue specific – there are no indications from the available data that dermal epithelial cells may be similarly affected –nasal epithelial degeneration, loss of cilia, and damage to the sustentacular cells without affecting basal membranes - does not have any correlates in the skin tissues examined pathologically.  Sustentacular cells are also found as sertoli cells in seminiferous tubules supplying nutrients to sperm but the testicular examinations completed in the study did not highlight testicular epithelial degeneration suggesting any systemic effect was not on sustentacular cells in general.  The highly specific cellular degeneration observed in the subchronic exposure study does not appear to be directly applicable to dermal epithelium. The dermal DNEL is therefore calculated using ECHA default assessment factors conservatively applied to a systemic NOAEL , using route to route extrapolation from oral exposure, since the systemic effects appear to be under metabolic control rather than dependent on the route of exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.043 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):

50

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2.17 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to Figure R. 8-3 Modification of the Starting Point - ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.8 (2012).

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Default (already considered in route-to-route extrapolation)

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.043 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

NOAEC

Value:

2.17 mg/m³

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA default (already considered in route-to-route extrapolation)

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

ECHA default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable.

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

ECHA default

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

ECHA default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified