Cyclopropanecarboxylic acid, [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl ester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 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:

8.9 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

10.98 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to oral absorption data available, oral absorption rate in Fischer rats is ca. 70%, inhalation absorption was estimated to be 100%.

Considering the respiratory volume of the rat (0.38 m3/kg bw) and correction for activity driven differences of the respiratory volume in workers compared to workers in rest (6.7 m3/10 m3), the following calculation was done:

NOAEC corrected = 8.9 x (70/100) x (1/0.38) x (6.7/10) = 10.98 mg/m3

AF for dose response relationship:

1

Justification:

A NOAEL was used as starting point, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The 1-year study in rats does not cover the whole life span, according to ECHA guidance R.8, an assessment factor of 2 is adequate.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences / remaining uncertainties (ECHA guidance R.8)

AF for intraspecies differences:

10

Justification:

Accounting for differences in worker population with regard to the effects observed.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical (guideline and GLP study).

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose oral toxicity study is available. However, time scaling is required since animals were exposed for 6 hours whereas workers can be assumed to work for 8 hours per day. Therefore, the NOAEL was corrected according to:

NOAEL corrected = 1000 x (6h/8h) = 750 mg/kg bw/d

AF for dose response relationship:

1

Justification:

A NOAEL was used as starting point, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point), according to ECHA Guidance R.8

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used (ECHA Guidance R.8).

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences / remaining differences (ECHA Guidance R.8).

AF for intraspecies differences:

10

Justification:

Accounting for differences in worker population with regard to the effects observed.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The test material is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP).

 

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA.  

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly via inhalation route, and may also occur via dermal route. Therefore two long-term DNELs are calculated for workers.

Long-term inhalation DNEL

There are no relevant experimental data on repeated exposure by inhalation, therefore the oral NOAEL of 8.9 mg/kg bw/d (determined in a 1-year study in F344 rats) was used as point of departure and converted into a corrected inhalation NOAEC of 10.98 mg/m³. Application of the appropriate assessment factors led to the determination of along-term systemic inhalation DNEL of 0.2 mg/m³.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 8.9 mg/kg bw/day	as determined in 1-year study in rats
Step 2) Modification of starting point	70%/100%   0.38 m^3/kg bw   6.7 m^3/10 m^3	Ratio of oral to inhalation absorption   Respiratory volume of a rat, corrected for 8 h exposure Correction for activity driven differences of respiratory volumes in workers compared to workers in rest
Modified dose-descriptor	NOAEC corrected = 8.9 * (70/100) * (1/0.38) * (6.7/10) = 10.98 mg/m^3
Step 3) Assessment factors
Allometric scaling	1	not required (according to ECHA guidance document R.8)
Remaining differences	2.5	accounting for interspecies differences (according to ECHA guidance document R.8)
Intraspecies	10	Accounting for differences in worker population
Exposure duration	2	1-year study as point of departure
Dose response	1	NOAEL is used as starting point
Quality of database	1	Guideline and GLP study
DNEL	Value
	10.98 / (1 x 2.5 x 10 x 2 x 1 x 1) =0.2 mg/m^3

Since no local effects or acute toxicity was observed, the long-term inhalation DNEL of 0.2 mg/m³ is considered sufficient to cover inhalation effects.

 

Long-term dermal DNEL

For derivation of the long-term systemic dermal DNEL, the dermal NOAEL of 1000 mg/kg bw/d (as determined in a dermal 28-day study in rats) was taken as a basis. This was converted into a corrected dermal NOAEL of 750 mg/kg bw/d based on time extrapolation. Applying all assessment factors, a dermal long-term DNEL for systemic effects of 1.25 mg/kg bw/d is derived.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	as determined in dermal 28-day study in rats
Step 2) Modification of starting point	6h/8h	time scaling for standard 8 hour shift of workers (experimental exposure: 6h)
Modified dose-descriptor	NOAEL corrected dermal = 750 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	according to ECHA guidance R.8
Remaining differences	2.5	according to ECHA guidance R.8
Intraspecies	10	according to ECHA guidance R.8
Exposure duration	6	28-day study as point of departure
Dose response	1	NOAEL is used as starting point
Quality of database	1	Guideline and GLP study
DNEL	Value
	750 / (4 x 2.5 x 10 x 6 x 1 x 1) =1.25 mg/kg bw/day

Since no local effects or acute toxicity was observed, the long-term dermal DNEL of 1.25 mg/kg bw/d is considered sufficient to cover dermal effects.

General Population - 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:

no hazard identified

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:

no hazard 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

General Population - Hazard via oral 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General 

General population is not intended to be exposed to test item via inhalation, oral or dermal route. Therefore, no DNEL (long-term, inhalation and dermal exposure) is derived for general population. As the test item has no bioaccumulation potential no risk assessment for secondary poisoning is required for the general population.

References

(not included as endpoint study record)

 

- ECHA (2014) Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1 ECHA-2010 -G-19 –EN.