4-(1,1-dimethylethyl)cyclohexyl acrylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.4 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

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

185.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

The conversion of the rat oral NOAEL of 150 mg/kg bw/day from the OECD 442 study to a corrected inhalatory human NOAEC was based on the different respiratory volume of the rat (0.38 m³/kg) and the different rate during light activity at work (10 m³) and under standard conditions (6.7 m³). Addtionally, the NOAEL has been corrected for differences in exposure duration (7 days (study) vs. 5 days (workdays)). In the absence of data on absorption, an additional factor of 2 was also included to account for potentially higher absorption via the lung.

AF for dose response relationship:

1

Justification:

NOAEL used

AF for differences in duration of exposure:

2

Justification:

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not consistently observed in the OECD 408 study, because rats were not observed at this relevant time point, except during FOB assessments. However, it did not became more severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study or at lower doses during the FOB. Therefore, the AF factor for duration of exposure was set to 2.

AF for interspecies differences (allometric scaling):

1

Justification:

included in route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

no further uncertainties

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:

2.1 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

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

210 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The same absorption after oral or dermal exposure has been assumed. The NOAEL of 150 mg/kg bw/day from the OECD 422 study was corrected for the differences in exposure times (7 days/ week exposure vs. 5 workdays/week; factor 1.4).

AF for dose response relationship:

1

Justification:

NOAEL used

AF for differences in duration of exposure:

2

Justification:

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not consistently observed in the OECD 408 study, because rats were not observed at this relevant time point, except during FOB assessments. However, it did not became more severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study or at lower doses during the FOB. Therefore, the AF factor for duration of exposure was set to 2.

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for rat to human

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

no further uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high 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

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation:

An OECD TG 422 and an OECD 408 study with the substance are available. In the OECD 422 study daily oral administration of the test item to Wistar rats did not elicit any signs of reproductive and developmental toxicity up to the highest dose tested. Oral gavage to male and female Wistar rats revealed signs of systemic toxicity at a dose level of 500 mg/kg bw/day. The NOAEL for general systemic toxicity was 150 mg/kg bw/day for male and female Wistar rats taking into account that tubular damage in the kidneys of male animals of all test groups as a consequence of an α2µ-nephropathy does not represent a risk for humans. In the subchronic study according to OECD 408, 10 males and females per group were exposed orally via gavage to 50, 150, and 500 mg/kg bw/day. The human relevant NOAEL (excluding a2µ-globulin nephropathy) was set at 500 mg/kg bw/day.

In the OECD 422 study, head twitching was observed. However, this was only observed on very few days in the OECD 408 despite longer treatment with the same doses. This difference is likely due to differences in observation times. In the OECD 422, it was stated that twitching occurred mostly between 0-2 h, partly between 2-5 h after dosing. According to the lab, the technicians leave the room after dosing and return for the 0-2 h observation close to the end of the interval. In the OECD 408, cage side observations were performed within 1 h after dosing. No later time points were checked, except on the days of the FOB examinations, when tremors were observed. In addition, in the concurrently performed OECD 414 (same lab as the OECD 408), the rats were observed 2 h after dosing and twitching was observed comparable to the OECD 422.

All studies agree that the effect of head twitching is transient and histopathology revealed no neural damage. No classification for STOT RE is warranted.

For human risk assessment (DNEL derivation) the lower NOAEL of 150 mg/kg bw/day was used as a starting point, since the relevant effect was likely missed in the OECD 408.

Step 1: PoD: NOAEL = 150 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 150 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 185.1 mg/m3

Step 3: Overall AF= 25

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 2

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not observed in the OECD 408 study, because rats were not observed at this relevant time point. However, it did not became severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study. Therefore, the AF factor for duration of exposure was set to 2.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic inhalation DNEL, workers = 7.4 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

Due to the low vapour pressure (0.6 kPa) of the substance, inhalation exposure is not considered as relevant. The substance is unlikely to be available as a vapor. Furthermore, as the substance is marketed in a non-solid form no formation of dust is expected. Therefore, no DNEL was derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

No irritation to the eyes and only slight irritation to the skin (not leading to classification according to GHS, EU) were observed. No irritation after inhalation is expected. Due to the low vapour pressure of the substance, inhalation exposure is not considered as relevant and local respiratory irritation is expected to be low. Furthermore, as the substance is marketed in a non-solid form no dust formation is expected. Therefore, no DNEL was derived.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 150 mg/kg bw/day derived from an OECD TG 422 study performed with the target was used as the PoD.

Step 1: PoD: NOAEL = 150 mg/kg bw/day

Step 2: Modification into a correct starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 150 mg/kg bw/day x 1.4

= 210 mg/kg bw/day

Step 3: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 2

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not observed in the OECD 408 study, because rats were not observed at this relevant time point. However, it did not became severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study. Therefore, the AF factor for duration of exposure was set to 2.

In conclusion, long term systemic dermal DNEL, workers = 2.1 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

The substance is not classified for acute toxic effects. Therefore, no DNEL was derived.

 

Long term & acute, local DNEL- dermal exposure (workers)

The test item is classified and labelled for skin sensitization, cat.1, according to Regulation 1272/2008 (CLP) and associated to the high Hazard Band. A qualitative risk assessment is conducted according to ECHA Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation.

Hazard to the eye-local effects (worker)

The substance is not irritating in conducted eye irritation tests and it is not classified for eye irritation. Therefore, no qualitative assessment is conducted.

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

65.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

The conversion of the rat oral NOAEL of 150 mg/kg bw/day to a corrected inhalatory human NOAEC was based on the different respiratory volume of the rat (1.15 m³/kg) for a 24h exposure period. In the absence of data on absorption, an additional factor of 2 was also included to account for potentially higher absorption via the lung.

AF for dose response relationship:

1

Justification:

NOAEL used

AF for differences in duration of exposure:

2

Justification:

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not consistently observed in the OECD 408 study, because rats were not observed at this relevant time point, except during FOB assessments. However, it did not became more severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study or at lower doses during the FOB. Therefore, the AF factor for duration of exposure was set to 2.

AF for interspecies differences (allometric scaling):

1

Justification:

included in route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default factor for consumers

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

no further uncertainties

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:

DNEL (Derived No Effect Level)

Value:

0.75 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:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The same absorption after oral or dermal exposure has been assumed.

AF for dose response relationship:

1

Justification:

NOAEL used

AF for differences in duration of exposure:

2

Justification:

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not consistently observed in the OECD 408 study, because rats were not observed at this relevant time point, except during FOB assessments. However, it did not became more severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study or at lower doses during the FOB. Therefore, the AF factor for duration of exposure was set to 2.

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for rat to human

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

10

Justification:

default factor for consumers

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

no further uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high 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:

0.75 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:

150 mg/kg bw/day

AF for dose response relationship:

1

Justification:

NOAEL used

AF for differences in duration of exposure:

2

Justification:

An OECD TG 422 and an OECD 408 study with the substance are available. From the OECD 422 study and the OECD 414 study performed in rats it was observed that the substance causes head twitching 2 h after administration which resumes after approx. 5 h. The head twitching did only occur in the high dose groups of these studies. This effect was not consistently observed in the OECD 408 study, because rats were not observed at this relevant time point, except during FOB assessments. However, it did not became more severe and did not persist in the 90 day study, otherwise it should have been observed also at other time points after dosing in the 90-day study or at lower doses during the FOB. Therefore, the AF factor for duration of exposure was set to 2.

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for rat to human

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

10

Justification:

default factor for consumers

AF for the quality of the whole database:

1

Justification:

GLP guideline study

AF for remaining uncertainties:

1

Justification:

no further uncertainties

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

There are no consumer applications for this substance. DNELs have solely been derived to allow for man via environment exposure assessments.