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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.882 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:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
44.079 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant data for repeated exposure by inhalation. The systemic NOAEL of 50 mg/kg/day from OECD 422 repeat dose oral study with rats (6 - 8 weeks) was used for DNEL derivation. Assuming an oral /inhalation absorption of 0.5 a dose descriptor NOAEC of 44.079 mg/m3 was derived as the modified starting point. This study is a well conducted repeated dose study in rats and is of good quality (GLP, OECD guideline). For details, please see under "Additional information - Workers".

AF for dose response relationship:
1
Justification:
per REACH Guidance. The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
Per REACH Guidance. (OECD 422 study duration was 6-8 weeks), less than subhronic study duration, but more than subacute study duration.
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for inhalation DNEL, per REACH Guidance. Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
per REACH Guidance
AF for intraspecies differences:
5
Justification:
per REACH Guidance. Default value for the relatively homogeneous group,"Worker" is used.
AF for the quality of the whole database:
1
Justification:
per REACH Guidance. Default value
AF for remaining uncertainties:
1
Justification:
per REACH Guidance. Default value. No further AF are required as a conservative approach was used.
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:
0.5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no specific experimental data on repeated dermal exposure or on dermal absorption. The systemic NOAEL of 50 mg/kg bw/day from OECD 422 repeat dose oral study in rats was used. Assuming a dermal absorption of 50% (taking into account the physico-chemical properties of molecular weight and water solubility and logKow), a dose descriptor of 100 mg/kg bw/d was derived as the starting point.This study was used for DNEL derivation as it is of good quality (GLP, OECD). Details can be found under "Additional information - Workers"

AF for dose response relationship:
1
Justification:
per REACH Guidance
AF for differences in duration of exposure:
4
Justification:
Per REACH Guidance. (OECD 422 study duration was 6-8 weeks)
AF for interspecies differences (allometric scaling):
4
Justification:
per REACH Guidance (allometric scaling)
AF for other interspecies differences:
2.5
Justification:
per REACH Guidance
AF for intraspecies differences:
5
Justification:
per REACH Guidance. Default value
AF for the quality of the whole database:
1
Justification:
per REACH Guidance. Default value
AF for remaining uncertainties:
1
Justification:
per REACH Guidance. Default value
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Phys-Chem properties of CAS# 4203-89-8 ( 2-(1-oxa-4-azaspiro[4.5]dec-4-yl)ethyl methacrylate)

Physical state

Liquid

Molecular Weight

253.34

Log Kow , Experimental

3.2 at 25 °C

Vapor pressure

0.0485 Pa at 25 °C

Water solubility, measured,25oC

Not possible to measure; 918.6 g/L (calculated per EPISuite)

Eye, in vivo

Non irritant

Skin, in vivo

Corrosive, Cat 1

Skin sensitization, QSAR predictions

Sensitizer, Cat 1

NOAEL (oral, rat, m/f, OECD 422)

50 mg/kg bw/d

 

Absorption through Inhalation: The test substance has a molecular weight of 253.3, and a log Kow of 3.2. Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (< 1mg/L) that would otherwise be poorly absorbed. Since the oral absorption study indicated some systemic toxicity, the potential for absorption through inhalation is likely. However, the vapor pressure (0.0485 Pa at 25oC) of the test item is very low. Therefore, inhalation is not expected to be a major route of exposure / absorption. The respiratory absorption is considered to be 100% for DNEL calculations.

Dermal absorption: For molecular weights above 500 and log P values below -1 or above 4 a conservative default absorption factor at 10% cutaneous absorption has been set (EC 2007). The test substance has a molecular weight of 253.3, and a log Kow of 3.2. Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (< 1mg/L) that would otherwise be poorly absorbed. Low vapor pressure (0.0485 Pa at 25degrees C) may favor dermal uptake. The substance also has skin corrosive property (in rabbits) making it more available to the deeper layers of the skin. It is considered to be a skin sensitizer by by QSAR predictions. Based on all these factors, the dermal absorption is therefore considered to be 50%.

 

In a GLP, OECD 422“Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test”, study, daily oral administration of2 -(1 -oxa-4 -azaspiro[4.5]dec-4 -yl)ethyl methacrylate

(CAS 4203 -89 -8) to Wistar Han™:RccHan™:WIST strain rats for 6 -8 weeks (including 2 weeks pre-pairing, gestation and early lactation for females) at dose levels 50, 150 and 375 mg/kg bw/day resulted inthe following findings: 

 

Treatment of males at 375 mg/kg bw/day was associated with lower body weight (BW) gains and inferior food conversion efficiency, compared to control, changes for hematology and blood chemistry parameters suggestive of mild anemia and liver and kidney effects and increased BW-relative liver and kidneys weights. Histopathology revealed minimal tubular vacuolation of the kidneys. Collectively these findings precluded this dosage from representing a No Observed Adverse Effect Level (NOAEL) for male systemic toxicity. Treatment at 150 mg/kg bw/day was associated with inferior BW gain, compared to control, changes in hematology parameters and blood chemistry parameters suggestive of mild anemia and effects on the liver and kidney, and increased BW relative liver and kidneys weights. Histopathological examination revealed minimal tubular vacuolation of the kidneys. These findings occurred to a lesser extent than observed at 375 mg/kg bw/day, and a dosage of 150 mg/kg bw/day was considered to represent the Lowest Observed Adverse effect Level (LOAEL) for male systemic toxicity. At 50 mg/kg bw/day, there were no effects on BW gains or food consumption apparent and only occasional changes for hematology and blood chemistry parameters. While increased BW relative liver and kidneys weights were apparent, treatment related histopathological findings were restricted to a low incidence of minimal tubular vacuolation of the kidneys. The extent of effects at this dosage were considered insufficient to represent an adverse effect and, as such,this dosage was regarded as the NOAEL for male systemic toxicity.

 

Treatment of females at 375 mg/kg bw/day was generally associated with lower BW gains throughout most of the study, including pre-mating, gestation and late lactation. Food conversion efficiency was inferior during the first week of treatment and food consumption was lower throughout gestation. Effects on hematology and blood chemistry parameters were minor but increases in BW-relative liver and kidney weights were apparent. Histopathology reveal minimal tubular vacuolation and, more significantly, multifocal basophilic tubules of the kidneys; the latter finding was considered to be adverse and clearly precluded this dosage from being regarded as a NOAEL for female systemic toxicity. At 150 mg/kg bw/day, inferior BW gain and food conversion efficiency was apparent during the 2 week pre-mating phase with lower BW gain continuing throughout gestation. Effects on hematology and blood chemistry parameters were minor. Increases in BW- relative liver and kidney weights were apparent, but treatment related histopathological changes were restricted to minimal tubular vacuolation of the kidneys. This dosage probably represents the LOAEL for female systemic toxicity. At 50 mg/kg bw/day, there were no effects on BW gain and only isolated differences from control for hematology and blood chemistry parameters. Increased BW-relative liver and kidneys weights were observed but there were no treatment related histopathological findings. The extent of effects at this dosage were considered insufficient to represent an adverse effect and, as such, thisdosage was regarded as the NOAEL for female systemic toxicity.

 

At 375 mg/kg bw/day, there was an increased incidence of females with extended gestation length and a reduction in the number of implantations. Despite the lower number of implantations, early post-natal survival of the offspring was inferior to control and whilst offspring survival improved after Day 4 of age, BW gains of the offspring was inferior to control. No obvious morphological changes were apparent for the offspring. At 150 mg/kg bw/day, there were no effects apparent for gestation length or for the survival and growth of the offspring. This dosage therefore represents a clear NOAEL and, probably alsorepresents a NOEL, for reproduction and the survival, growth and development of the offspring.

DNEL inhalation-systemic-worker for 4-(1,1-dimethylethyl)cyclohexyl methacrylate:

Corrected inhalatory NOAEC: Oral NOAELx(1/sRVrat)x(ABSoral-rat/ABSinh-human)x(sRVhuman/wRV)

Correction for inhalation and oral absorption rates: Assume ABSoral-rat/ABSinh-human is 50/100 = 0.5

based on phys-chem properties and Endpoint Specific Guidance chapters 8 and 7c (R.7.12).

 

[ABS: absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]

 

Conversion into an inhalatory rat NOAEC: dividing by 0.38 m3/kg (8-hour respiratory volume in the rat)

 

Correction for activity driven differences in respiratory volume in workers compared to individuals at rest: (6.7 m3/10 m3)

 

Therefore, Corrected NOAEC = 50 mg/kg/day x (1/0.38 m3/kg/day) x (0.5) x 6.7 m3/10m3= 44.079 mg/m3 (Dose descriptor)

 

Applying remaining assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

Correction for interspecies differences: 2.5

44.079 mg/m3/2.5 = 17.63 mg/m3

Correction for intraspecies differences: 5

17.63 mg/m3 /5 = 3.526 mg/m3

Correction for duration of exposure [between sub-acute-subchronic to chronic i.e., OECD 422]: 4

3.526 mg/m3/4 = 0.882 mg/m3

Correction for dose-response:1

0.882 mg/m3/1 = 0.882 mg/m3

Correction for whole database: 1 due to quality of study

0.882 mg/m3/1 = 0.882 mg/m3

Total AF = 50

DNEL, inhalation-systemic-worker = 0.882 mg/m3

 

DNEL dermal-systemic-worker for 4-(1,1-dimethylethyl)cyclohexyl methacrylate:

Corrections for dermal and oral absorption rates of 4-(1,1-dimethylethyl)cyclohexyl methacrylate based on Guidance on information reqirements and chemical safety assessment, Chapter R 7.12: Dermal absorption is assumed to be moderate due to (1) the substance is a liquid but poorly soluble in water; and (2) moderate log Kow and very low vapor pressure. The substance is a not a skin irritant but a skin corrosive and considered to be a skin sensitizer. The dermal absorption is assumed to be 50% (correction factor= 0.5) as actual dermal absorption data are unavailable. The oral absorption factor is considered as100%.

 

Oral NOAEL (50 mg/kg/day) / 0.5 (50% dermal absorption) =100 mg/kg/day = dermal dose descriptor.

 

Applying assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

Correction for interspecies differences (applying allometric scaling factor of 4 for rat x 2.5 for additional factors): 10

 

100 mg/kg/day/10 = 10 mg/kg/d

Correction for intraspecies difference: 5

10 mg/kg/day/5 = 2 mg/kg/d

Correction for duration of exposure [between sub-acute/subchronic to chronic; OECD 422]: 4

2 mg/kg/day/4 = 0.5 mg/kg/d

Correction for dose-response: 1 (due to NOAEL)

0.5 mg/kg/day/1 = 0.5 mg/kg/d

Correction for whole database: 1 (due to quality of study)

0.5 mg/kg/day/1 = 0.5 mg/kg/d

Total AF = 200

DNEL, Dermal-worker-systemic = 0.5 mg/kg/day

 

Additionally, the substance is classified for skin sensitivity and corrosivity.

Skin sensitization: Based on QSAR predictions, the registered substance is considered to be a skin sensitizer, Cat 1. (High hazard)

 

Skin corrosivity: In this study the test substance was applied to intact skin. It should be noted that the original Draize primary skin irritation index applies to the combined average of the scores for intact and abraded skin. The calculated primary irritation index (modified) for this substance is 5.0. One animal showed visible necrosis and effects were not fully reversible within 21 days. The substance was found to be corrosive to skin. Classified as Category 1 (corrosive) based on GHS criteria, and by EU CLP criteria. This is considered a high hazard (Part E. risk charactarization)

 

There are no consumer uses of this substance. Human exposure, via the environment, is unlikely. The general population is not expected to be exposed to the substance by inhalation, dermal or oral exposures. Therefore no inhalation and dermal DNELs are derived for general population. Only DNELs for the relevant populations will have to be derived (Guidance on information requirements and chemical safety assessment R.8.1.2.3).

 

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