Glycerol, propoxylated, esters with acrylic acid

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 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction of exposure duration in study (7 days/week) to default worker exposure (5 days/week); Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). Please refer to "Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling is needed in case of inhalation exposure.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to modern 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.

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

No repeated dose dermal toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. As a conservative approach, the same absorption is assumed after oral and dermal exposure. Dermal absorption will likely be lower, but no definite factor can be assigned. Please refer to "Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to modern 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.

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

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:

low hazard (no threshold derived)

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).

1.    Inhalation

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

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. 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 studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it will be necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation. Human data are not available.

Step 1:PoD and most sensitive endpoint: repeated dose toxicity (oral)

The administration of the test item by daily oral gavage according to OECD TG 408 was well tolerated in rats at levels up to 150 mg/kg bw/day. At 375 mg/kg bw/day adverse findings were noted in the forestomach. These findings are consistent with a response to an irritant material. However, as a conservative approach the NOAEL of 150 mg/kg bw/day was used for derivation of the systemic DNEL for inhalation since no route-to route extrapolation for local effects can be performed (ReachCentrum, 2019).

Step 2:Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 150 mg/kg bw/day

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

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

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

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

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× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 185 mg/m³

Step 3: Overall AF= 25

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Interspecies AF, remaining differences: no evidence for species differences in the general mode of Action

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

Whole database AF: 1

The repeated dose oral toxicity study was conducted according to modern 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)

No acute inhalation toxicity study is available. The test substance has a low vapor pressure, so the potential for the unintended generation of inhalable aerosols is low. According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute oral and dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

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

The substance is classified for eye irritation and in in repeated dose toxicity studies local irritation in the forestomach of rats has been reported. Therefore, damage of the respiratory membranes might be possible (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). However, due to the extremely 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. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure.

2.    Dermal

Two subacute repeated dose toxicity studies were conducted to assess dermal irritation and toxic potential of the substance in CDR rats and in New Zealand White rabbits for an exposure period of 12 or 14 days, respectively. In both studies only one dose was tested.

All treated rats survived throughout the study. Evaluations of physical observations and gross post-mortem observations revealed no evidence of systemic toxic effects. Dermal irritation seen in treated animals was first noted between day 2 and 4 and progressed to moderate or severe erythema with very slight or well-defined edema by study termination. Some animals also exhibited desquamation and evidence of tissue damage (necrosis with subsequent eschar and exfoliation). Body weights of treated males were lower than those of control male, likely secondary to severe local effects. Bodyweights for control and treated females were comparable. In conclusion, the repeated dermal application of GPOTA appeared to cause local dermal necrosis, but no specific systemic toxicity. The LOAEL was 0.1 mL/kg bw for local effects.

Treated rabbits exhibited clinical signs such as nasal discharge, ocular irritation, fecal or urinary staining, necrosis and bruising of the ears, necrosis on the neck, necrosis and swelling of the scrotum including respiratory rate irregularities, hypoactivity and hyperthermia of the ears. Dermal effects included moderate to severe erythema and edema, necrosis, eschar formation with subsequent exfoliation, ataxia, desquamation and fissuring. Gross post mortem examination of skin revealed desquamation, eschar, scabs and/or sores and exfoliations. Microscopically, extensive dermal necrosis accompanied by an acute purulent inflammatory response was recorded in animals sacrificed after 2 wk dosing. In recovery animals, inflammation with a conspicuous increase in the amount of dense fibrocollagenous tissue, minimal to mild inflammatory process in the epicardium and/ or pericardium observed in 3 females. In conclusion, the dermal application of GPOTA (500 mg/kg bw/day) for two weeks appeared to cause local dermal necrosis followed by fibrosis and clinical signs likely secondary of this effect, but no specific systemic toxicity. The LOAEL was 500 mg/kg bw/day for local effects.

Data from both dermal repeated dose toxicity studies are not sufficient for DNEL derivation. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

 

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

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

The administration of the test item by daily oral gavage according to OECD TG 408 was well tolerated in rats at levels up to 150 mg/kg bw/day. At 375 mg/kg bw/day adverse findings were noted in the forestomach. These findings are consistent with a response to an irritant material. Based on these results, the NOAEL was considered to be 150 mg/kg bw/day (ReachCentrum, 2019).

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NOAEL): 150 mg/kg bw/day

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 (subchromic to chronic): 2

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

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

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

The test substance is a skin sensitizer and causes eye irritation. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the eye as well as skin sensitizing properties of the substance. As a result, a high hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure. Appropriate chemical resistant gloves, protective clothing and suitable eye protection must be worn, if any skin/eye contact is foreseen. Workers should receive a task specific training on how to use the protective equipment, and the correct use needs to be supervised.

Hazard to the eye-local effects (worker)

The test item is classified for eye irritation Cat 2 (H319:”Causes serious eye irritation”) under Regulation (EC) No 1272/2008. Thus, a qualitative risk assessment is done and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016). Suitable eye protection should be worn when handling the substance.

 

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:

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

Since the substance is used at industrial and professional domains, no exposure of the general population to is expected. Therefore, no DNELs for the general population were calculated.