coconut oil, reaction products with glycerol esters of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.93 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Based on the available data, there is no need to classify the test substance under EU Annex VI of directive 67/548/EEC and CLP regulation (EC) 1272/2008.   

No systemic/local hazard was identified in rodent studies after short-term exposure. A NOAEL of 14 mg/kg bw was defined in a 90-days repeated toxicity study (Notox 487736, 2008, combined with a one-generation reproductive toxicity study). The test substance was administered orally to male and female rats at dose levels of 14, 56 and 222 mg/kg bw. Liver and thyroidal changes (increase in organ weights and epithelial hypertrophy at histopathology) in the 56 and 222 mg/kg bw dose groups were observed. This NOAEL is supported by the results of a one-generation reproductive toxicity study (Notox 487736, 2008), where the same effects on liver and thyroid were observed as in the subchronic study. The substance belongs to the group of metilox esters that is known to cause secondary effects on rat thyroid functions via induction of liver metabolism. The DNEL is derived from the NOAEL for liver epithelial cell hypertrophy.

 

Point of departure

The starting point is a NOAEL of 14 mg/kg bw/day obtained from a subchronic oral study with rats (Notox 487736, 2008).

DNEL calculation – workers

In general, the derivation of DNEL is based on the above described NOAEL, which is modified as described in ECHA-guidance R.8 (2008).

 

Inhalation

Extrapolation from oral rat NOAEL to a corrected inhalatory NOAEL - Worker:

In order to adjust the NOAEL for inhalation as relevant exposure route, factors were applied to adjust human respiratory conditions as well as duration of exposure as advised in the ECHA-guidance R.8: Conversion of oral dose to corresponding air concentration: 1/0.38; Correction for respiratory volume under light activity: 6.7/10.

 

Corrected starting point (worker):

14 mg/kg bw/day x (1/0.38 m3/kg/d) x (6.7 m3 (8h) / 10 m3 (8h)) = 24.68 mg/m3

 

Derivation of inhalative DNEL - Worker

No experimental data with repeated dosage regimen for this administration route is available. Therefore, the inhalation route is covered by route-to-route extrapolation (oral to inhalation). Toxicokinetic considerations indicate that the substance will undergo initial metabolism via digestive enzymes in the bile. This results in low molecular weight substances that are easily absorbed. Therefore, the bioavailability of the substance by oral uptake is assumed to be at least as good as for the other routes of exposure. and an assessment factor of 1 was used for route-to-route extrapolation. The assessment factors were used as advised in ECHA-guidance R.8 (2008): allometric scaling: 1, remaining differences: 2.5, intraspecies factor for worker: 5; exposure duration (subchronic to chronic): 2.

 

Inhalative DNEL – Worker: 50 mg/m3 / (1x1x2.5x5x2) = 1 mg/m3

 

Dermal

No experimental data for this administration route with repeated dosage regimen is available. Therefore the dermal route is covered by route-to-route extrapolation (oral to dermal). As described in the toxicokinetic section, the oral rout of the exposure is most favourable for this substance and skin permeability of 80% of the components is considered to be very poor. A factor of 0.3 is introduced to take into account the poorly permeable fraction. An additional factor of 0.5 is applied because the components that are predominantly responsible for the effects upon ingestion are the ones that are predicted to be very poorly permeating. Further assessment factors were used as advised in ECHA-guidance R.8 (2008): correction for differences in metabolic rate (rat to human): 4, remaining differences: 2.5, intraspecies factor for worker: 5; exposure duration (sub-chronic to chronic): 2.

 

Dermal DNEL – Worker: 14 mg/kg bw/day / (1x4x2.5x5x2x0.3x0.5) = 0.93 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.09 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral 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

DNEL related information

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

Point of departure

The starting point is a NOAEL of 14 mg/kg bw/day obtained from a subchronic oral study with rats (Notox 487736, 2008), which is corrected for the differences in the experimental and human exposure conditions (7 days of exposure for the general population and 5 days in the animal study). According to the procedure recommended in ECHA-guidance R.8 (2008), a converted NOAEL of (14*(5/7))=10 mg/kg bw/day is then obtained.

DNEL calculation – general population

In general, the derivation of DNEL is based on the above described NOAEL, which is modified as described in ECHA-guidance R.8 (2008).

Oral

Derivation of oral DNEL – general population

A corrected NOAEL of 10 mg/kg bw was assessed. Overall assessment factors were applied as advised in ECHA-guidance R.8 (2008): correction for differences in metabolic rate (rat to humans): 4; remaining differences: 2.5, intraspecies factor for general population: 10; exposure duration: (sub-chronic to chronic): 2.

 

Oral DNEL – general population: 10 mg/kg bw/day / (4x2.5x10x2) = 0.05 mg/kg bw/day

 

 

Corrected starting point (general population):

10 mg/kg bw/day x 1/1.15 m3/kg /day = 8.70 mg/m3

 

Derivation of inhalative DNEL - general population

No experimental data with repeated dosage regimen for this administration route is available. Therefore, the inhalation route is covered by route-to-route extrapolation (oral to inhalation). Since, no data on toxicokinetics and no information on the molecular weight and log Pow are available for the test substance, a prediction concerning bioavailability can not be stated. Therefore, the bioavailability of the substance by oral uptake is assumed to be 50 %, and 100 % for inhalation (worst case assumption) and an assessment factor of 2 was used for route-to-route extrapolation. The assessment factors were used as advised in ECHA-guidance R.8; remaining differences: 2.5, intraspecies for general population: 10; exposure duration (sub-chronic to chronic): 2 Inhalative DNEL – general population: 8.70 mg/m3 / (2x2.5x10x2) = 0.09 mg/m3

 

Dermal

No animal data are available investigating the repeated dose toxicity of the test substance after dermal application. Therefore, the dermal route is covered by route-to-route extrapolation from oral to dermal. Since no data on bioavailability after dermal application are available, it is assumed that dermal absorption will not be higher than oral absorption and a default factor of 1 is introduced. Further assessment factors were used as advised in ECHA-guidance R.8 : correction for differences in metabolic rate (rat to human): 4, remaining differences 2.5; intraspecies factor for general population: 10; exposure duration (sub-chronic to chronic): 2. As described in the section of the worker DNEL, two factors of 0.3 (skin permeability) and 0.5 (permeating component) are introduced.

 

Dermal DNEL – general population:

10 mg/kg bw/day / (1x4x2.5x10x2x0.5x0.3) = 0.33 mg/kg bw/day