reaction mass of isomers of: C7-9-alkyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.6 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

Modified dose descriptor starting point:

NOAEC

Value:

164 mg/m³

Explanation for the modification of the dose descriptor starting point:

90-day oral study in rats is available (Dunster et al., 2009) where a NOAEL of 186 mg/kg bw was established.

AF for dose response relationship:

1

Justification:

default (clear dose response)

AF for differences in duration of exposure:

2

Justification:

default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling is needed in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties are 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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable. Dermal study in rats and dermal route of exposure in humans.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute-to-chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default (workers)

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties are 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For isomeric mixture of reaction mass of isomers of: C7-9-alkyl 3-(3,5-di-trans-butyl-4-hydroxyphenyl) propionate, DNELs are needed for chronic exposure by the oral (only for consumers), dermal (for workers and consumers) and inhalation routes of exposure (workers and consumers). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance but the DNELs are calculated for a comparison with single events such a saturated atmosphere. Since isomeric mixture of reaction mass of isomers of: C7 -9 -alkyl 3 -(3,5 -di-trans-butyl-4 -hydroxyphenyl)propionate does not represent an acute hazard (not classified for acute toxicity), no DNELs for acute systemic toxicity need to be derived. The dermal systemic DNEL for acute toxicity is derived however only for comparison with the long-term values.

No DNELs are needed for local effects because there is no dose-response and route-specific information on these endpoints. Long-term systemic DNELs cover sufficiently local effects.

From all available data for the different human health endpoints it is clear that isomeric mixture of reaction mass of isomers of: C7 -9 -alkyl 3 -(3,5 -di-trans-butyl-4 -hydroxyphenyl) propionate exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the related substances, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment. There are following annotations for each endpoint:

- Since the substance is not acutely toxic by dermal route of exposure, no DNEL needs to be derived. A LD50 greater than 2000 mg/kg bw (as evident from all weight of evidence pieces) is considered to be a NOAEL because no mortalities, no systemic signs of toxicity or signs of dermal irritation were observed in treated animals in the dermal acute toxicity studies for two closest substances.

- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation.

- A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.

- For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

- There is no animal data on repeated inhalation exposure. To cover this endpoints, data from an oral dietary sub-chronic study in rats (Dunster et al., 2009) has been used to calculate the long-term DNEL.

- No DNELs for reprotoxic effects are needed because isomeric mixture of reaction mass of isomers of: C7 -9 -alkyl 3 -(3,5 -di-trans-butyl-4 -hydroxyphenyl) propionate is not toxic to reproduction (A rat NOAEL of 205 mg/kg bw for reproductive toxicity is the highest dose level tested (Marr, 2005). This NOAEL is higher than that for systemic toxicity. Therefore, long-term systemic DNELs ensure sufficient that reproductive toxicity effects in humans will not occur.

First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data. The assessment factors are applied in accordance with ECHA REACH Guidance R.8.

Modification of the relevant dose descriptors to the correct starting point:

Bioavailability (absorption)

10% of dermal absorption is considered for the target substance due to the lipophilicity of Z-72 (logPow of 7.18). The dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of target chemical in rats and in humans is available. In case of oral to inhalation extrapolation, 50% absorption is assumed for oral absorption in rats and 100% absorption for inhalation is assumed in humans (worst case; according to the ECETOC Report No 111, 100% absorption for inhalation can be used in case of absence of substance specific data for absorption).

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to assess long-term inhalation effects in humans.

Exposure conditions:

Exposure time differed in workers and in the 4 -week dermal study in rat. Rats were exposed to the test substance dermally 6h daily (5 days/week), while workers are exposed 8h daily (5days/week). However, the dose descriptor (the NOAEL of 500 mg/kg bw) was not adjusted to 8h exposure because exposure time is not really relevant for the systemic dose resulted from only dermal route of exposure.

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the sub-chronic dietary study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Applying of assessment factors:

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats is applied in case of usage of dermal NOAEL to derive dermal DNEL.

No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.

Additional assessment factor of 2.5 is applied for remaining interspecies differences in toxicodynamics between rat and human.

 

Intraspecies differences: 

Assessment factor of 5 is applied for workers for all endpoints and for all exposure routes.

Extrapolation of duration:

Assessment factor of 6 was applied in case of sub-acute to chronic extrapolation (4 -week dermal study is subchronic).

Assessment factor of 2 was applied in case of sub-chronic to chronic extrapolation (when 90 -day dietary study in rats was used to derive inhalation long-term DNEL).

 

Quality of whole data base:

The assessment factor for uncertainties to the quality of the data base is regarded to be 1.

 

Issues related to dose response:

Assessment factor of 1 was used.

Calculation of endpoint-specific DNELs for workers

Acute/short-term exposure systemic inhalation

Isomeric mixture of reaction mass of isomers of: C7-9-alkyl 3-(3,5-di-trans-butyl-4-hydroxyphenyl) propionate does not possess toxicity potential by inhalation due to its low vapour pressure (2.0 x 10E-5 Pa at 25°C). Furthermore, the derivation of an acute DNEL for inhalation route of exposure will be high uncertain because of extrapolation procedure of LD50 from an acute oral toxicity study to LC50 (and accordingly NOAEC).

For instance:

LD50 of greater than 2000 mg/kg bw was established in several acute oral studies for the related substances. No mortalities, clinical signs of toxicity or abnormalities at necropsy were observed in treated animals in nearly all studies. Therefore, the overall weight of evidence allows to conclude that the LD50 is equal NOAEL. The derivation of such a DNEL would be as follows:

1. Corrected NOAEC = oral rat NOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 2000 mg/kg bw x (1/0.38m³) x (50%/100%) x (6.7/10)m³ = 1763 mg/m³.

2. DNEL = 1763 mg/m³/3 = 353 mg/m³. AFs are: 5 - intraspecies.

Such a procedure is discouraged and obtained DNEL is high uncertain because it represents 8 hour frame. In case of extrapolation to shorter period (acute DNEL should usually be calculated for 15 min), the DNEL will rise, to a value which in reality will never be reached (technically not achievable concentration). So, the long-term DNEL is sufficient to cover acute exposures.

Long-term exposure - systemic effects (dermal)

4 -week repeated dose toxicity in rats (Rusty and Rusch, 2002) was taken for the DNEL derivation:

1. Corrected NOAEL = dermal rat NOAEL x (ABS dermal-rat/ABS dermal-human) = 500 mg/kg bw x (10%/10%) = 500 mg/kg bw.

2. DNEL = 500 mg/kg bw /(4 x 5 x 2.5 x 6) = 1.67 mg/kg bw/day. AFs are: 4 -interspecies, 5 - intraspecies, 2.5 -remaining interspecies differences, 6 -sub-acute-to-chronic. Total AF amounts to 300.

Long-term exposure - systemic effects (inhalation)

Repeated dose toxicity sub-chronic dietary study in rats (Dunster et al., 2009) was taken for the DNEL derivation:

1.Corrected NOAEC = oral rat NOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 186 mg/kg bw x (1/0.38m³) x (50%/100%) x (6.7/10)m³ = 164 mg/m³.

2. DNEL = 164 mg/m³/ (2.5 x 5 x 2) = 6.6 mg/m³. AFs are: 2.5 - remaining differences in toxicokinetic and toxicodynamic between human and rat; 5 - intraspecies (workers); 2 sub-chronic-to-chronic. Total AF amounts to 25.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.62 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

Modified dose descriptor starting point:

NOAEC

Value:

80.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

90-day oral study in rats is available (Dunster et al., 2009) where a NOAEL of 186 mg/kg bw was established.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

2

Justification:

default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling is needed in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties are 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:

DNEL (Derived No Effect Level)

Value:

0.83 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

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable. Dermal study in rats and dermal route of exposure in humans.

AF for dose response relationship:

1

Justification:

default (clear dose response)

AF for differences in duration of exposure:

6

Justification:

default (sub-acute-to-chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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:

DNEL (Derived No Effect Level)

Value:

0.93 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

Modified dose descriptor starting point:

NOAEL

Value:

186 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable. Oral study in rats and oral route of exposure in humans.

AF for dose response relationship:

1

Justification:

default (clear dose response)

AF for differences in duration of exposure:

2

Justification:

default (sub-chronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption)

50% of oral absorption is considered for the target substance (worst case). The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. 1.15 m³/kg bw is a standard respiratory volume of rats during 24 h.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNEL for general population

The conversion of the repeated oral rat NOAEL into inhalation NOAEC was performed as follows:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day x (ABS oral-rat/ABS inhal-human),where 1.15 is standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Long-term exposure - systemic effects (inhalation)

Repeated dose toxicity sub-chronic dietary study in rats (Dunster et al., 2009) was taken for the DNEL derivation:

1.Corrected NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inh-human) = 186 mg/kg bw x (1/1.15 m³/kg bw/day) x (50%/100%) = 80.9 mg/m³.

2. DNEL = 80.9 mg/m³/ (2.5 x 10 x 2) = 1.62 mg/m³. AFs are: 2.5 - remaining differences in toxicokinetic and toxicodynamic between human and rat; 10 - intraspecies (general population); 2 sub-chronic-to-chronic. Total AF amounts to 50.

Long-term exposure - systemic effects (dermal)

4 -week repeated dose toxicity in rats (Rusty and Rusch, 2002) was taken for the DNEL derivation:

1. Corrected NOAEL = dermal rat NOAEL x (ABS dermal-rat/ABS dermal-human) = 500 mg/kg bw x (10%/10%) = 500 mg/kg bw.

2. DNEL = 500 mg/kg bw /(4 x 2.5 x 10 x 6) = 0.83 mg/kg bw/day. AFs are: 4 -interspecies, 10 - intraspecies, 2.5 -remaining interspecies differences, 6 -sub-acute-to-chronic. Total AF amounts to 600.

Long-term exposure - systemic effects (oral)

The oral NOAEL of 186 mg/kg bw from 90-day repeated dose toxicity study in rats (Dunster et al., 2009) is used to calculate oral DNEL.

1. Corrected NOAEL = oral rat NOAEL x (ABS oral-rat/ABS oral-human) = 186 mg/kg bw x (50%/50%) = 186 mg/kg bw.

2. DNEL = 186 mg/kg bw /(4 x 2.5 x 10 x 2) = 0.93 mg/kg bw/day. AFs are: 4 -interspecies, 10 - intraspecies, 2.5 -remaining interspecies differences, 2 -sub-chronic-to-chronic. Total AF amounts to 200.