Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The following Derived No-Effect Levels (DNEL) were based on the recommendations of the ECHA "Guidance on information requirements and chemical safety assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health" (May 2008). Recommendations from ECETOC (refer to Technical Report "Guidance on Assessment Factors to Derive DNELs", Final draft dated 17 March 2010) have also been taken into consideration.

 

The adverse effects selected for DNEL derivation were considered to bear a threshold mode of action.

 

-      Acute toxicity:

In the absence of any relevant toxic effect and in particular any acute toxicity hazard leading to Classification & Labelling, no specific DNEL was derived.

 

-      Irritation/Corrosion:

In the absence of clear information on dose-response relationship, no specific DNEL was derived.

 

-      Sensitization:

In the absence of skin sensitization effects, no specific DNEL was derived.

 

-      Repeat-dose toxicity:

 

Dermal exposure:

Considering the skin irritation effects observed in the 14-day repeat-dose dermal toxicity study in rats using dibasic esters blend (Kirkpatrick, 2000), it might be considered appropriate to calculate a dermal DNEL for local effects. However this has not been done for the following reasons:

1) The substance is a solvent and so repeated exposure might be expected to be irritating to the skin under the occlusive conditions of the study due to the drying and de-fatting of the skin by the solvent.

2) The study protocol used a 6-hour occlusive exposure to the skin for 14 days. Such an exposure condition is designed to ensure the best take up of the compound through the skin, however it does not represent realistic exposure conditions for a worker or consumer.

Taking these into account it is argued that the LOEL for irritation from this study is not relevant to a human exposure scenario and therefore cannot be used as a relevant basis for the calculation of a dermal DNEL for local effects.

 

Inhalation exposure:

Following inhalatory exposure of rats to dibasic ester blend for 90 days up to the top concentrations of 390 mg/m3 (blend) or 400 mg/m3 (each individual component), the only consistent toxic findings were decreases in body weight and/or bodyweight gain, usually correlating with decreased food consumption. However the amplitude of body weight decreases was low (below biological significance threshold) and the changes limited to one gender (down to -5% vs. respective controls in females exposed to 390 mg/m3 blend at the end of exposure period, or down to -10% vs. respective controls in males exposed to 400 mg/m3 dimethyl glutarate or dimethyl adipate at the end of the recovery period). This is not indicative of a specific target organ or direct systemic toxicity, but could rather be considered as an indirect consequence of repeated local effects such as irritation caused by hydrolysis of esters and subsequent release of acids. Therefore in the absence of relevant treatment-related systemic toxicity it was not considered appropriate to derive DNELs for systemic effects.

 

Although such effects raise a low level of concern for human exposure due to morphological and physiological differences between rats and humans (see Endpoint summary: Repeated dose toxicity, for details), the local effects observed in the inhalation studies (degeneration/atrophy of the olfactory mucosa) considered as a consequence of a local metabolisation of the parent substance were used to derive a long-term DNEL for local effects (inhalation). The study selected for dermal DNEL derivation was the 90-day repeat-dose inhalation toxicity study in rats using dimethyl glutarate (Brebner, 2000).

 

-      Dose descriptor: NOAEC = 50 mg/m3 in rats (see section "7.5 Repeat-dose" summary discussion for justification)

 

-      Corrected dose descriptor: No correction to be applied because local effects are considered.

 

-      Assessment factors:

No interspecies differences applied

Other toxicokinetic differences = 1 (critical effect is local tissue damage due to irritation caused by the pH of the material after it hydrolyses locally inthe upper respiratory tract. This effect is unlikely to be influenced by 'other differences' between rats and humans)

Intraspecies differences = 3 (according to ECETOC report and a more recent report by the BfR a factor of 3 is considered to be adequate, particularly in the case of a local effect)

Differences in exposure duration = 2 (due to the starting point coming from a 90-day study and the lack of information about how duration of exposure affects the NOEC, a factor of 2 is justified to extrapolate from sub-chronic to chronic exposure)

Dose-response issues = 1 (use of a NOAEC as a starting point)

Quality of the database = 1 (data are obtained with dimethyl glutarate, the main component of dibasic esters blend, but no differences are expected between all 3 components in terms of local effects, when comparing the results of both 90-day inhalation studies provided, using either the dibasic ester blend or each individual component)

 

=> Global assessment factor = 6 (Worker)

 

-      DNEL calculation:

Worker-DNEL long-term for inhalation route, local effects = 50 / 6 = 8.3 mg/m3

-      Reproductive and developmental toxicity:

In the absence of effects on fertility or prenatal development, no specific DNEL was derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
extrapolation fromsub-chronic to chronic exposure
AF for intraspecies differences:
5
Justification:
according to recommendations by ECETOC
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The following Derived No-Effect Levels (DNEL) were based on the recommendations of the ECHA "Guidance on information requirements and chemical safety assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health" (May 2008). Recommendations from ECETOC (refer to Technical Report "Guidance on Assessment Factors to Derive DNELs", Final draft dated 17 March 2010) have also been taken into consideration.

 

The adverse effects selected for DNEL derivation were considered to bear a threshold mode of action.

 

-      Acute toxicity:

In the absence of any relevant toxic effect and in particular any acute toxicity hazard leading to Classification & Labelling, no specific DNEL was derived.

 

-      Irritation/Corrosion:

In the absence of clear information on dose-response relationship, no specific DNEL was derived.

 

-      Sensitization:

In the absence of skin sensitization effects, no specific DNEL was derived.

 

-      Repeat-dose toxicity:

 

Dermal exposure:

Considering the skin irritation effects observed in the 14-day repeat-dose dermal toxicity study in rats using dibasic esters blend (Kirkpatrick, 2000), it might be considered appropriate to calculate a dermal DNEL for local effects. However this has not been done for the following reasons:

1) The substance is a solvent and so repeated exposure might be expected to be irritating to the skin under the occlusive conditions of the study due to the drying and de-fatting of the skin by the solvent.

2) The study protocol used a 6-hour occlusive exposure to the skin for 14 days. Such an exposure condition is designed to ensure the best take up of the compound through the skin, however it does not represent realistic exposure conditions for a worker or consumer.

Taking these into account it is argued that the LOEL for irritation from this study is not relevant to a human exposure scenario and therefore cannot be used as a relevant basis for the calculation of a dermal DNEL for local effects.

 

Inhalation exposure:

Following inhalatory exposure of rats to dibasic ester blend for 90 days up to the top concentrations of 390 mg/m3 (blend) or 400 mg/m3 (each individual component), the only consistent toxic findings were decreases in body weight and/or bodyweight gain, usually correlating with decreased food consumption. However the amplitude of body weight decreases was low (below biological significance threshold) and the changes limited to one gender (down to -5% vs. respective controls in females exposed to 390 mg/m3 blend at the end of exposure period, or down to -10% vs. respective controls in males exposed to 400 mg/m3 dimethyl glutarate or dimethyl adipate at the end of the recovery period). This is not indicative of a specific target organ or direct systemic toxicity, but could rather be considered as an indirect consequence of repeated local effects such as irritation caused by hydrolysis of esters and subsequent release of acids. Therefore in the absence of relevant treatment-related systemic toxicity it was not considered appropriate to derive DNELs for systemic effects.

 

Although such effects raise a low level of concern for human exposure due to morphological and physiological differences between rats and humans (see Endpoint summary: Repeated dose toxicity, for details), the local effects observed in the inhalation studies (degeneration/atrophy of the olfactory mucosa) considered as a consequence of a local metabolisation of the parent substance were used to derive a long-term DNEL for local effects (inhalation). The study selected for dermal DNEL derivation was the 90-day repeat-dose inhalation toxicity study in rats using dimethyl glutarate (Brebner, 2000).

 

-      Dose descriptor: NOAEC = 50 mg/m3 in rats (see section "7.5 Repeat-dose" summary discussion for justification)

 

-      Corrected dose descriptor: No correction to be applied because local effects are considered.

 

-      Assessment factors:

No interspecies differences applied

Other toxicokinetic differences = 1 (critical effect is local tissue damage due to irritation caused by the pH of the material after it hydrolyses locally inthe upper respiratory tract. This effect is unlikely to be influenced by 'other differences' between rats and humans)

Intraspecies differences = 5 (according to ECETOC report and a more recent report by the BfR a factor of 5 is considered to be adequate, particularly in the case of a local effect)

Differences in exposure duration = 2 (due to the starting point coming from a 90-day study and the lack of information about how duration of exposure affects the NOEC, a factor of 2 is justified to extrapolate from sub-chronic to chronic exposure)

Dose-response issues = 1 (use of a NOAEC as a starting point)

Quality of the database = 1 (data are obtained with dimethyl glutarate, the main component of dibasic esters blend, but no differences are expected between all 3 components in terms of local effects, when comparing the results of both 90-day inhalation studies provided, using either the dibasic ester blend or each individual component)

 

=> Global assessment factor = 10 (general population)

 

-      DNEL calculation:

General population-DNEL long-term dor inhalation route, local effects = 50 / 10 = 5 mg/m3

 

Oral exposure:

Due to the lack of relevant systemic toxicity associated with repeated oral dosing (only poorly specific and significant decreases in body weight were observed), it was not considered appropriate to generate a long-term oral DNEL for systemic toxicity.

 

-      Reproductive and developmental toxicity:

In the absence of effects on fertility or prenatal development, no specific DNEL was derived.