Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
50 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: OEL method of German Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA)
Overall assessment factor (AF):
28
Dose descriptor starting point:
other: NAEL (rat)
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
other: OEL (human)
DNEL value:
42 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only oral route is available.
AF for differences in duration of exposure:
1.4
Justification:
AF=2: Extrapolation to chronic exposure based on sub-chronic toxicty study. AF=0.7: Correction for exposure time 7 days in the study, 5 days exposure at the workplace.
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.25 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):
40
Dose descriptor starting point:
other: NAEL (rat)
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
other: NAEL (rat)
DNEL value:
170 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral route is available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on sub-chronic toxicty study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for other interspecies differences:
1
Justification:
A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Long-term – dermal, systemic effects (based on 90 day repeated dose oral toxicity study with rats as evaluated by the German Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA) in 2007) 

In 2007 the German Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA) has evaluated Triisobutyl phosphate to estimate an OEL (Begründung zu Triisobutylphosphat in TRGS 900 Ausgabe: Januar 2006 zuletzt geändert und ergänzt: März 2007). In this evaluation the study of Monsanto (1990) was also evaluated and assessed. The BAuA concluded that the observed effects, seen at the highest dose level of 5000 mg/kg diet, could not conclusively be determined as toxicological relevant. The observed effect of changes in cholesterol and the number of leucocytes are not associated with changes in white blood cell counts. Additionally the slight increase inmean corpuscular hemoglobin content and concentration did not result in other effects on red blood cells. In addition no correlation was found between the observed changes in blood parameters and the results of the clinical and histopathological assessments. The BAuA therefore, decided that the dosis of 5000 mg/kg diet can be assumed to be a marginal LOEL which will only be slightly above the actual NOAEL. According to the BauA it can thus be assumed that for the estimation of an OEL, a NAEL of 2500 mg/kg diet, which corresponds to 170 mg/kg bw for male and 210 mg/kg bw for female rats, can be used. To derive an OEL for triisobutyl phosphate based on a 13 week exposure study in rats with a NAEL of 170 mg/kg bw/day, assessment factors were taken into account by the BauA as shown in the table below. Using the total assessment factors of 28 a OEL of 6 mg/kg bw/day is derived. The BAuA assumes a body weight of 70 kg for a worker and a inhalation volume of 10 m³ in 8 hours. Thus the OEL of 6 mg/kg bw/day corresponds to an air concentration of 42 mg/m³ triisobutyl phosphate. Additionally, the BAuA adopts the “preferred value approach” in its estimation of the OEL and the resulting OEL value thus becomes 50 mg/m³.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NAEL: 170 mg/kg bw/day

The effects observed at the highest tested dose  

in a 90 day repeated dose study

re considered not conclusively toxicologically relevant acc to BAuA. Therefore the dose of 5000 mg/kg diet is considered a marginal LOEL. Which is assumed to be only slightly above the NOAEL. According to the BAuA in this case a NAEL of 2500 mg/kg diet. This corresponds to a dose of 170 mg/kg bw/day in male rats

Modified dose-descriptor

170 / 1 = 170 mg/kg bw/day

Step 2) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling in case of rat to human extrapolation. A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.

Intraspecies

5

Default assessment factor for worker

Exposure duration

2

Default assessment factor for the extrapolation sub-chronic to chronic exposure

Correction factor for exposure time 

 0.7

7 days in the study; 5 days exposure at workplace

OEL (mg/kg bw/day)

170 / (4 x 5 x 2 x 0.7) = 6.07

 OEL human  42 mg/m³

Assuming a bodyweight of 70 kg for a worker and inhalation volume of 10 m³ in 8 hours

OEL   50 mg/m³ Using the preferred value approach

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure. Long-term –dermal, systemic effects (based on 90 day repeated dose oral toxicity study with rats.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NAEL: 170 mg/kg bw/day

The effects observed at the highest tested dose 

in a 90 day repeated dose study

re considered not conclusively toxicologically relevant acc to BAuA. Therefore the dose of 5000 mg/kg diet is considered a marginal LOEL. Which is assumed to be only slightly above the NOAEL. According to the BAuA in this case a NAEL of 2500 mg/kg diet. This corresponds to a dose of 170 mg/kg bw/day in male rats

Step 2) Modification of starting point

1

 

Ratio of dermal to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Modified dose-descriptor

170 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor for worker

Exposure duration

2

Default assessment factor for the extrapolation sub-chronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

170 / (4 x 5 x 2 x 1 x 1) = 4.25 mg/kg bw/day

 

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating to skin upon exposure for 4 hours under semiocclusive conditions, no local effects are expected by repeated dermal exposure. The substance is classified as sensitising to skin. However, it is not possible to derive a DNEL on the basis of the available data.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.89 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
5.6
Dose descriptor starting point:
other: OEL worker
DNEL value:
50 mg/m³
Modified dose descriptor starting point:
other: OEL worker
DNEL value:
50 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
4.2
Justification:
AF=3: Default assessment factor for the extrapolation from 8h to 24h exposure. AF=1.4: Extrapolation from 5 days exposure for workers to 7 days exposure for consumers
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
0.7
Justification:
Lower mean respiration volume for general population (6.7 m3 respiratory volume for 8h with no activity divided by 10 m3 respiratory volume for 8h with light activity).
AF for intraspecies differences:
2
Justification:
Default assessment factor from workers to general population
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
other: NAEL
DNEL value:
170 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral route is available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on sub-chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for other interspecies differences:
1
Justification:
A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.
AF for intraspecies differences:
10
Justification:
Default assessment factor
AF for the quality of the whole database:
1
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:
2.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
other: NAEL
DNEL value:
170 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on sub-chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for other interspecies differences:
1
Justification:
A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.
AF for intraspecies differences:
10
Justification:
Default assessment factor
AF for the quality of the whole database:
1
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

In 2007 the German Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA) has evaluated Triisobutyl phosphate to estimate an OEL (Begründung zu Triisobutylphosphat in TRGS 900 Ausgabe: Januar 2006 zuletzt geändert und ergänzt: März 2007).In this evaluation the study of Monsanto (1990) was also evaluated and assessed. The BAuA concluded that the observed effects, seen at the highest dose level in the 90 repeated dose study of 5000 mg/kg diet, could not conclusively be determined as toxicological relevant. The observed effect of changes in cholesterol and the number of leucocytes are not associated with changes in white blood cell counts. Additionally the slight increase in mean corpuscular hemoglobin content and concentration did not result in other effects on red blood cells. In addition no correlation was found between the observed changes in blood parameters and the results of the clinical and histopathological assessments. The BAuA therefore, decided that the dosis of 5000 mg/kg diet can be assumed to be a marginal LOEL which will only be slightly above the actual NOAEL. According to the BauA it can thus be assumed that for the estimation of an OEL, a NAEL of 2500 mg/kg diet, which corresponds to 170 mg/kg bw for male and 210 mg/kg bw for female rats, can be used. To derive an OEL for triisobutyl phosphate based on a 13 week exposure study in rats with a NAEL of 170 mg/kg bw/day, assessment factors were taken into account by the BauAas shown in the table below.Using the total assessment factors of 28 a OEL of 6 mg/kg bw/day is derived. The BAuA assumes a body weight of 70 kg for a worker and a inhalation volume of 10 m³ in 8 hours. Thus the OEL of 6 mg/kg bw/day corresponds to an air concentration of 42 mg/m³ triisobutyl phosphate. Additionally, the BAuA adopts the “preferred value approach” in its estimation of the OEL and the resulting OEL value thus becomes 50 mg/m³.

Long-term – dermal, systemic effects (based on 90 day repeated dose oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NAEL: 170 mg/kg bw/day

The effects observed at the highest tested dose in a 90 day repeated dose study,are considered not conclusively toxicologically relevant acc to BAuA. Therefore the dose of 5000 mg/kg diet is considered a marginal LOEL. Which is assumed to be only slightly above the NOAEL. Therefore the NAEL is assumed to be 2500 mg/kg diet. This corresponds to a dose of 170 mg/kg bw/day in male rats.

Step 2) Modification of starting point

1

Ratio of dermal to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

Modified dose-descriptor

170 / 1=170 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling in case of rat to human extrapolation. A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.

Intraspecies

10

Default assessment factor

Exposure duration

2

Default assessment factor for the extrapolation sub-chronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

170 / (4 x 10 x 2 x 1 x 1) = 2.13 mg/kg bw/day

 

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating to skin upon exposure for 4 hours under semiocclusive conditions, no local effects are expected by repeated dermal exposure. The substance is classified as sensitising to skin. However, it is not possible to derive a DNEL on the basis of the available data.

Long-term – inhalation, systemic effects (based on 90 day repeated dose oral toxicity study with rats) 

Description

Value

Remark

Step 1) Relevant dose-descriptor

OEL worker: 50 

mg/m³

Based on an triisobutyl phosphate evaluation by BAuA for the determination of a inhalation OEL value.

Modified dose-descriptor

50 mg/m³

Step 3) Assessment factors

 

 

Intraspecies

2

Default assessment factor for extrapolation from workers to the general population

Exposure duration

3

Default assessment factor for the extrapolation from 8h to 24h exposure

Dose response

1

 

Quality of database

1

 

Correction factor for exposure time

1.4 

Extrapolation from 5 days exposure for workers to 7 days exposure for consumers

 Respiration volume

 0.67

Lower mean respiration volume for general population (6.7 m³ respiratory volume for 8h with no activity divided by 10 m³ respiratory volume for 8h with light activity).

  DNEL

Value

    

50 / (1 x 2 x 3 x 1.4 x 0.67) = 8.89 mg/m³

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

Long-term – oral, systemic effects (based on 90 day repeated dose oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NAEL: 170 mg/kg bw/day

The effects observed at the highest tested dose in a 90 day repeated dose study,are considered not conclusively toxicologically relevant acc to BAuA. Therefore the dose of 5000 mg/kg diet is considered a marginal LOEL. Which is assumed to be only slightly above the NOAEL. Therefore the NAEL is assumed to be 2500 mg/kg diet using a safety factor of 2. This corresponds to a dose of 170 mg/kg bw/day in male rats

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling in case of rat to human extrapolation. A factor for remaining differences has not been applied, because there is no indication for interspecies differences in addition to the differences covered by the default interspecies factor.

Intraspecies

10

Default assessment factor

Exposure duration

2

Default assessment factor for the extrapolation sub-chronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

170 / (4 x 10 x 2 x 1 x 1) = 2.13 mg/kg bw/day