Bis(2-ethylhexyl) hydrogen phosphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.52 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

264.47 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012). It is assumed that the inhalation absorption in human is similar to the oral absorption in rat. NOAEL(oral, rat) = 150 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(0.38 m3/kg bw/day) x 6.7 m3/10 m3 = 264.47 mg/m3

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value (ECHA)

AF for intraspecies differences:

5

Justification:

Default value (ECHA) for workers

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available study is performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.52 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other:

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other:

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assuption, that dermal absorption is not higher than oral absorption, the NOAEL of the oral subacute study is used (ECHA guidance, chapter R.8, R.8.4.1). => NOAEL(oral) = NOAEL(dermal) = 150 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

2.5

Justification:

Default value (ECHA)

AF for intraspecies differences:

5

Justification:

Default value (ECHA) for workers

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available study is performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Known occupational exposure limit(s):

No occupational exposure limits known.

 

DNEL systemic (worker)

Basis for delineation of the DNELs systemic (worker):

Bis(2-ethylhexyl) hydrogen phosphate was administered orally by gavage to 5 male and 5 female Wistar (HsdRCCHan:Wist) rats per dose group using corn oil as vehicle, in daily doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks. This GLP study was performed according to OECD guideline 407.

The animals were regularly observed and weighed and food and water intakes were determined. In addition, clinical laboratory investigation of blood samples was performed. Organs and tissues were subjected to gross and histopathological investigation.

Daily oral treatment of rats with bis(2-ethylhexyl) hydrogen phosphate at doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks resulted in effects in the alimentary tract (hyper- and parakeratosis, edema, gastritis, erosions and ulcers), partially leading to peritonitis, partly starting at the low dose of 30 mg/kg bw/day and indicating a local irritating and corrosive effect of the test substance.

Most of further findings are regarded to reflect or to be secondary to the poor general condition of the animals due to this effect, e.g.: the death of one animal (at 750 mg/kg), several clinical findings including findings at FOB and motor activity measurement (at 750 mg/kg), retarded body weight development of males (at 750 mg/kg), increased water intake (in males starting at 30 mg/kg and in females at 750 mg/kg), decreased weight of seminal vesicles (at 750 mg/kg) and reduced secretion in the prostate and seminal vesicle and a minimally increased proportion of round spermatids in the epididymides (at 750 mg/kg).

Furthermore, findings giving evidence for activation of the liver metabolism and enzyme induction were observed starting at 150 mg/kg, e.g. increase in liver weights, hepatocellular hypertrophy. Secondary to the impact of this metabolic activation, hypertrophy of the follicular epithelia in the thyroid gland was noted.

Finally, weights of adrenals were increased (at 750 mg/kg in males) and diffuse hyperplasia of the zona fasciculata in the adrenal gland was observed (in males starting at 150 mg/kg and in females at 750 mg/kg). This effect is seen as a sequel of the stress of the animals of this dose group.

Under the conditions described a local no observed adverse effect level (NOAEL) for administration of bis(2-ethylhexyl) hydrogen phosphate to male and female Wistar rats was not established, due to local irritating effects on the alimentary tract. The systemic NOAEL was set at the dose of 150 mg/kg bw/day due to effects on the adrenal glands, although this might be secondary to the local irritating effects.

Study

Title: Di-2-ethylhexylphosphat - Repeated dose systemic toxicity study in Wistar rats

Administration period: 28 days

Doses: 0, 30, 150 or 750 mg/kg bw/day (male and female rats)

NOAEL, Effects

NOAEL (systemic) = 150 mg/kg bw (effects apart from alimentary tract)

LOAEL (local) = 30 mg/kg bw (target organ: alimentary tract, forestomach, liver weight increase is not regarded as adverse)

Effects

Daily oral treatment of rats with bis(2-ethylhexyl) hydrogen phosphate at doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks resulted in effects in the alimentary tract (hyper- and parakeratosis, edema, gastritis, erosions and ulcers), partially leading to peritonitis, partly starting at the low dose of 30 mg/kg bw/day and indicating a local irritating and corrosive effect of the test substance.

Most of further findings are regarded to reflect or to be secondary to the poor general condition of the animals due to this effect, e.g.: the death of one animal (at 750 mg/kg), several clinical findings including findings at FOB and motor activity measurement (at 750 mg/kg), retarded body weight development of males (at 750 mg/kg), increased water intake (in males starting at 30 mg/kg and in females at 750 mg/kg ), decreased weight of seminal vesicles (at 750 mg/kg) and reduced secretion in the prostate and seminal vesicle and a minimally increased proportion of round spermatids in the epididymides (at 750 mg/kg).

Reference

Schladt L (2013, draft)

Di-2-ethylhexylphosphat - Repeated dose systemic toxicity study in Wistar rats (4 weeks daily administration by gavage), Bayer Pharma AG, Toxicology, 42096,

 

 

Reproductive Toxicity - systemic effects (worker)

In the 28 day repeated dose systemic toxicity study, at the dose of 750 mg/kg bw/day the weight of seminal vesicles was decreased correlating to reduced secretion in the prostate and seminal vesicle at histopathology. Additionally, a minimally increased proportion of round spermatids in the epididymides was noted in male animals after 750 mg/kg. These findings might indicate a primary systemic effect but also it is more likely that they reflect delayed sexual maturation as a sequel of poor condition of these animals.

Since potential fertility effects are observed at 750 mg/kg bw/day only, a dose 5 fold above the NOAEL (systemic), and might be secondary due to the poor general condition, the DNEL (systemic) is regarded to be protective for potential fertility effects.

 

 

DNEL local effects (worker)

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In the key studies for skin irritation/corrosion and eye irritation, bis(2-ethylhexyl) hydrogen phosphate is corrosive to the skin and irritating to the eyes.

A classification as R34 (causes burns) and R41 (Risk of serious damage to eyes); GHS: Skin Corr. 1C (H314, Causes severe skin burns and eye irritation) and Eye Damage 1 (H318: Causes serious eye damage) is proposed.

Sensitization

No data are available for skin sensitization. Bis(2-ethylhexyl) hydrogen phosphate is corrosive to the skin, therefore animal testing is prohibited. No reliable in-vitro tests are on hand.

A classification is therefore not possible.

Conclusion on local DNEL

There are no studies available to define a threshold for local toxicity after dermal application or inhalation. Consequently, for local effects bis(2-ethylhexyl) hydrogen phosphate is allocated to the moderate hazard band.

 

 

DNEL (long term, local) for inhalation

In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.

A toxicological TF within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m³; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m³ is developed.

Since bis(2-ethylhexyl) hydrogen phosphate is classified as R34, an upper boundary value of 1 mg/m³ is proposed as a long term inhalation DNEL for local effects.

 

 

Short term toxicity – local effects (workers)

For local dermal effects bis(2-ethylhexyl) hydrogen phosphate should be allocated to the moderate hazard band. We propose to take the above mentioned long term inhalation DNEL value also for short term exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.87 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

130.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012). It is assumed that the inhalation absorption in human is similar to the oral absorption in rat. NOAEL(oral, rat) = 150 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(1.15 m3/kg bw/day) = 130.43 mg/m3

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value (ECHA)

AF for intraspecies differences:

10

Justification:

Default value (ECHA) for general population

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available study is performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.87 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assuption, that dermal absorption is not higher than oral absorption, the NOAEL of the oral subacute study is used (ECHA guidance, chapter R.8, R.8.4.1). => NOAEL(oral) = NOAEL(dermal) = 150 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

2.5

Justification:

Default value (ECHA)

AF for intraspecies differences:

10

Justification:

Default value (ECHA) for general population

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available study is performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

2.5

Justification:

Default value (ECHA)

AF for intraspecies differences:

10

Justification:

Default value (ECHA) for general population

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available study is performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

DNEL systemic (general population)

 

Basis for delineation of the DNELs systemic (general population):

Bis(2-ethylhexyl) hydrogen phosphate was administered orally by gavage to 5 male and 5 female Wistar (HsdRCCHan:Wist) rats per dose group using corn oil as vehicle, in daily doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks. This GLP study was performed according to OECD guideline 407.

The animals were regularly observed and weighed and food and water intakes were determined. In addition, clinical laboratory investigation of blood samples was performed. Organs and tissues were subjected to gross and histopathological investigation.

Daily oral treatment of rats with bis(2-ethylhexyl) hydrogen phosphate at doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks resulted in effects in the alimentary tract (hyper- and parakeratosis, edema, gastritis, erosions and ulcers), partially leading to peritonitis, partly starting at the low dose of 30 mg/kg bw/day and indicating a local irritating and corrosive effect of the test substance.

Most of further findings are regarded to reflect or to be secondary to the poor general condition of the animals due to this effect, e.g.: the death of one animal (at 750 mg/kg), several clinical findings including findings at FOB and motor activity measurement (at 750 mg/kg), retarded body weight development of males (at 750 mg/kg), increased water intake (in males starting at 30 mg/kg and in females at 750 mg/kg), decreased weight of seminal vesicles (at 750 mg/kg) and reduced secretion in the prostate and seminal vesicle and a minimally increased proportion of round spermatids in the epididymides (at 750 mg/kg).

Furthermore, findings giving evidence for activation of the liver metabolism and enzyme induction were observed starting at 150 mg/kg, e.g. increase in liver weights, hepatocellular hypertrophy. Secondary to the impact of this metabolic activation, hypertrophy of the follicular epithelia in the thyroid gland was noted.

Finally, weights of adrenals were increased (at 750 mg/kg in males) and diffuse hyperplasia of the zona fasciculata in the adrenal gland was observed (in males starting at 150 mg/kg and in females at 750 mg/kg). This effect is seen as a sequel of the stress of the animals of this dose group.

Under the conditions described a local no observed adverse effect level (NOAEL) for administration of bis(2-ethylhexyl) hydrogen phosphate to male and female Wistar rats was not established, due to local irritating effects on the alimentary tract. The systemic NOAEL was set at the dose of 150 mg/kg bw/day due to effects on the adrenal glands, although this might be secondary to the local irritating effects.

Study

Title: Di-2-ethylhexylphosphat - Repeated dose systemic toxicity study in Wistar rats

Administration period: 28 days

Doses: 0, 30, 150 or 750 mg/kg bw/day (male and female rats)

NOAEL, Effects

NOAEL (systemic) = 150 mg/kg bw (effects apart from alimentary tract)

LOAEL (local) = 30 mg/kg bw (target organ: alimentary tract, forestomach, liver weight increase is not regarded as adverse)

Effects

Daily oral treatment of rats with bis(2-ethylhexyl) hydrogen phosphate at doses of 0, 30, 150, 750 mg/kg bw for a period of 4 weeks resulted in effects in the alimentary tract (hyper- and parakeratosis, edema, gastritis, erosions and ulcers), partially leading to peritonitis, partly starting at the low dose of 30 mg/kg bw/day and indicating a local irritating and corrosive effect of the test substance.

Most of further findings are regarded to reflect or to be secondary to the poor general condition of the animals due to this effect, e.g.: the death of one animal (at 750 mg/kg), several clinical findings including findings at FOB and motor activity measurement (at 750 mg/kg), retarded body weight development of males (at 750 mg/kg), increased water intake (in males starting at 30 mg/kg and in females at 750 mg/kg ), decreased weight of seminal vesicles (at 750 mg/kg) and reduced secretion in the prostate and seminal vesicle and a minimally increased proportion of round spermatids in the epididymides (at 750 mg/kg).

Reference

Schladt L (2013, draft)

Di-2-ethylhexylphosphat - Repeated dose systemic toxicity study in Wistar rats (4 weeks daily administration by gavage), Bayer Pharma AG, Toxicology, 42096,

 

 

Reproductive Toxicity - systemic effects (general population)

In the 28 day repeated dose systemic toxicity study, at the dose of 750 mg/kg bw/day the weight of seminal vesicles was decreased correlating to reduced secretion in the prostate and seminal vesicle at histopathology. Additionally, a minimally increased proportion of round spermatids in the epididymides was noted in male animals after 750 mg/kg. These findings might indicate a primary systemic effect but also it is more likely that they reflect delayed sexual maturation as a sequel of poor condition of these animals.

Since potential fertility effects are observed at 750 mg/kg bw/day only, a dose 5 fold above the NOAEL (systemic), and might be secondary due to the poor general condition, the DNEL (systemic) is regarded to be protective for potential fertility effects.

 

 

DNEL local (general population)

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In the key studies for skin irritation/corrosion and eye irritation, bis(2-ethylhexyl) hydrogen phosphate is corrosive to the skin and irritating to the eyes.

A classification as R34 (causes burns) and R41 (Risk of serious damage to eyes); GHS: Skin Corr. 1C (H314, Causes severe skin burns and eye irritation) and Eye Damage 1 (H318: Causes serious eye damage) is proposed.

Sensitization

No data are available for skin sensitization. Bis(2-ethylhexyl) hydrogen phosphate is corrosive to the skin, therefore animal testing is prohibited. No reliable in-vitro tests are on hand.

A classification is therefore not possible.

Conclusion on local DNEL

For local effects the derivation of a long term DNEL for dermal toxicity is not appropriate due to the corrosive effects of bis(2-ethylhexyl) hydrogen phosphate.

Therefore, for local effects bis(2-ethylhexyl) hydrogen phosphate should be allocated to the moderate hazard band.