Dimethyl propylphosphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.96 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):

18

Modified dose descriptor starting point:

NOAEC

Value:

35.26 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) = 20 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(0.38 m3/kg bw/day) x 6.7 m3/10 m3 = 35.26 mg/m3

AF for dose response relationship:

1

Justification:

Default value (ECHA)

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:

1

Justification:

Data are also available for mice in a dominant lethal assay. No major systemic toxicity is observed at 500 mg/kg bw/day. Main effect in rats is alpha-2-microglobulin related nephropathy, a mechanism not relevant for humans. Consequently, it is likely that rodents are more sensitive than humans and no factor for "additional uncertainty" is applied.

AF for intraspecies differences:

3

Justification:

The default value (ECHA) for workers is reduced because in rodents alpha-2-microglobulin accumulates in the kidney after oral dosing, an effect not relevant for human risk assessment. In addition a rapid and efficient excretion is anticipated based on the rodent data on dimethyl propylphosphonate and diethyl ethylphosphonate.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.56 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):

72

Modified dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the available physicochemical and toxicological data some dermal absorption might be assumed. Dermal absorption is likely to be lower than oral absorption based on the high water solubility and a low Log Kow = 0.5 only slightly above 0. For DNEL calculation dermal absorption is taken to be 2-fold lower than oral absorption. NOAEL(oral, rat) = 20 mg/kg bw/day => NOAEL(dermal, rat) = 2 x NOAEL(oral, rat) = 40 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value (ECHA)

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:

1

Justification:

Data are also available for mice in a dominant lethal assay. No major systemic toxicity is observed at 500 mg/kg bw/day. Main effect in rats is alpha-2-microglobulin related nephropathy, a mechanism not relevant for humans. Consequently, it is likely that rodents are more sensitive than humans and no factor for "additional uncertainty" is applied.

AF for intraspecies differences:

3

Justification:

The default value (ECHA) for workers is reduced because in rodents alpha-2-microglobulin accumulates in the kidney after oral dosing, an effect not relevant for human risk assessment. In addition a rapid and efficient excretion is anticipated based on the rodent data on dimethyl propylphosphonate and diethyl ethylphosphonate.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

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:

low hazard (no threshold derived)

Additional information - workers

DNEL systemic (worker)

Basis for delineation of the DNELs systemic:

Short description of key study and/or point of departure

 

Title:

Levagard DMPP - subacute toxicity study in rats (4-week administration by gavage)

and

Levagard DMPP - subacute toxicity study in rats (4-week administration by gavage) Supplementary study

Administration period:

28 days

Doses:

0, 40, 200, or 1000 mg/kg bw/day or 0, 5, or 20 mg/kg bw/day (Suppl.) (males + females)

Local effects:

No local effects observed. Therefore no hazard identified

Systemic effects:

NOAEL 20 mg/kg bw/d

LOAEL: 40 mg/kg bw/d

Based on the following effects: alpha-2-microglobulin nephropathy and secondary kidney toxicity. The observed alpha-2-micro-globulin nephropathy is not regarded as relevant for humans, therefore a NOAEL of 20 mg/kg bw/d is stated.

 

Based on 2 oral subacute toxicity studies (T1074343 and T3074714) a NOAEL of 20 mg/kg bw/day is taken as a starting point. Observations in males and females at lower doses are considered to be related to alpha-2-microglobulin nephropathy and secondary kidney toxicity and consequently, not regarded as adverse effects in human risk assessment. The LOAEL is 40 mg/kg bw/day in these studies based on liver effects (hypertrophy) and clinical chemistry (decreased alkaline phosphatates) at this dose level.

 

Long-term toxicity – systemic effects (worker)

Assumption on respiratory absorption:

- Vapour pressure: 2.2E-06 hPa at 20°C (values below 5 hPa are regarded as low volatility according to the ECHA guidance document)

- Particle size: Physical state: Dimethyl propylphosphonate is a clear, colorless liquid

- Partition coefficient n-octanol/water (log value): Log Kow (Pow) = 0.5 (experimental)

- Water solubility: completely miscible with water (> 90% at 15°C); (according to the REACH guidance document passive diffusion might be limited, but dimethyl propylphosphonate might pass through aqueous pores based on a molecular weight below 200)

- Hydrolysis test: see Section 5.1.2 "Hydrolysis" (2011/0144/02)

- Acute inhalation toxicity: see Section 7.2.2 "Acute toxicity: inhalation" (T5083374)

Based on the data above respiratory absorption is assumed. Based on the physicochemical data and the oral toxicity data oral absorption is confirmed in a subacute toxicity study (although alpha-2-microglobulin nephropathy is not relevant for humans these systemic observations confirm oral absorption). In the course of this DNEL calculation respiratory absorption = oral absorption is regarded as a reasonable assumption.

 

Assumption on dermal absorption:

- Physical state: Dimethyl propylphosphonate is a clear, colorless liquid

- Molecular weight: 152.1287

- Water solubility: completely miscible with water (> 90% at 15°C).

- Partition coefficient n-octanol/water (log value): Log Kow (Pow) = 0.5 (experimental)

- Vapour pressure: 2.2E-06 hPa at 20°C

- Surface tension: no data available. Based on the structure, surface activity of the dimethyl propylphosphonate is not expected.

- Skin irritation: "slightly irritating"; no classification necessary

- Dermal toxicity: no data available

- Skin sensitization: not sensitizing in local lymph node assay (LLNA)

Based on the data above some dermal absorption might be assumed. Dermal absorption is likely to be lower than oral absorption based on the high water solubility and a low Log Kow (Pow) = 0.5 only slightly above 0. For DNEL calculation dermal absorption is taken to be 2-fold lower than oral absorption.

 

Reproductive Toxicity – systemic effects

Effects on fertility are observed in mice and rats and dimethyl propylphosphonate will be classified as Repr. 1B; H360.

In mice fertility parameter (e.g. dead implants) were affected in a dominant lethal mutation assay at 500 mg/kg bw/day. Based on comprehensive follow up investigations it was concluded that the observations are not due to genotoxic effects.

In a pilot reproduction/developmental toxicity screening test in rats (doses: 0, 20, 100 and 500 mg/kg bw/day) a low fertility index and pup survival was observed at 500 mg/kg bw/day.

Since effects on fertility are observed in rats and mice at 500 mg/kg bw/day, a dose 25-fold higher than the starting point for systemic toxicity, it is assumed that the systemic DNEL covers the endpoint reproduction.

 

DNEL local (worker)

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

 

Irritation/corrosion:

In the skin irritation/corrosion study dimethyl propylphosphonate was 'slightly irritating to the skin' (exposure period: 4 hours).

Very slight, barely perceptible erythematous reactions were observed in all three animals. In one animal signs were evident only 1 hour post administration and in the other animals up to and at 72 hours and 14 days, respectively. Mean scores at 24, 48, and 73 hours: Erythema score = 0.66, edema score = 0.

In the eye irritation study dimethyl propylphosphonate was 'slightly irritating to the eye' (exposure period: 24 hours).

Reactions of the mucous membranes and cornea were observed in all three animals. The iris was also transiently affected in all three animals, but at different times. Discharge was observed in all three animals. Signs proved to be fully reversible within 21 days. Mean scores at 24, 48, and 72 hours: Cornea score = 1, iris score = 0.33, conjunctiva score = 1.55, chemosis score = 1.44)

No classification for skin irritation according GHS is justified. According GHS a classification as Eye Irrit. 2 (H319: Causes serious eye irritation) is required.

 

Sensitization:

A modified Local Lymph Node Assay (IMDS) was performed on 24 female NMRI mice (6 animals/test item group and 6 control animals) to determine if there is any specific (sensitizing) or non-specific (irritant) stimulating potential of the test item dimethyl propylphosphonate.

Compared to vehicle-treated animals, none of the parameters measured in the substance treated groups, i.e. cell counts and weights of the draining lymph nodes, ear weights and ear swelling, reached or exceeded the "positive levels" defined for this assay. These results show that there is no indication for a skin sensitizing effect after administration of a concentration up to and including 100% dimethyl propylphosphonate in this test system.

A classification is therefore not required.

 

Conclusion on local DNEL

There are no studies available to define a threshold for local toxicity after dermal application or inhalation. No Classification is required according to GHS. Therefore for local effects (dermal and inhalation) no hazard is identified.

For eye irritation, criteria for classification of dimethyl propylphosphonate with Eye irrit. 2; H319 according to GHS are fulfilled. According to ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterization (version 2.0, November 2012) an allocation to the low hazard band is appropriate for compounds labeled with H319. 

 

Long term DNEL local toxicity

Since dimethyl propylphosphonate is only slightly irritating in an in vivo irritation assay on the skin and on the eye and not sensitizing in LLNA, no local DNEL will be calculated. It is anticipated that the systemic DNEL covers the slight local effects.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 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):

30

Modified dose descriptor starting point:

NOAEC

Value:

17.39 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) = 20 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(1.15 m3/kg bw/day) = 17.39 mg/m3

AF for dose response relationship:

1

Justification:

Default value (ECHA)

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:

1

Justification:

Data are also available for mice in a dominant lethal assay. No major systemic toxicity is observed at 500 mg/kg bw/day. Main effect in rats is alpha-2-microglobulin related nephropathy, a mechanism not relevant for humans. Consequently, it is likely that rodents are more sensitive than humans and no factor for "additional uncertainty" is applied.

AF for intraspecies differences:

5

Justification:

The default value (ECHA) for general population is reduced because in rodents alpha-2-microglobulin accumulates in the kidney after oral dosing, an effect not relevant for human risk assessment. In addition a rapid and efficient excretion is anticipated based on the rodent data on dimethyl propylphosphonate and diethyl ethylphosphonate

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

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

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

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the available physicochemical and toxicological data some dermal absorption might be assumed. Dermal absorption is likely to be lower than oral absorption based on the high water solubility and a low Log Kow = 0.5 only slightly above 0. For DNEL calculation dermal absorption is taken to be 2-fold lower than oral absorption. NOAEL(oral, rat) = 20 mg/kg bw/day => NOAEL(dermal, rat) = 2 x NOAEL(oral, rat) = 40 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value (ECHA)

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:

1

Justification:

Data are also available for mice in a dominant lethal assay. No major systemic toxicity is observed at 500 mg/kg bw/day. Main effect in rats is alpha-2-microglobulin related nephropathy, a mechanism not relevant for humans. Consequently, it is likely that rodents are more sensitive than humans and no factor for "additional uncertainty" is applied.

AF for intraspecies differences:

5

Justification:

The default value (ECHA) for general population is reduced because in rodents alpha-2-microglobulin accumulates in the kidney after oral dosing, an effect not relevant for human risk assessment. In addition a rapid and efficient excretion is anticipated based on the rodent data on dimethyl propylphosphonate and diethyl ethylphosphonate.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.16 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):

120

Modified dose descriptor starting point:

NOAEL

Value:

20 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

Default value (ECHA)

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:

1

Justification:

Data are also available for mice in a dominant lethal assay. No major systemic toxicity is observed at 500 mg/kg bw/day. Main effect in rats is alpha-2-microglobulin related nephropathy, a mechanism not relevant for humans. Consequently, it is likely that rodents are more sensitive than humans and no factor for "additional uncertainty" is applied.

AF for intraspecies differences:

5

Justification:

The default value (ECHA) for general population is reduced because in rodents alpha-2-microglobulin accumulates in the kidney after oral dosing, an effect not relevant for human risk assessment. In addition a rapid and efficient excretion is anticipated based on the rodent data on dimethyl propylphosphonate and diethyl ethylphosphonate.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

AF for remaining uncertainties:

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:

low hazard (no threshold derived)

Additional information - General Population

DNELs (general population)

Basis for delineation of the DNELs systemic:

Short description of key study and/or point of departure

  

Title:

Levagard DMPP - subacute toxicity study in rats (4-week administration by gavage)

and

Levagard DMPP - subacute toxicity study in rats (4-week administration by gavage) Supplementary study

Administration period:

28 days

Doses:

0, 40, 200, or 1000 mg/kg bw/day or 0, 5, or 20 mg/kg bw/day (Suppl.) (males + females)

Local effects:

No local effects observed. Therefore no hazard identified

Systemic effects:

NOAEL 20 mg/kg bw/d

LOAEL: 40 mg/kg bw/d

Based on the following effects: alpha-2-microglobulin nephropathy and secondary kidney toxicity. The observed alpha-2-micro-globulin nephropathy is not regarded as relevant for humans, therefore a NOAEL of 20 mg/kg bw/d is stated.

 

Based on 2 oral subacute toxicity studies (T1074343 and T3074714) a NOAEL of 20 mg/kg bw/day is taken as a starting point. Observations in males and females at lower doses are considered to be related to alpha-2-microglobulin nephropathy and secondary kidney toxicity and consequently, not regarded as adverse effects in human risk assessment. The LOAEL is 40 mg/kg bw/day in these studies based on liver effects (hypertrophy) and clinical chemistry (decreased alkaline phosphatates) at this dose level.

  

Long-term toxicity – systemic effects (general population)

Assumption on respiratory absorption:

- Vapour pressure: 2.2E-06 hPa at 20°C (values below 5 hPa are regarded as low volatility according to the ECHA guidance document)

- Particle size: Physical state: Dimethyl propylphosphonate is a clear, colorless liquid

- Partition coefficient n-octanol/water (log value): Log Kow (Pow) = 0.5 (experimental)

- Water solubility: completely miscible with water (> 90% at 15°C); (according to the REACH guidance document passive diffusion might be limited, but dimethyl propylphosphonate might pass through aqueous pores based on a molecular weight below 200)

- Hydrolysis test: see Section 5.1.2 "Hydrolysis" (2011/0144/02)

- Acute inhalation toxicity: see Section 7.2.2 "Acute toxicity: inhalation" (T5083374)

Based on the data above respiratory absorption is assumed. Based on the physicochemical data and the oral toxicity data oral absorption is confirmed in a subacute toxicity study (although alpha-2-microglobulin nephropathy is not relevant for humans these systemic observations confirm oral absorption). In the course of this DNEL calculation respiratory absorption = oral absorption is regarded as a reasonable assumption.

 

Assumption on dermal absorption:

- Physical state: Dimethyl propylphosphonate is a clear, colorless liquid

- Molecular weight: 152.1287

- Water solubility: completely miscible with water (> 90% at 15°C).

- Partition coefficient n-octanol/water (log value): Log Kow (Pow) = 0.5 (experimental)

- Vapour pressure: 2.2E-06 hPa at 20°C

- Surface tension: no data available. Based on the structure, surface activity of the dimethyl propylphosphonate is not expected.

- Skin irritation: "slightly irritating"; no classification necessary

- Dermal toxicity: no data available

- Skin sensitization: not sensitizing in local lymph node assay (LLNA)

Based on the data above some dermal absorption might be assumed. Dermal absorption is likely to be lower than oral absorption based on the high water solubility and a low Log Kow (Pow) = 0.5 only slightly above 0. For DNEL calculation dermal absorption is taken to be 2-fold lower than oral absorption.

 

Reproductive Toxicity – systemic effects (general population)

Effects on fertility are observed in mice and rats and dimethyl propylphosphonate will be classified as Repr. 1B; H360.

In mice fertility parameter (e.g. dead implants) were affected in a dominant lethal mutation assay (T0058232) at 500 mg/kg bw/day. Based on comprehensive follow up investigations it was concluded that the observations are not due to genotoxic effects.

In a pilot reproduction/developmental toxicity screening test (T0083513) in rats a low fertility index and pup survival was observed at 500 mg/kg bw/day.

Since effects on fertility are observed in rats and mice at 500 mg/kg bw/day, a dose 25-fold higher than the starting point for systemic toxicity, it is assumed that the systemic DNEL covers the endpoint reproduction.

 

DNEL local (general population)

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

 

Irritation/corrosion:

In the skin irritation/corrosion study dimethyl propylphosphonate was 'slightly irritating to the skin' (exposure period: 4 hours).

Very slight, barely perceptible erythematous reactions were observed in all three animals. In one animal signs were evident only 1 hour post administration and in the other animals up to and at 72 hours and 14 days, respectively. Mean scores at 24, 48, and 73 hours: Erythema score = 0.66, edema score = 0.

In the eye irritation study dimethyl propylphosphonate was 'slightly irritating to the eye' (exposure period: 24 hours).

Reactions of the mucous membranes and cornea were observed in all three animals. The iris was also transiently affected in all three animals, but at different times. Discharge was observed in all three animals. Signs proved to be fully reversible within 21 days. Mean scores at 24, 48, and 72 hours: Cornea score = 1, iris score = 0.33, conjunctiva score = 1.55, chemosis score = 1.44).

No classification for skin irritation according to GHS is justified. According GHS a classification as Eye Irrit. 2 (H319: Causes serious eye irritation) is required.

 

Sensitization:

A modified Local Lymph Node Assay (IMDS) was performed on 24 female NMRI mice (6 animals/test item group and 6 control animals) to determine if there is any specific (sensitizing) or non-specific (irritant) stimulating potential of the test item dimethyl propylphosphonate.

Compared to vehicle-treated animals, none of the parameters measured in the substance treated groups, i.e. cell counts and weights of the draining lymph nodes, ear weights and ear swelling, reached or exceeded the "positive levels" defined for this assay. These results show that there is no indication for a skin sensitizing effect after administration of a concentration up to and including 100% dimethyl propylphosphonate in this test system.

A classification is therefore not required.

 

Conclusion on local DNEL

There are no studies available to define a threshold for local toxicity after dermal application or inhalation. No Classification is required according to GHS. Therefore for local effects (dermal and inhalation) no hazard is identified.

For eye irritation, criteria for classification of dimethyl propylphosphonate with Eye irrit. 2; H319 according to GHS are fulfilled. According to ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterization (version 2.0, November 2012) an allocation to the low hazard band is appropriate for compounds labeled with H319. 

 

Long term DNEL local toxicity

Since dimethyl propylphosphonate is only slightly irritating in an in vivo irritation assay on the skin and on the eye and not sensitizing in LLNA, no local DNEL will be calculated. It is anticipated that the systemic DNEL covers the slight local effects.