Dimethyl octadecylphosphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard 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:

4.17 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:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the findings in the repeated dose toxicity study which indicated some degree of systemic exposure, it was considered that dermal absorption would not be higher than oral absorption and therefore no conversion factor was implemented.

AF for dose response relationship:

1

Justification:

See discussion

AF for differences in duration of exposure:

6

Justification:

see discussion

AF for interspecies differences (allometric scaling):

4

Justification:

see discussion

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

3

Justification:

see discussion

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard 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:

2.5 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):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the findings in the repeated dose toxicity study which indicated some degree of systemic exposure, it was considered that dermal absorption would not be higher than oral absorption and therefore no conversion factor was implemented.

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

6

Justification:

see discussion

AF for interspecies differences (allometric scaling):

4

Justification:

see discussion

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

5

Justification:

see discussion

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

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:

2.5 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):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not required, NOAEL is from the same route of exposure

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

6

Justification:

see discussion

AF for interspecies differences (allometric scaling):

4

Justification:

see discussion

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

5

Justification:

see discussion

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

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

Study contributing to the NOAEL: Zmarowski, A. (2013) Combined 28-Day Repeated Dose Toxicity Study With The Reproduction/Developmental Toxicity Screening Test Of M-5925 In Rats By Oral Gavage, Project number 500036. GLP, Unpublished.

Repeated dose toxicity study summary and conclusion:

Dimethyl octadecylphosphonate (DMOP) was administered by daily oral gavage to groups of 10 male and 10 female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.

Mortality (one male), adverse clinical signs, reduced food consumption and severe weight loss were noted mostly for males when initially exposed to DMOP at 1000 mg/kg. After lowering the dose level to 600 mg/kg from Day 14 onwards, the animals’ condition improved. While the body weights and body weight gains remained lower for the males for the treatment duration, this was not considered to be adverse since the gains were at the level or higher than controls when re-calculated from the time the dose level was lowered. Fasted blood samples harvested prior to necropsy examination revealed increases in ALAT in both sexes at 600 mg/kg and females at 300 mg/kg, and other changes that were inconsistent across the sexes (increased potassium (males) and cholesterol (females), decreased total protein (males). None of these changes was associated with a histopathological correlate and they were not considered to be of toxicological significance.

Additional treatment related findings at 600 mg/kg were characterized by increased absolute and relative liver weights and hepatocellular hypertrophy (considered to be a non-adverse adaptive change¹), microscopic findings (vacuolation of the zona glomerulosa, minimal to slight) in the adrenals in both sexes and

congestion /erythrophagocytosis in the mesenteric lymph nodes (correlating with necropsy findings of enlargement and discoloration) in females and increased incidence/severity of sinus histiocytosis of the same lypmh node in males.

Microscopic findings on the stomach were noted which were typical of local contact irritation and included irritation, inflammation and erosion/ulceration. The adaptive liver change and local contact irritation in the stomach were also noted for rats at 300 mg/kg. Due to the nature of these findings they were not considered to represent systemic toxicity¹. No toxicologically significant changes were noted in functional observations or haematology parameters investigated up to 600 mg/kg.

It may therefore be concluded that rats treated at 300 mg/kg showed evidence of adaptive change or local contact irritation but systemic toxicity was not identified. Based on these results, the following No Observed Adverse Effect Level (NOAEL) was derived: Parental NOAEL: 300 mg/kg/day (males/females)

Reproduction / developmental toxicity screening study summary and conclusion:

DMOP was administered by daily oral gavage to groups of 10 male and 10 female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. Pups were not treated directly but were exposed to the test substance in utero and through lactational transfer.

General reproductive data for the parenteral animals was recorded. This included male number paired with, mating data, confirmation of pregnancy and delivery date. Pregnant females were examined to detect signs of difficult or prolonged parturition and cage debris of pregnant females was examined top detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined. Each litter of pups was examined for mortality and viability. The numbers of live and dead pups on Day 1 of lactation and daily thereafter was determined and if possible, cause of death was evaluated. Clinical signs examinations were performed at least once daily. On lactation days 1 and 4 the pups were weighed and their sex determined. The pups were sacrificed on Days 5 to 7 of lactation. Sex was confirmed and descriptions of any external abnormalities recorded. The stomach of any pup not surviving to the scheduled termination was examined for the presence of milk and cause of death established if possible. The following indices were calculated: mating index, fertility index, conception index, gestation index, duration of gestation, percentage of live males at first litter check, percentage of live females at first litter check, percentage of postnatal loss, viability index.

No toxicologically relevant effects on reproductive parameters such as mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites. For developmental data, no toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed. It was concluded that based on these results the NOAEL for reproductive and developmental effects was at least 600 mg/kg bw/day.

 

DNELs that may need to be derived for DMOP (REACH Guidance R.8-1):

Exposure pattern	DNEL/DMEL (appropriate unit)
	Workers	General population^3
Acute – inhalation, systemic effects^1	worker-DNEL acute for inhalation route-systemic	General population-DNEL acute for inhalation route-systemic
Acute – dermal, local effects^2	worker-DNEL acute for dermal route-local	General population-DNEL acute for dermal route-local
Acute – inhalation, local effects^2	worker-DNEL acute for inhalation route-local	General population-DNEL acute for inhalation route-local
Long-term – dermal, systemic effects^1	worker-DNEL long-term for dermal route-systemic	General population-DNEL long-term for dermal route-systemic
Long-term – inhalation, systemic effects^1	worker-DNEL long-term for inhalation route-systemic	General population-DNEL long-term for inhalation route-systemic
Long-term – oral, systemic effects^1	Not relevant	General population-DNEL long-term for oral route-systemic
Long-term – dermal, local effects^2	worker-DNEL long-term for dermal route-local	General population-DNEL long-term for dermal route-local
Long-term – inhalation, local effects^2	worker-DNEL long-term for inhalation route-local	General population-DNEL long-term for inhalation route-local

¹Units for systemic exposure are mg/m³for inhalation, and mg/kg bw for oral and dermal exposure

²Units for local effects are mg/m³for inhalation; and for dermal exposure: mg/cm2 skin, mg/person/day (e.g., calculated based on the deposited amount per cm²times the actually exposed body area), or a measure of concentration (% or ppm)

³General population includes consumers and humans via the environment. In rare cases it may also be relevant to derive a DNEL for specific subpopulations, such as children.

 

Exposure pattern for DMOP and DNELs required for the RCR:

Exposure pattern	DNEL REQUIRED
	Workers	General population^3
Acute – inhalation, systemic effects^1	Inhalation exposure is not a relevant route of exposure as dimethyl octadecylphosphonate is a solid with a low vapour pressure (0.89 x 10^-5kPa at 25^oC)
Acute – dermal, local effects^2	A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.
Acute – inhalation, local effects^2	Inhalation exposure is not a relevant route of exposure as dimethyl octadecylphosphonate is a solid with a low vapour pressure (0.89 x 10^-5kPa at 25^oC)
Long-term – dermal, systemic effects^1	worker-DNEL long-term for dermal route-systemic	General population-DNEL long-term for dermal route-systemic
Long-term – inhalation, systemic effects^1	Inhalation exposure is not a relevant route of exposure as dimethyl octadecylphosphonate is a solid with a low vapour pressure (0.89 x 10^-5kPa at 25^oC)
Long-term – oral, systemic effects^1	Not relevant	General population-DNEL long-term for oral route-systemic
Long-term – dermal, local effects^2	A DNEL for long term duration local effect will not need to be derived in the case where an acute toxicity hazard (leading to C&L) for local effects has not been identified.
Long-term – inhalation, local effects^2	Inhalation exposure is not a relevant route of exposure as dimethyl octadecylphosphonate is a solid with a low vapour pressure (0.89 x 10^-5kPa at 25^oC)

 

Based on the table above the DNELS that require to be derived for dimethyl octadecylphosphonate are as follows:

DNEL long term – dermal, systemic effects for worker and the general population risk assessment

DNEL long-term – oral, systemic effects for the general population.

 

ASSESSMENT FACTORS FOR USE IN THE DERIVATION OF THE DNELs

Study duration: Note that as the long-term DNEL for workers and the general population (chronic exposure) should be derived from a chronic toxicity study, the duration extrapolation factor of 6 should be used to convert the derived DNEL from a sub-acute study to a chronic study (REACH Guidance R8.4.3, Table R8-5, Chapter R.8).

Route to route extrapolation: Oral absorption: Absorption of a chemical from the GI tract depends on its physical properties, including lipid solubility and the dissociation rate (REACH Guidance R. 7c, Table R.7.12-1). Dimethyl octadecylphosphonate has very low water solubility (0.0007656 mg/L) and Log Kow of 8.41 which indicate that the substance is lipophilic and can diffuse across the lipid domain of cellular membranes. Although Log Kow values between 0 and 4 are generally optimal for absorption, DMOP has been shown to be irritant to the forestomach after repeated exposure which would aid absorption. Additionally its molecular weight of 362.5 would indicate that it is small enough to diffuse across the lipid domain of the membrane as molecular weights < 500 are optimal for absorption. Histopathological examination of a full range of tissues in the combined 28-day repeated dose and reproductive / developmental toxicity screen study identified adaptive changes in the liver, vacuolation of the adrenal zona glomerulosa and findings in the mesenteric lymph nodes which confirmed that there was systemic exposure of the test substance.

Dermal absorption: dermal absorption of the substance dimethyl octadecylphosphonate has not been characterised, therefore based on the physic-chemical properties (REACH Guidance R. 7c, Table R.7.12-3) the following assumptions may be made: Dermal absorption for the pure a.i. is predicted to be poor due to the solid physical state, very low water solubility (0.0007656 mg/L), and log Kow of 8.41 which would predict that there would be slow transfer from the stratum corneum to the epidermis which would limit absorption. For most uses under REACH for example lubricant use, DMOP would be included in a liquid mixture nevertheless, low dermal absorption is predicted due to the log Kow value of 8.41.

For the conversion of an oral NOAEL to a dermal DNEL no correction factor (i.e. factor 1) will be used as it is predicted that dermal absorption will not be higher than oral absorption.

Interspecies Assessment factors: In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH Guidance R8, section R8.4.3.3, Table R.8-6, however no scientific basis for this is reported. In Ecetoc Technical Report No 86 (ECETOC 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. As a specific mode of action has not been identified for Dimethyl octadecylphosphonate it has not been considered necessary to apply this factor.

Intraspecies assessment factors: A factor for workers of 5 and for the general population of 10 has been suggested by the REACH guidance (8.4.3.1), however, based on several analyses of large data sets and in accordance with many workplace OEL setting practices an intraspecies factor for workers of 3 is considered appropriate for the worker population (ECETOC, 2003). Additionally following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95^thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population and thus a default assessment factor of 5 is recommended (ECETOC, 2003).

Dose response:As the NOAEL has been derived from a repeated dose toxicity study with groups exposed at 0, 100, 300 and 100/600, a factor of 1 is used.

Quality of the database: As the NOAEL has been derived according to a recommended guideline and is GLP compliant without deviations, a factor of 1 is used.

 

Conversion of oral NOAEL to dermal DNEL, Workers.

REACH ECHA guidance Chapter R. 8: Characterisation of dose [concentration]-response for human health, Appendix R8-2, route to route extrapolation and allometric scaling, Part 2, Modification of starting point, Example B. 5.

Correct oral NOAEL rat (in mg/kg bw/d) into dermal NOAEL rat (in mg/kg bw/d) by correcting for differences in absorption between routes (if the case) as well as for differences in dermal absorption between rats and humans (if the case):

Corrected dermal NOAEL = oral NOAEL * ABS_oral-rat/ABS_dermal-rat* ABS_dermal-rat/ ABS_derm-human

               = oral NOAEL * ABS_oral-rat/ ABS_derm-human

(note - on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (chapter R8.4.2).

For interspecies differences, apply factor for allometric scaling (4 for rat).

               = 300/4

               =75

For intraspecies differences apply factor of 3(workers).

= 75 mg/kg bw/d / 3

               = 25 mg/kg bw/d

Conversion from sub-acute to chronic DNEL

               = 25 mg/kg bw/d / 6

               = 4.17 mg/kg bw/d

Dermal DNEL_{long-termsystemic}(workers) = 4.17 mg/kg bw/d

 

Conversion of oral NOAEL to dermal DNEL, general population

REACH ECHA guidance Chapter R. 8: Characterisation of dose [concentration]-response for human health, Appendix R8-2, route to route extrapolation and allometric scaling, Part 2, Modification of starting point, Example B. 5.

Correct oral NOAEL rat (in mg/kg bw/d) into dermal NOAEL rat (in mg/kg bw/d) by correcting for differences in absorption between routes (if the case) as well as for differences in dermal absorption between rats and humans (if the case):

Corrected dermal NOAEL = oral NOAEL * ABS_oral-rat/ABS_dermal-rat* ABS_dermal-rat/ ABS_derm-human

               = oral NOAEL * ABS_oral-rat/ ABS_derm-human

(note - on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (chapter R8.4.2).

For interspecies differences, apply factor for allometric scaling (4 for rat).

               = 300/4

               =75

For intraspecies differences apply factor of 5 (general population).

= 75 mg/kg bw/d / 5

               = 15 mg/kg bw/d

Conversion from sub-acute to chronic DNEL

               = 15 mg/kg bw/d / 6

               = 2.5 mg/kg bw/d

Dermal DNEL_{long-termsystemic}(general population) = 2.5 mg/kg bw/d

 

ORAL DNEL_long-term(general population)

The oral DNEL_long-term(general population) is required in order to assess the risk to man via the environment and the derivation of this DNEL is shown below:

Using 300 mg/kg/d NOAEL from the Combined 28-day repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats. No modification of the starting point is required.

For interspecies differences, apply factor for allometric scaling (4 for rat)

                               = 300 mg/kg bw/d /4
                               = 75

For intraspecies differences, apply factor of 5

                               = 75 mg/kg bw/d /5
                               = 15

Conversion from sub-acute to chronic DNEL, apply a factor of 6

                              = 15 mg/kg bw/d / 6
                               = 2.5

Oral DNEL_long-term(general population) = 2.5 mg/kg bw/d

 

REFERENCES

1)        Adverse effect means “a change in the morphology, physiology, growth, development, reproduction, or life span of an organism, system, or (sub) population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences”. http://www.inchem.org/documents/harmproj/harmproj/harmproj1.pdf-OECDdefinition of adverse effects (IPCS RISK ASSESSMENT TERMINOLOGY, 2004). 

2)           ECETOC, 2003, Technical Report No. 86, derivation of Assessment Factors for Human Health Risk Assessment.