Diallyl phthalate

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):

25

Modified dose descriptor starting point:

NOAEC

Value:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

DNEL related information A DNEL has been derived (adjusted for route-route differences) according to ECHA guidance from oral subchronic repeated dose toxicity data. Dose descriptor, there were no systemic long term inhalation study data available. The data are taken from a 13 weeks 5 days/week oral gavage study (NTP 1985) in the rat in which hepatocellular periportal necrosis, fibrosis, cirrhosis and bile duct hyperplasia were present. The NOAEL was identified at 50 mg/kg/day.

The NOAEL after 13 weeks was the same as the NOAEL identified after a 2 year oral gavage study in rats (NTP 1985). Modification of dose descriptor Convert the rat oral NOAEL into a human inhalation NOAEC (mg/m3) after adjusting for differences in uptake between the two routes using a default factor of 1 (100% oral/100% inhalation). (TGD, Appendix R.8-2 Example Workers) Oral absorption of diallylphthalate is extensive (Eigenberg et al 1986) so assumption of 100% oral absorption and 100% inhalation absorption is appropriate. CorrectedNOAECinhalation = Oral NOAEL x [1/ sRVrat] x [ABSoral-rat/ABSinhal-human] x [sRVhuman/wRV] CorrectedNOAECinhalation = 50 x [1/0.38] x [100/100] x [6.7/10] = 88 mg/m3

AF for dose response relationship:

1

Justification:

Default AF. Clear NOAEL

AF for differences in duration of exposure:

2

Justification:

Default AF. Sub chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No difference in metabolic rate (inhalation)

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

Default AF. Study design in accordance with generally accepted scientific standards and described in sufficient detail

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.22 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

62.5

Modified dose descriptor starting point:

other: LC1

Value:

580 mg/m³

AF for dose response relationship:

5

Justification:

Default AF. Clear NOAEL is not identified. Endpoint was lethality. An extra assessment factor has therefore been used

AF for interspecies differences (allometric scaling):

1

Justification:

No difference in metabolic rate (inhalation)

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Default AF, workers.

AF for the quality of the whole database:

1

Justification:

Default AF

AF for remaining uncertainties:

1

Justification:

Differences in duration of exposure. Default AF. 1 hour exposure is considered to be protective of peak exposure duration of 15 minutes.

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:

0.5 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):

100

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DN(M)EL related information A DNEL has been derived (adjusted for route-route differences) according to ECHA guidance from oral subchronic repeated dose toxicity data.

AF for dose response relationship:

1

Justification:

Default AF. Clear NOAEL

AF for differences in duration of exposure:

2

Justification:

Default AF. Subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF (rat)

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Default AF (worker)

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:

DNEL (Derived No Effect Level)

Value:

20 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

other: EC3 [μg/cm2] considered LOAEL for induction

Value:

1 000 µg/m³

AF for dose response relationship:

4

Justification:

Clear DR curve to extrapolate EC3. ECHA recommends AF of 3-10 for LOAEL as the point of departure. AF of 4 selected to account for shallow slope of the DR curve and spacing of doses at 10-fold intervals (0.5, 5 and 50 % (w/v) in acetone/olive oil (4:1). ECHA and ECETOC guidance detail a starting AF of 3 when the LOAEL is the point of departure.

AF for differences in duration of exposure:

1

Justification:

Default AF for local effects. The potential for accumulation is considered low due to de-esterification of DAP and DAIP by skin esterases and the subsequent clearance of metabolites, phthalic acid and allyl alcohol.

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA REACH Guidance (Default AF for local effects)

AF for other interspecies differences:

2.5

Justification:

Default value of 2.5 entered for local effects on the skin via local metabolism. ECHA requires default values to be used in the absence of relevant substance specific info (which is not available). Default AF of 2.5 entered to allow for the difference in esterase activity between the mouse and human.

AF for intraspecies differences:

5

Justification:

ECHA guidance (Default AF for workers)

AF for the quality of the whole database:

1

Justification:

ECHA guidance (Default AF). GLP study with robust data to OECD 429

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

other: EC3 [μg/cm2] considered LOAEL for induction

AF for dose response relationship:

4

Justification:

Clear DR curve to extrapolate EC3. ECHA (p29) recommends AF of 3-10 for LOAEL as the point of departure. AF of 4 selected to account for shallow slope of the DR curve and spacing of doses at 10-fold intervals (0.5, 5 and 50 % (w/v) in acetone/olive oil (4:1).
(ECHA and ECETOC guidance detail a starting AF of 3 when the LOAEL is the point of departure.

AF for interspecies differences (allometric scaling):

1

Justification:

Default AF for local effects. The potential for accumulation is considered low due to efficiency of removal by enzyme esterification within the skin and the effective clearance of metabolites, phthalic acid and allyl alcohol.

AF for other interspecies differences:

2.5

Justification:

Default value of 2.5 entered for local effects on the skin via local metabolism. ECHA (p32) requires default values to be used in the absence of relevant substance specific info (which is not available). Default AF of 2.5 entered to allow for the difference in esterase activity between the mouse and human.

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

Default AF. GLP study with robust data to OECD 429

AF for remaining uncertainties:

1

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Discussion for workers

Diallyl phthalate is a liquid at room temperature and has a relatively low vapour pressure (0.0213 Pa).  

Diallyl phthalate (DAP) is not classified as an eye irritant. Therefore there is no hazard associated with this endpoint and a DNEL for local ocular hazard has not been derived.  Although DAP is not classified as a skin irritant or corrosive it has been classified as a skin sensitiser (cat.1B)and therefore a quantitative risk characterisation for local dermal hazard is proposed. DNELs for local long term and acute dermal hazard have been derived for workers based on information from a reliable LLNA study.Correlation between dose and response was observed within the study and allowed for calculation of an EC3 value, which allowed for derivation of a DNEL. A quantitative risk assessment has been carried out to cover local hazardsviathe dermal route and the use of appropriate gloves and LEV is recommended for tasks where exposure may arise.A quantitative risk assessment has been carried out to cover local hazardsviathe dermal route.The DNEL for acute local dermal hazard is not required since the short term exposure conditions are controlled by the long term exposure conditions. There are no specific studies on local inhalation hazard and it is difficult to identify local effects from the available information which is confined to acute inhalation toxicity studies where the endpoint was lethality, however, there was no indication of specific local irritation from these studies. In addition, the control measures put in place for long term systemic exposure should prevent local effects occurring in workers. Therefore although the specific hazard is unknown, no further information is required. Acute systemic inhalation exposure is considered to be a slim possibility at peak exposures, and DAP is classified as an acute inhalation hazard (cat 4) hence a DNEL has been derived (6.22 mg/m3), however, the control measures put in place for long term systemic exposure via the inhalation route should prevent acute effects occurring in workers. In addition the low vapour pressure should limit the potential for significant exposure.

 

The critical DNELs were found to be long term systemic exposure, 3.52 mg/m3 (inhalation) or 0.5 mg/kg/day (dermal). The DNELs were derived from oral subchronic and carcinogenicity studies where the NOAEL for adverse hepatocellular effects was 50 mg/kg/day. A combined fertility and developmental toxicity study was conducted according to OECD 421 which corroborated this dose descriptor selection for adults but no effects were observed on F1 animals at the highest dose of 150 mg/kg/day. In an embryofetal/teratogenicity study (OECD 414) the results were supportive of the previous reproductive study and a NOAEL of 150 mg/kg/day for fetal skeletal variations and reduced litter weights.  Therefore the NOAEL of 50 mg/kg/day is supported by several animal studies and is considered to be robust and the critical endpoint. The 2 year carcinogenicity study in rats (NTP, 1985) did provide evidence of an increased incidence of mononuclear cell leukaemia associated with DAP administration but it was confined to high dose female rats (100 mg/kg/day) and is commonly found in control rats. The authors concluded the study provided only equivocal evidence of carcinogenicity. In a 2 year oral study (NTP, 1983) in B6C3F1 mice there was evidence of chronic inflammatory and hyperplastic responses of the forestomach leading to squamous cell papillomas which may have been associated with DAP administration. An increased incidence of lymphomas in male mice (100 mg/kg) was observed that was considered to be only equivocally related to DAP treatment. The equivocal or negative carcinogenicity data in rats and mice are considered to be of limited relevance to human exposure at the high doses employed. Therefore DAP has not been classified as a carcinogen. The equivocal genotoxicity data, weakly positive in vitro and negative in the in vivo micronucleus test do not suggest a clear genotoxic mode of action. The positive in vivo chromosome aberration study (Shelby and Witt, 1995) was only weakly positive at a high dose (300 mg/kg) with a poor dose-response relationship and only 50 cells per animal analysed instead of the recommended 100 cells (OECD TG 475). Further information is required to explain this equivocal finding. It is considered that in vivo manifestation of genotoxicity leading to tumours on lifetime administration has not been demonstrated.  In conclusion, there is insufficient evidence of a non-threshold mechanism of toxicity and therefore DNELs (not DMELs) were derived according to REACH criteria Annex 1 1.4.1.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.43 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):

100

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

DN(M)EL related information Dose descriptor There were no systemic long term inhalation study data. The data are taken from a 13 weeks 5 days/week oral gavage study (NTP 1985) in which hepatocellular periportal necrosis, fibrosis, cirrhosis and bile duct hyperplasia were present. The NOAEL was identified at 50 mg/kg/day. Conversion of rat oral NOAEL from 90 day study to is required. Significant exposure via the inhalation route is considered to be unlikely since the vapour pressure of DAP is relatively low. Modification of dose descriptor Convert the rat oral NOAEL into a human inhalation NOAEC (mg/m3) after adjusting for differences in up take between the two routes using a default factor of 1 (100% oral/100% inhalation). (TGD, Appendix R.8-2 Example Workers) Oral absorption of diallylphthalate is extensive (Eigenberg et al 1986) so assumption of 100% oral absorption and 100% inhalation for both rats and humans is appropriate. CorrectedNOAECinhalation = Oral NOAEL x [1/ sRVrat1] x [ABSoral-rat/ABSinhal-human] x[ABSinhal-rat/ABSinhal-human] CorrectedNOAECinhalation = 50 x [1/1.15] x [100/100] x [100/100] = 43.5 mg/m3 Assessment factors Uncertainty ECHA AFs Justification Dose-response relationship 1 Default AF; Clear NOAEL Differences in duration of exposure 2 Default AF;sub-chronic to chronic Interspecies differences (allometric scaling) 1 No difference in metabolic rate (inhalation) Other interspecies differences 2.5 Remaining differences Intraspecies differences 10 Default AF; general population Quality of database 2 Study design in accordance with generally accepted scientific standards and described in sufficient detail. However, 5 day per week dosing design is less relevant to the general population so a factor of 2 added Overall AF 100 General populationDNELlong-term inhal = 43..5 mg/m3/100 = 0.43 mg/m3

AF for dose response relationship:

1

Justification:

Default AF. Clear NOAEL

AF for differences in duration of exposure:

2

Justification:

Default AF. Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No difference in metabolic rate (inhalation)

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

Default AF (general population)

AF for the quality of the whole database:

2

Justification:

Study design in accordance with generally accepted scientific standards and described in sufficient detail. However, 5 day per week dosing design is less relevant to the general population so a factor of 2 added

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.64 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

125

Modified dose descriptor starting point:

other: LC 1

Value:

580 mg/m³

AF for dose response relationship:

5

Justification:

LC1 used as no clear NOAEL identified. Additional AF added.

AF for interspecies differences (allometric scaling):

1

Justification:

No difference in metabolic rate (inhalation)

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

Default AF; general population

AF for the quality of the whole database:

1

Justification:

Study design in accordance with generally accepted scientific standards and described in sufficient detail.

AF for remaining uncertainties:

0

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:

0.12 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):

400

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

AF for dose response relationship:

1

Justification:

ECHA Guidance document details when the point of departure is a NOAEL the default AF is 1. As a clear NOAEL was selected from a repeated dose study an AF of 1 was assigned as there were no uncertainties in the dose descriptor.

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance. Sub-chronic to chronic default AF entered

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidance. Default AF of 4 added to extrapolate dose from experimental animals to humans based on relative differences in basal metabolic rate.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance. Default AF for remaining differences for systemic effects.

AF for intraspecies differences:

10

Justification:

ECHA guidance. Default AF of 10 assigned. This is considered a sufficient AF to protect the larger part of the general population.

AF for the quality of the whole database:

2

Justification:

Although the study is of good/standard quality there is a deficiency in extrapolation to the general population for 7-day exposure. An AF of 2 has therefore been assigned to account for the potential of 7-day exposure and accumulation to the general population over an extended period.

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:

DNEL (Derived No Effect Level)

Value:

10 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor:

other: EC3 [μg/cm2], LOAEL for induction

Value:

1 000 µg/m³

AF for dose response relationship:

4

Justification:

Clear DR curve to extrapolate EC3. ECHA recommends AF of 3-10 for LOAEL as the point of departure. AF of 3 selected for local long-term effects to account for shallow slope of the DR curve and spacing of doses at 10-fold intervals (0.5, 5 and 50 % (w/v) in acetone/olive oil (4:1). ECHA and ECETOC guidance detail a starting AF of 3 when the LOAEL is the point of departure.

AF for differences in duration of exposure:

1

Justification:

Default AF for local effects. The potential for accumulation is considered low due to de-esterification of DAP and DAIP by skin esterases and the subsequent clearance of metabolites, phthalic acid and allyl alcohol.

AF for interspecies differences (allometric scaling):

1

Justification:

Default AF for local effects. The potential for accumulation is considered low due to efficiency of removal by enzyme esterification within the skin and the effective clearance of metabolites, phthalic acid and allyl alcohol.

AF for other interspecies differences:

2.5

Justification:

Default value of 2.5 entered for local effects on the skin via local metabolism. ECHA requires default values to be used in the absence of relevant substance specific info (which is not available). Default AF of 2.5 entered to allow for the difference in esterase activity between the mouse and human.

AF for intraspecies differences:

10

Justification:

ECHA guidance (Default AF for general population)

AF for the quality of the whole database:

1

Justification:

ECHA guidance (Default AF) GLP study with robust data to OECD 429

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

other: EC3 [μg/cm2], LOAEL for induction

Value:

1 000 µg/m³

AF for dose response relationship:

4

Justification:

Clear DR curve to extrapolate EC3. ECHA recommends AF of 3-10 for LOAEL as the point of departure. AF of 3 selected for local long-term effects to account for shallow slope of the DR curve and spacing of doses at 10-fold intervals (0.5, 5 and 50 % (w/v) in acetone/olive oil (4:1). ECHA and ECETOC guidance detail a starting AF of 3 when the LOAEL is the point of departure.

AF for interspecies differences (allometric scaling):

1

Justification:

Default AF for local effects. The potential for accumulation is considered low due to de-esterification of DAP and DAIP by skin esterases and the subsequent clearance of metabolites, phthalic acid and allyl alcohol.

AF for other interspecies differences:

2.5

Justification:

Default value of 2.5 entered for local effects on the skin via local metabolism. ECHA requires default values to be used in the absence of relevant substance specific info (which is not available). Default AF of 2.5 entered to allow for the difference in esterase activity between the mouse and human.

AF for intraspecies differences:

10

Justification:

ECHA guidance (Default AF for general population)

AF for the quality of the whole database:

1

Justification:

ECHA guidance (Default AF for general population) GLP study with robust data to OECD 429

AF for remaining uncertainties:

1

Justification:

No AF entered for remaining uncertainties as we do not consider substance accumulation will arise and present an increased risk for skin sensitisation.

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 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):

400

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The data are taken from a 13 weeks 5 days/week oral gavage study (NTP 1985) in which hepatocellular periportal necrosis, fibrosis, cirrhosis and bile duct hyperplasia were present. The NOAEL was identified at 50 mg/kg/day. Two chronic 2 year studies have been conducted which provided only equivocal evidence of carcinogenicity and the tumour types were of limited relevance to humans.  DAP has not been classified with respect to carcinogenicity under CLP.

AF for dose response relationship:

1

Justification:

Default AF; Clear NOAEL

AF for differences in duration of exposure:

2

Justification:

Default AF ;sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF; Differences in metabolic rate

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

Default AF; general population

AF for the quality of the whole database:

2

Justification:

Study design in accordance with generally accepted scientific standards and described in sufficient detail. However, 5 day per week dosing design is less relevant to the general population so a factor of 2 added.

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:

no hazard identified

Additional information - General Population

Data for dermal exposure and exposure by inhalation are limited to acute toxicity tests. For dermal exposure, the dose descriptors are not unequivocally reliable. The key study shows an LD50 of 3300 mg/kg bw, but 30% mortality was recorded at a dose level of 200 mg/kg bw. Although other references more or less confirm the LD50 of 3300 mg/kg bw, most of these data originate from secondary sources. Hence, the only source for calculating the Derived Minimum Effect Level (DMEL) was this dose level of 200 mg/kg bw. As discussed for this study, the three rabbits that died at this level, died on the first day of exposure, whereas only one rabbit had died at each of the other dose levels, which were a magnitude higher. As no data were provided on treatment controls, the results could not be verified. For these reasons, the DMELs calculated here should be taken as an indicative value, rather than a workable value for hazard assessment. However, when comparing these DMELs with the DNEL\ for oral toxicity, they are within the same range. Comparison with the DNELs for inhalation is not possible due to the difference in expression of the descriptive values.