Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.26 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

881.58 mg/m³

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation absorption between rats and humans. For workers an additional correction was applied for the difference between respiratory rates under standard conditions and under conditions of light activity.

Corrected inhalatory NOAEC

= oral NOAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human) x (sRVhuman / wRV)

= 1000 mg/Kg bw/day x (1/0.38 m³/Kg/day) x (1/2) x (6.7 m³(8h) /10 m³(8h))

Corrected inhalatory NOAEC = 881.58 mg/m³

ABS: Absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor - allometric scaling factor not applied (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Default assesment factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

88.16 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

Value:

881.58 mg/m³

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor of 1 applied - no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

1

Justification:

Additional factor of 1 for other interspecies differences; local effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal NOAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL

= oral NOAEL x (ABSoral-rat/ ABSdermal-rat) x (ABSdermal-rat/ABSdermal-human)

= 1000 mg/Kg bw/day x (ABSoral-rat/ ABSdermal-human)

= 1000 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 1000 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8:Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

140.5 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor:

other: NOAEL (oral Rat = 1000 mg/Kg bw/day)

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

1

Justification:

Additional factor of 1 for other interspecies differences; local effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. Propylene Glycol Dibenzoate (PGDB) is not acutely toxic following oral, inhalation, or dermal exposure. No DNELs for acute toxicity are therefore necessary.

Irritation

PGDB is not a primary skin or eye irritant and is not classified under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Sensitisation

LLNA data is available and shows that PGDB is a very weak skin sensitiser. A weight of evidence assessment of the skin sensitization hazard of PGDB (Earl, L., 2015) has been generated to ensure that the correct decision is taken on the classification of PGDB as a skin sensitiser/non sensitiser. The report contains a review of LLNA accuracy of predictions, physicochemical and hazard data of the substance, its metabolites and impurities and closely related substances and computational prediction tools to detect skin sensitisation structural alerts. Taking into consideration the weight of evidence available from the LLNA assay, the expert judgement report, and resutls from the guinea pig maximization test conducted using structural analogue DPGDB, it was concluded that PGDB does not have significant skin sensitisation potential and should therefore, not be classified as a skin sensitizer according to theEU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Repeated dose toxicity

Key short-term and supporting sub-chronic oral repeat dose toxicity data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant sub-chronic repeat dose toxicity information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

In a key OECD Guideline 422 combined repeat dose / reproductive and developmental toxicity screening study (Huntingdon Life Sciences, 2014g; Klimisch score = 1), the systemic toxicity potential of the test material (PGDB) was assessed in Crl:CD(SD) rats (10/sex/dose) following oral gavage administration at doses of 0, 100, 300 or 1000 mg/Kg bw/day over a period of at least five weeks. Male rats were treated daily two weeks before pairing up to necropsy after a minimum of five consecutive weeks and female rats were treated daily for two weeks before pairing, throughout mating, gestation and until Day 6 of lactation. A similarly constituted control group received the vehicle, corn oil.

During the study, clinical condition, detailed physical and arena observations, sensory reactivity,grip strength, motor activity, body weight, food consumption, haematology, blood chemistry,oestrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight,macroscopic and microscopic investigations were undertaken for all adult animals.

There were 3 premature decedents, all with changes in the thorax or thoracic tissues, which wereconsistent with dosing injuries. Additionally, some animals at scheduled termination also hadmacroscopic and microscopic evidence of similar changes indicating dosing trauma. There wasno indication of a dose related trend in these changes and the test material was not considered to be the cause of these difficulties. The use of non-standard dosing equipment, due to incompatibilities of the test material with rubber catheters was attributed to be the cause.

Treatment with the test material at dose levels up to 1000 mg/Kg bw/day was well tolerated. No adverse treatment-related effects were observed on clinical condition , dosing observations, bodyweight performance of females, food consumption, behaviour, and reflexes or grip strength. Gross necropsy did not reveal any remarkable findings. There was no effect of treatment on oestrus cycle, mating ability of animals, fertility, sex ratio or offspring clinical signs.

Haematology assessment revealed low haematocrit, haemoglobin levels, and red blood cell counts for females receiving 1000 mg/Kg bw/day. Eosinophil counts were also observed to be lower thancontrols for males and females at this dose level. Males receiving 1000 mg/Kg bw/day exhibited high calcium and phosphorus levels and females receiving 1000 mg/Kg bw/day exhibited low calcium and albumin levels. Additionally, females receiving 300 or 1000 mg/Kg bw/day exhibited high creatinine levels although a dose response was not apparent.

Adjusted mean organ weights at the 1000 mg/Kg bw/day dose level included low brain weights formales and high heart weights for females. In the absence of any adverse effects on clinicalcondition or pathological correlates, the above differences were considered not to be adverse.Other effects attributed to the test material at the 1000 mg/Kg bw/day level included increasedwater consumption, low bodyweight gain of males and high motor activity for males andfemales including both, ambulatory(low beam) and rearing (high beam) activity.

At terminal sacrifice, changes were observed in the liver of the 1000 mg/Kg bw/day animals. Centrilobular hypertrophy was observed in males and increased cytoplasmic rarefaction was observed in females. Centrilobular hypertrophy is suggestive of an adaptive response to mixed function oxidase induction in the liver (Cattley et al., 2002) and considered to be of limited toxicological significance. The increased cytoplasmic rarefaction (likely due to glycogen deposition) isconsidered in rodents to be adaption, possibly related to hepatic metabolism of the test substance(Greaves, 2007). These changes correlate with the increase in organ weight noted at necropsyand the change in females maybe linked to the variation in glucose levels in the clinical chemistry findings. Slightly raised blood enzymes seen in the 1000 mg/Kg bw/day animals may also be linked to the minor changes in the liver.

In males dosed at 1000 mg/Kg bw/day, at terminal sacrifice, myofibre degeneration / necrosis in the skeletal muscle was observed in 3/5 animals (focal, minimal in one and multifocal, slight in two). Afocal, minimal change was present in 1/5 animals at 100 mg/Kg bw/day and 2/5 animals at 300 mg/Kg bw/day. This change, present only in males, is seen occasionally as a background change at a minimal level and whilst the significance is not clear, it was an unusual finding and a direct relationship to the test substance at a slight, multifocal level in males at 1000 mg/Kg bw/day could not be ruled out. This may be linked to the raised aspartate amino-transferase (AST) levels seen in males at 1000 mg/Kg bw/day.

Based on the results observed, the no observed adverse effect level (NOAEL) for systemic toxicity was determined to be 300 mg/Kg bw/day, based on the myofibre degeneration / necrosis observed in the skeletal muscle at 1000 mg/Kg bw/day.

In a key OECD Guideline 408 read across 13-week repeated oral dose study (Huntingdon Life Sciences, 1999c; Klimisch score = 1) conducted to determine the effects of prolonged exposure of the test material DPGDB in rats, Crl: (IGS) CD BR rats (5/sex/concentration) were orally administered (via diet) DPGDB at 0 (untreated diet control), 250, 1000, 1750, and 2500 mg/Kg bw/day for a period of 13 weeks. Additional rats were dosed at 0 and 2500 mg/Kg bw/day to allow for an assessment of recovery from treatment 4 weeks after the end of dosing.

Clinical observations showed no signs of adverse effects with the exception of a decrease in body weight gain and final body weight in both sexes at the higher doses. The major toxicological findings were limited to the liver, spleen and caecum at the 1750 and/or 2500 mg/Kg bw/day doses. The liver showed minimal to slight liver cell hypertrophy (enlargement) and alterations in associated biochemical parameters. At 1000 mg/Kg bw/day, there was a slight increase in liver enzymes but not judged to be sufficient for toxicity. The spleen showed a slight to moderate increase in the normal degree of haemosiderosis (iron accumulation) and the caecum showed a minimal epithelial hyperplasia only at 2500 mg/Kg bw/day. Urinary pH was decreased in a dose related manner in both sexes which was likely due to acidic metabolites being excreted in the urine and may have been related to the decreased elimination of sodium and potassium at the 1750 and 2500 mg/Kg bw/day doses only. Most importantly all treatment related affects were reversible or showed tendency to reverse in the 2500 mg/Kg bw/day day 4 week recovery group.

No findings of toxicological importance were detected in this study at a dosage of 1000 mg/Kg bw/day or below. The NOAEL was 1000 mg/Kg bw/day.

In a supporting oral 90-day study (FDRL, 1972; Klimisch score = 2), the test material (Propylene Glycol Dibenzoate) was administered continuously in the diet to FDRL-Wistar derived weanling rats (15/sex/dose) at doses of 0, 100, 500, or 2000 mg/Kg bw/day (equivalent toactual intake of propylene glycol dibenzoate of 126, 633, and 2541 mg/Kg bw/day (combining and averaging box sexes, respectively)) for a period of 90 days. Based on lack of adverse systemic toxicity effects observed in the study, the NOAEL for systemic toxicity was determined to be >2541 mg/Kg bw/day).

Genetic Toxicity

Adequate substance specific and read across (DPGDB) information exists to characterise the mutagenicity of PGDB. Results of bacterial mutation assays demonstrate that PGDB and its structural analogue DPGDB were not mutagenic to strains of S. typhimurium and E. coli in the absence and presence of metabolic activation. When tested for cytogenicity in vitro, in the absence and in the presence of S9 fraction, PGDB and DPGDB showed no evidence of clastogenic activity in human lymphocytes and Chinese Hamster Lung (CHL) cells, respectively. Both PGDB and DPGDB did not demonstrate mutagenic potential when tested in mouse lymphoma L5178Y cells in the absence and presence of metabolic activation (±S9).

Reproductive / Developmental Toxicity

Key screening reproductive/developmental toxicity data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB).

Reproductive Toxicity

In a key OECD Guideline 422 combined repeat dose / reproductive and developmental toxicity screening study (Huntingdon Life Sciences, 2014g; Klimisch score = 1), the systemic toxicity potential of the test material (PGDB) was assessed in Crl:CD(SD) rats (10/sex/dose) following oral gavage administration at doses of 0, 100, 300 or 1000 mg/Kg bw/day over a period of at least five weeks. Male rats were treated daily two weeks before pairing up to necropsy after a minimum of five consecutive weeks and female rats were treated daily for two weeks before pairing, throughout mating, gestation and until Day 6 of lactation. A similarly constituted control group received the vehicle, corn oil.

During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology, blood chemistry, oestrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight, macroscopic and microscopic investigations were undertaken for all adult animals.

There were 3 premature decedents, all with changes in the thorax or thoracic tissues, which were consistent with dosing injuries. Additionally, some animals at scheduled termination also had macroscopic and microscopic evidence of similar changes indicating dosing trauma. There was no indication of a dose related trend in these changes and the test material was not considered to be the cause of these difficulties. The use of non-standard dosing equipment, due to incompatibilities of the test material with rubber catheters was attributed to be the cause.

Treatment with the test material at dose levels up to 1000 mg/Kg bw/day was well tolerated. No adverse treatment-related effects were observed on clinical condition, dosing observations, bodyweight performance of females, food consumption, behaviour, and reflexes or grip strength. Gross necropsy did not reveal any remarkable findings. There was no effect of treatment on oestrus cycle, mating ability of animals, fertility, sex ratio or offspring clinical signs.

Haematology assessment revealed low haematocrit, haemoglobin levels, and red blood cell counts for females receiving 1000 mg/Kg bw/day. Eosinophil counts were also observed to be lower than controls for males and females at this dose level. Males receiving 1000 mg/Kg bw/day exhibited high calcium and phosphorus levels and females receiving 1000 mg/Kg bw/day exhibited low calcium and albumin levels. Additionally, females receiving 300 or 1000 mg/Kg bw/day exhibited high creatinine levels although a dose response was not apparent.

Adjusted mean organ weights at the 1000 mg/Kg bw/day dose level included low brain weights for males and high heart weights for females. In the absence of any adverse effects on clinical condition or pathological correlates, the above differences were considered not to be adverse. Other effects attributed to the test material at the 1000 mg/Kg bw/day level included increased water consumption, low bodyweight gain of males and high motor activity for males and females including both, ambulatory(low beam) and rearing (high beam) activity.

At terminal sacrifice, changes were observed in the liver of the 1000 mg/Kg bw/day animals. Centrilobular hypertrophy was observed in males and increased cytoplasmic rarefaction was observed in females. Centrilobular hypertrophy is suggestive of an adaptive response to mixed function oxidase induction in the liver (Cattley et al., 2002) and considered to be of limited toxicological significance. The increased cytoplasmic rarefaction (likely due to glycogen deposition) is considered in rodents to be adaption, possibly related to hepatic metabolism of the test substance (Greaves, 2007). These changes correlate with the increase in organ weight noted at necropsy and the change in females maybe linked to the variation in glucose levels in the clinical chemistry findings. Slightly raised blood enzymes seen in the 1000 mg/Kg bw/day animals may also be linked to the minor changes in the liver.

In males dosed at 1000 mg/Kg bw/day, at terminal sacrifice, myofibre degeneration / necrosis in the skeletal muscle was observed in 3/5 animals (focal, minimal in one and multifocal, slight in two). A focal, minimal change was present in 1/5 animals at 100 mg/Kg bw/day and 2/5 animals at 300 mg/Kg bw/day. This change, present only in males, is seen occasionally as a background change at a minimal level and whilst the significance is not clear, it was an unusual finding and a direct relationship to the test substance at a slight, multifocal level in males at 1000 mg/Kg bw/day could not be ruled out. This may be linked to the raised aspartate amino-transferase (AST) levels seen in males at 1000 mg/Kg bw/day.

Reproductive endpoints which were affected by oral gavage administration of PGDB included; an extended pre-coital interval for two animals and slightly lower mating evidence (sperm evidence in vaginal smears) for animals receiving 1000 mg/Kg bw/day. There was a slight decrease in live birth index and a small increase in the number of offspring dying between birth and Day 7 of age for the group receiving 1000 mg/Kg bw/day.

Male and female offspring body weight on Day 1 of age was low at 1000 mg/Kg bw/day; this was despite a tendency towards a longer gestation length which was probably secondary to restricted intra uterine growth. Offspring body weight gain thereafter remained slightly low at 300 or 1000 mg/Kg bw/day. Macroscopic examination at scheduled termination on Day 7 of age confirmed this with, a number of offspring in the 1000 mg/Kg bw/day group noted to be of thin build and with no milk in stomach. As the effects on offspring survival were limited to the 1000 mg/Kg bw/day group, the effects at 300 mg/Kg bw/day were considered not to be adverse at the degree observed.

Based on the results observed, the no observed adverse effect level (NOAEL) for systemic toxicity was determined to be 300 mg/Kg bw/day, based on the myofibre degeneration/necrosis observed in the skeletal muscle at 1000 mg/Kg bw/day. The NOAEL for reproductive and developmental toxicity was also determined to be 300 mg/Kg bw/day, based on the low offspring growth and small increase in post-natal offspring mortality.

In a key read across OECD Guideline 416 two generation study in rats (Huntingdon Life Sciences, 2001c; Klimisch score = 1) conducted to assess the effects of the test material DPGDB on reproductive performance, dietary administration of DPGDB at concentrations of 1000, 3300 or 10000 ppm was generally well tolerated by the P (F0) and subsequent F1 parental animals and their respective progeny. Exposure to the test material was in line with expectation throughout both generations fluctuations reflected the different physiological status of the animals and were predictably highest for females during peak lactation and in young animals. Bodyweight change of F1 females before paring and F1 males were slightly but significantly lower than in Controls. No adverse effects were seen on overall parental food consumption; food conversion efficiency calculated during the 10 week pre-mating phase was considered similar to controls for both generations. Oestrous cycle, mating performance, fertility and fecundity were similar in all groups. Gestation lengths and the parturition process were unaffected by treatment. Assessment of the terminal vaginal smears taken from F0 females revealed a higher incidence of females in oestrus in groups treated with DPGDB compared with controls. This finding was not apparent among F1 females and is considered to be of doubtful biological significance.

Litter parameters at birth of the F1 and F2 progeny and their survival to weaning showed no apparent detrimental effects of treatment with DPGDB. However, in both F1 and F2 offspring at 10000 ppm there was a slight reduction on weight gain during days 14-21 of age and this finding may be linked to the transition to direct exposure to the test material as the offspring weaned on to solid diet at the same dietary inclusion levels as their parents.

No treatment related findings were seen at microscopic examination of the F1 offspring not selected to form the next generation or the F2 offspring killed after weaning. Macropathology, histopathology assessment and sperm analysis for the F0 and F1 adults showed no adverse effects of treatment.

The only possible effect of treatment detected at assessment of organ weights from F1 and F2 offspring was significantly lower absolute and relative spleen weight among F2 males and females compared to controls. The toxicological significance if this finding is uncertain since it was not detected among F1 offspring or among F0/F1 adult animals. The evidence from this study suggested that a dietary concentration of DPGDB at 10000 ppm should be considered as the No Observed Adverse Effect Level (NOAEL) for P (F0) and F1 parent animals. The NOAEL for developing offspring is considered to be 3300 ppm. The No Observed Effect Level (NOEL) for reproductive parameters is considered to be 10000 ppm.

The evidence from this study suggested that a dietary concentration of DPGDB at 10000 ppm should be considered as the No-Observed-Effect-Level (NOEL) for F0 and F1 parent animals. The No-Observed-Adverse-Effect-Level (NOAEL) for survival and growth of the offspring is considered to be 10000 ppm (equivalent to a minimum estimated daily achieved dosage of 500 mg/Kg bw/d).

Developmental Toxicity

In a key read across OECD Guideline 414 pre-natal development study in rats (Huntingdon, 2000c; Klimisch score = 1), conducted to determine the effect of the test material (DPGDB) when administered during and beyond the organogenesis phase of gestation, groups of 22 female rats were selected after mating, and were dosed by oral gavage with corn oil fortified with the test material between day 6 and day 19 of gestation. Dose levels examined were 0 (vehicle control), 250, 500, and 1000 mg/Kg bw/day. According to preliminary results obtained in rats in a dose range-finding study (HLS 2000, VCL313/980305), doses up to 1500 mg/Kg bw/day during gestation days 6 to 19 gave no adverse effect on dams or foetuses, but maternal toxicity was observed at the highest dose. The highest dose used in the main study was therefore 1000 mg/Kg bw/day.

In the rat study, an association between treatment at 1000 and 500 mg/Kg bw/day and the greater number of fetuses with incomplete ossification of the 5th and/or 6th sternebrae cannot be discounted particularly since a delay in ossification would be expected to be the most sensitive marker of an effect on pre-natal development where treatment has continued through to the day before sacrifice (treatment period: Days 6 to 19 of gestation). The assessment of fetal ossification on Day 20 of gestation represents a snapshot in time as the ossification will continue as the animals grow and mature. Although the relationship of these findings to treatment is uncertain they are considered to be transient in nature rather than representing permanent structural changes and therefore are considered to be of no long-term toxicological importance.

The increase in cervical ribs at 1000 mg/Kg bw/day is considered to be of greater toxicological significance as it occurred at a dosage which has not produced any detectable signs of maternal toxicity however cervical ribs were only found in a small number of fetuses (10/155) at the limit dosage of 1000 mg/Kg bw/day and there was no concomitant change in vertebral configuration.

Salivation after dosing was observed at all dosages of the test material; the incidence was dose related but this finding was not considered to be of toxicological importance. At 1000 mg/Kg bw/day, there were no detectable signs of maternal toxicity, there were no maternal deaths and all females had a live litter sacrifice. It was concluded that the 1000 mg/Kg bw/day is the NOAEL for maternal toxicity. There were no treatment related effects observed at prenatal survival or growth. At 1000 mg/Kg bw/day, treatment related small but definite increase in the number of fetuses with cervical ribs were observed. The no-observed adverse effect level for all aspects of pre-natal development was concluded to be 500 mg/Kg bw/day.

In a key read across OECD Guideline 414 pre-natal development study in rabbits (Charles River Laboratories, 2018a; Klimisch score = 1), the test material (dipropyleneglycol dibenzoate (DPGDB)), in the vehicle (0.5% carboxymethylcellulose in deionized water) was administered orally by gavage to 3 groups of 24 time-mated female New Zealand White [Hra:(NZW)SPF] rabbits once daily from Gestation Days 7–28. Dosage levels were 100, 250, and 500 mg/Kg bw/day administered at a dose volume of 5 mL/Kg.

No fetal malformations were attributed to the test substance. Other fetal developmental variations occurred infrequently or at a frequency similar to that in the control group, did not occur in a dose-related manner, and/or were within the Charles River Ashland historical control data ranges, and therefore were not attributed to the test substance. Adverse effects on maternal survival, mean body weight changes, and food consumption were noted in the 500 mg/Kg bw/day group; therefore, a dosage level of 250 mg/Kg bw/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity.

Based on lower mean fetal weights at 500 mg/Kg bw/day, a dosage level of 250 mg/Kg bw/day was considered to be the NOAEL for embryo/fetal developmental toxicity when dipropylene glycol dibenzoate was administered orally by gavage to time-mated New Zealand White rabbits. Importantly, a 10.5% decrease in fetal body weight in the 500 mg/Kg bw/day dosage group reflects the 17% decrease in feed consumption in the dams during the fetal period and therefore this reduced fetal body weight is related to the maternal toxicity that was observed at that dose level.

In a key OECD Guideline 422 combined repeat dose / reproductive and developmental toxicity screening study (Huntingdon, 2014g; Klimisch score = 1), the systemic toxicity potential of the test material (PGDB) was assessed in Crl:CD(SD) rats (10/sex/dose) following oral gavage administration at doses of 0, 100, 300 or 1000 mg/Kg bw/day over a period of at least five weeks. Male rats were treated daily two weeks before pairing up to necropsy after a minimum of five consecutive weeks and female rats were treated daily for two weeks before pairing, throughout mating, gestation and until Day 6 of lactation. A similarly constituted control group received the vehicle, corn oil.

There was a slight decrease in live birth index and a small increase in the number of offspring dying between birth and Day 7 of age for the group receiving 1000 mg/Kg bw/day. Male and female offspring body weight on Day 1 of age was low at 1000 mg/Kg bw/day; this was despite a tendency towards a longer gestation length which was probably secondary to restricted intra uterine growth. Offspring body weight gain thereafter remained slightly low at 300 or 1000 mg/Kg bw/day. Macroscopic examination at scheduled termination on Day 7 of age confirmed this with, a number of offspring in the 1000 mg/Kg bw/day group noted to be of thin build and with no milk in stomach. As the effects on offspring survival were limited to the 1000 mg/Kg bw/day group, the effects at 300 mg/Kg bw/day were considered not to be adverse at the degree observed.

Based on the results observed, the NOAEL for developmental toxicity was determined to be 300 mg/Kg bw/day, based on the low offspring growth and small increase in post-natal offspring mortality.

DNEL Worker long-term lnhalation-systemic

Dose descriptor: A NOAEL of 1000 mg/Kg bw/day will be used as the starting point.

Modification of dose descriptor

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) (no allometric scaling factor applied)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	25

DNEL Worker long-term-systemic via inhalation route = 881.58 / 25 = 35.26 mg/m³

DNEL Worker long-term Inhalation-local

Dose descriptor: A NOAEL of 1000 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	1 (for local effects) (no allometric scaling factor applied)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	10

DNEL Worker long-term-local via inhalation route = 881.58 / 10 = 88.16 mg/m³

DNEL Worker long-term Dermal-systemic

Dose descriptor: A NOAEL of 1000 mg/Kg bw/day will be used as the starting point.

Modification of dose descriptor

Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) 4 (allometric scaling factor for rats)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	100

DNEL Worker long-term-systemic via dermal route = 1000 / 100 = 10 mg/Kg bw/day

DNEL Worker long-term Dermal-local

Dose descriptor: A NOAEL of 1000 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

The Corrected dermal NOAEL was further corrected to enable comparison with human exposure, expressed in mg/cm²/day. For this purpose, for rats , the approximate weight was considered to be 250 grams (0.25 Kg) and 445 cm²was considered to be the approximate total body surface area.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	1 (for local effects) 4 (allometric scaling factor for rats)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	40

DNEL Worker long-term-local via dermal route = 5620 / 40 = 140.5 µg/cm²

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.69 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

434.78 mg/m³

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation

absorption between rats and humans.

Corrected inhalatory NOAEC

= oral NOAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human)

= 1000 mg/Kg bw/day x (1/1.15 m³/Kg bw/day) x (1/2)

Corrected inhalatory NOAEC = 434.78 mg/m³

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor of 1 applied – no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21.74 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor:

other: NOAEL (oral Rat = 1000 mg/Kg bw/day)

Value:

434.78 mg/m³

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor of 1 applied – no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

1

Justification:

Additional factor of 1 for other interspecies differences; local effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal N(L)OAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL

= oral NOAEL x (ABSoral-rat / ABSdermal-rat) x (ABSdermal-rat / ABSdermal-human)

= 1000 mg/Kg bw/day x (ABSoral-rat / ABSdermal-human)

= 1000 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 1000 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation(ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose

[concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

70.25 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Dose descriptor:

other: NOAEL (Rat oral - 1000 mg/Kg bw/day)

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor of 4 applied – Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

1

Justification:

Additional factor of 1 for other interspecies differences; local effects (ECHA Guidance on information equirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification necessary (assuming 100% absorption for both routes in both species)

Corrected Oral NOAEL= 1000 mg/Kg bw/day

Note: 100% absorption for both routes in both species assumed (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

2

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified.Propylene Glycol Dibenzoate (PGDB) is not acutely toxic following oral, inhalation, or dermal exposure. No DNELs for acute toxicity are therefore necessary.

Irritation

PGDBis not a primary skin or eye irritant and is not classified under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.