Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
DNEL related information
DNEL derivation method:
other: ECHA Guidance. Generic ECHA recommendation for a long-term DNEL (inhalation, worker)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.73 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:
1 272.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 272.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

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 / ABSderm-rat) x (ABSderm-rat / ABSderm-human)

 

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

 

                                       = 1272.8 mg/Kg bw/day x (1 / 1) 

 

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).
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

Additional information - workers

Acute toxicity

No key acute oral toxicity data are available for linear esters of rosin. Key data available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters) and bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; and Resin acids and Rosin acids, esters with pentaerythritol), and supporting data available for Resin acids and rosin acids, esters with diethylene glycol, demonstrate that Rosin esters are not acutely hazardous after ingestion.

 

The physico-chemical properties of the category members indicate that they do not present a hazard with regard to aspiration. Other information for Resin acids and rosin acids, esters with diethylene glycol indicates they are not acutely hazardous after skin contact.

 

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified.

 

Irritation/Sensitisation

No skin or eye irritation data are available for linear esters of rosin. Key data available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters) and bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and Rosin acids, hydrogenated, esters with glycerol; and Resin acids and rosin acids, esters with pentaerythritol) demonstrate that Rosin Esters were not irritating to skin or eye.

 

Other information available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters), bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; Resin acids and rosin acids, esters with pentaerythritol; and Resin acids and Rosin acids, hydrogenated, esters with pentaerythritol), along with supporting data from Resin acids and rosin acids, esters with triethylene glycol indicates that Rosin esters are not sensitising in humans, mouse (LLNA) or guinea pig (Maximization Test).

 

Repeated dose toxicity

 

The potential for the members of the sub-category Linear Rosin Esters to cause target organ toxicity following repeated exposure is well understood. Key information is available from two guideline (OECD 408) studies that have investigated the repeated dose oral toxicity of Resin acids and Rosin acids, esters with triethylene glycol and Resin acids and Rosin acids, esters with ethylene glycol.

 

In a key guideline (OECD 408) repeated dose oral toxicity study (Envigo Research Limited, 2017a), the test material (Rosin, esters with ethylene glycol; CAS# 68512-65-2) was administered by continuous dietary admixture to three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 205.7, 506.6 and 1202.5 mg/kg bw/day for males and 243.2, 594.4 and 1377.8 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet only.

  

Based on the results of this ninety-day study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000 ppm (equivalent to 1202.5 mg/kg bw/day for males and 1377.8 mg/kg bw/day for females). The No Observed Effect Level (NOEL) was considered to be 3000 ppm based on non-adverse absolute and relative liver weight changes in males at 7500 ppm and both sexes at 15000 ppm.

 

In a key Guideline (OECD 408) oral repeated dose toxicity study (Envigo Research Limited, 2017b), the test material (Rosin, Triethylene Glycol Ester; CAS# 8050-25-7) was administered by continuous dietary admixture to three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 217.6, 544.6 and 1272.8 mg/Kg bw/day for males and 240.6, 579.4 and 1453.0 mg/Kg bw/day for females). A control group of ten males and ten females were treated with basal laboratory diet.

  

Based on the results observed in this study, the No Observed Adverse Effect Level (NOAEL) for dietary administration of Rosin, Triethylene Glycol Ester (CAS# 8050-25-7) for ninety consecutive days was considered to be 18000 ppm (equivalent to a mean achieved dosage of 1272.8 mg/Kg bw/day for males and 1453.0 mg/Kg bw/day for females). The No Observed Effect Level (NOEL) was considered to be 7500 ppm (equivalent to a mean achieved dosage of 544.6 mg/Kg bw/day for males and 579.4 mg/Kg bw/day for females), based on non-adverse effects observed on absolute and relative liver (both sexes) weights and kidney (male) weights and adaptive centrilobular hypertrophy in male livers at 18000 ppm.

 

The potential for Resin acids and rosin acids, esters with ethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Envigo Research Limited., 2015a) conducted according to OECD Guideline 422. In that study, rats were treated for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No mortality or adverse treatment-related systemic toxicity effects were observed at the highest concentration tested (18000 ppm (male) and 15000 ppm (female)). Based on the results for this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm. 

 

The potential for Resin acids and rosin acids, hydrogenated, esters with triethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study Envigo Research Limited., 2015b) conducted according to OECD Guideline 422. In that study, the test material was administered to rats for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No treatment-related systemic toxicity effects were observed in the study. Based on this, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with diethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2014a) conducted according to OECD Guideline 422. In that study, the test material was administered orally to rats for about eight weeks at concentrations of 3000, 7500 and 15000/18000 ppm. No unscheduled deaths occurred during the study and no treatment-related clinical changes were observed. Microscopic changes in the liver of males and females exposed at the highest concentration and only in males exposed at the mid concentration were observed. Histopathological examination confirmed that this condition is considered to be adaptive in nature. Microscopic kidney changes were observed in one male treated at 18000 ppm and microscopic lung changes were observed in females treated at 18000/15000 ppm. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 3000 ppm for either sex. The ‘No Observed Adverse Effect Level’ (NOAEL) for either sex was therefore considered to be 18000/15000 ppm.

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and rosin acids, esters with diethylene glycol indicates that the test material was not mutagenic towards five strains of Salmonella typhimurium when tested in the absence or presence of exogenous metabolic activation.

 

No additional key or supporting in vitro toxicity data are available for linear esters of rosin. However, data are available from simple and bulky esters of rosin. When tested using mammalian cellsin vitro, in the absence and in the presence of S9 fraction, Resin acids and rosin acids, hydrogenated, Me esters and Resin acids and rosin acids, esters with pentaerythritol were inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in a cytogenetics assay (human lymphocytes).

 

Reproductive / developmental toxicity

Three key reproductive/developmental toxicity screening studies (OECD 422) and two key developmental toxicity studies (OECD 414) are available to evaluate the reproductive toxicity potential of Linear Rosin Esters.

 

The potential for Resin acids and rosin acids, esters with ethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015a) conducted according to OECD Guideline 422. In that study, rats were treated for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No mortality or adverse treatment-related systemic or reproductive toxicity effects were observed at the highest concentration tested (18000 ppm (male) and 15000 ppm (female)). Based on the results for this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, hydrogenated, esters with triethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015b) conducted according to OECD Guideline 422. In that study, the test material was administered to rats for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No treatment-related systemic or reproductive toxicity effects were observed in the study. Based on this, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with diethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2014a) conducted according to OECD Guideline 422. In that study, the test material was administered orally to rats for about eight weeks at concentrations of 3000, 7500 and 15000/18000 ppm. No unscheduled deaths occurred during the study and no treatment-related clinical changes were observed. Microscopic changes in the liver of males and females exposed at the highest concentration and only in males exposed at the mid concentration were observed. Histopathological examination confirmed that this condition is considered to be adaptive in nature. Microscopic kidney changes were observed in one male treated at 18000 ppm and microscopic lung changes were observed in females treated at 18000/15000 ppm. No adverse treatment-related reproductive toxicity effects were observed at the highest concentration tested. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 3000 ppm for either sex. The ‘No Observed Adverse Effect Level’ (NOAEL) for either sex was therefore considered to be 18000/15000 ppm. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 18000/15000 ppm.

 

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017c), the test material (Rosin, esters with ethylene glycol; CAS# 68512-65-2), was administered by continuous dietary admixture to three groups each of twenty-four time mated Sprague-Dawley Crl:CD®(SD) IGS BR strain rats, between gestation days 3 and 19 (inclusive) at dietary concentrations of 3250, 8750, and 18750 ppm (equivalent to a mean achieved dosage of 266.7, 715.0 and 1487.0 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

 

No mortality or signs of clinical toxicity were observed through the study period. Initial dietary exposure at 18750 ppm was associated with a mean body weight loss, thereafter body weight gain was similar to control to gestation day 14. Lower body weight gain was observed from gestation days 14 to 20. During the later stage of gestation, body weight gain in the high exposure group may have been influenced by lower foetal/litter weight, however overall body weight remained lower than control, when adjusted for the contribution of the gravid uterus. Food consumption at this dietary level was lower than control during the first two days of dietary exposure, which probably reflected an initial reluctance to eat the treated diet (due to its palatability), but subsequent food intake was similar to control.

 

For litters at 18750 ppm, there was no effect of maternal exposure on pre-implantation loss, implantation count, embryofoetal survival, litter size or sex ratio but mean foetal, litter and placental weight were all lower than control. External examination of the foetuses at necropsy and subsequent detailed skeletal evaluation did not indicate any effect of maternal exposure on foetal development. However, there was a cluster of visceral findings (kinked ureters, dilated ureters, increased renal pelvic cavitation, absent renal papilla misshapen kidneys and absent renal medulla) that indicated a treatment-related disturbance of the normal development of the kidneys and ureters. One litter at 18750 ppm showed five foetuses with gastroschisis and encephalocoele. Despite the limitation of this finding to one litter, the group mean incidence of affected foetuses was higher than both concurrent and historical control values. As this finding was observed in the highest treated group an association with treatment cannot be discounted resulting in confirmation that dietary exposure at 18750 ppm is regarded as an adverse effect level for offspring development.

 

At 3250 and 8750 ppm, there was no effect of dietary exposure on maternal body weight gain or food consumption and pre-implantation loss, implantation count, embryofoetal survival, litter size, sex ratio and mean foetal, litter and placental weight were also considered to be unaffected by maternal exposure at these dietary levels. However, at 8750 ppm, the incidence of foetuses/litters showing kinked ureters, dilated ureters, increased renal pelvic cavitation and absent renal papilla was higher than control and the historical control range, indicating a treatment-related effect on the normal development of the kidneys and ureters. At 3250 ppm, the incidences of foetuses/litters showing kinked ureters or dilated ureters were similar to control and were within the historical control range. However, the incidence of foetuses/litters showing increased renal pelvic cavitation was higher than both concurrent control and the historical control range. While this higher incidence of increased renal pelvic cavitation was only slightly higher than the historical control range, in view of the findings apparent at higher dietary levels, an association with treatment cannot be discounted. However, increased renal pelvic cavitation is frequently observed amongst neonatal and adult animals within this laboratory without any obvious adverse impact of the viability of these animals and may be regarded, to a certain extent, as a variation of the normal. As this finding occurred in the absence of any increased incidence of more significant findings with the potential to effect offspring viability, such as absent renal papilla, and in the absence of any effect on skeletal development, this dietary level could be regarded as a No Observed Adverse Effect Level (NOAEL) for foetal development.

 

Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) for the pregnant rat was considered to be 8750 ppm (equivalent to 715 mg/kg bw/day) and the NOAEL for developmental toxicity was considered to be 3250 ppm (equivalent to 266.7 mg/kg bw/day).

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016b), the test material (Resin acids and rosin acids, esters with triethylene glycol; CAS# 8050-25-7) was administered by continuous dietary admixture to three groups, each composed of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between gestation days 3 and 19 (inclusive) at dietary concentrations 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 258.4, 634.1 or 1268.4 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control. The oral administration of the test material to pregnant rats by continuous dietary admixture from gestation days 3 to 19, at dietary concentrations of 3000, 7500 and 15000 ppm did not result in any treatment related effects. The No Observed Adverse Effect Level (NOAEL) for the pregnant female was considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day).

 

All members of Category 2 with the exception of Resin acids and rosin acids, esters with ethylene glycol (CAS# 68512-65-2) are not classified for reproductive or developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

 

In the OECD 414 study with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) presented above, foetal developmental toxicity was observed at dietary exposure levels below those that resulted in maternal toxicity. This key OECD 414 study provides data to trigger Reproductive Category 2 Classification for Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) under EU CLP. However, the results of the OECD 414 with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) will not be used for read across within the category Rosin, Esters.  H4R commissioned a study to assess and compare the in vitro gut absorption and chemistry of the Ethylene Glycol (EG), Diethylene Glycol (DEG), and Triethylene Glycol (TEG) esters and decided that the appropriate read across for the linear esters developmental toxicity will be from the TEG to the DEG ester.

Following the CXR study, H4R analysed samples of Rosin EG, DEG and TEG esters with GPC.  It was observed that the EG-Rosin was clearly different in its composition from both the DEG-Rosin and TEG-Rosin, in that it had a much larger fraction rosin acids and the mono-EG ester was almost absent, compared to the DEG- and TEG-Rosin esters.  It was concluded that TEG- and DEG-Rosin esters are much more alike with respect to their mono and di-ester compositions and the EG-Rosin ester is unlike the other members of the linear esters subcategory because of the large fraction of rosin acids present.  Consequently, H4R concluded that the most appropriate read across within the linear subcategory is from TEG-Rosin ester  to DEG-Rosin ester. The rationale for this decision is provided in the 'Sameness Report' for EG, DEG, and TEG rosin esters that has been attached to Section 13.

 

Additionally, there is only one registration of Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) and the registrant had stopped production/sale of this substance in the EU.

DNEL Worker long-term-systemic via dermal route

Dose descriptor

A NOAEL of 1272.8 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

100% absorption after ingestion and 100% after skin contact are assumed.

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

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

5 (for worker)

Exposure duration

2 (subchronic 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 dermal-systemic = 1272.8 / 100 = 12.73 mg/Kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.36 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 272.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 272.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

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 / ABSderm-rat) x (ABSderm-rat / ABSderm-human)

 

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

 

                                     = 1272.8 mg/Kg bw/day x (1 / 1) 

 

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).
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:
6.36 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 272.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 272.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

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 / ABSderm-rat) x (ABSderm-rat / ABSderm-human)

 

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

 

                                     = 1272.8 mg/Kg bw/day x (1 / 1) 

 

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).
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

Acute toxicity

No key acute oral toxicity data are available for linear esters of rosin. Key data available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters) and bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; and Resin acids and Rosin acids, esters with pentaerythritol), and supporting data available for Resin acids and rosin acids, esters with diethylene glycol, demonstrate that Rosin esters are not acutely hazardous after ingestion.

 

The physico-chemical properties of the category members indicate that they do not present a hazard with regard to aspiration. Other information for Resin acids and rosin acids, esters with diethylene glycol indicates they are not acutely hazardous after skin contact.

 

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified.

 

Irritation/Sensitisation

No skin or eye irritation data are available for linear esters of rosin. Key data available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters) and bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and Rosin acids, hydrogenated, esters with glycerol; and Resin acids and rosin acids, esters with pentaerythritol) demonstrate that Rosin Esters were not irritating to skin or eye.

 

Other information available for simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me esters), bulky esters of rosin (Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; Resin acids and rosin acids, esters with pentaerythritol; and Resin acids and Rosin acids, hydrogenated, esters with pentaerythritol), along with supporting data from Resin acids and rosin acids, esters with triethylene glycol indicates that Rosin esters are not sensitising in humans, mouse (LLNA) or guinea pig (Maximization Test).

 

Repeated dose toxicity

 

The potential for the members of the sub-category Linear Rosin Esters to cause target organ toxicity following repeated exposure is well understood. Key information is available from two guideline (OECD 408) studies that have investigated the repeated dose oral toxicity of Resin acids and Rosin acids, esters with triethylene glycol and Resin acids and Rosin acids, esters with ethylene glycol.

 

In a key guideline (OECD 408) repeated dose oral toxicity study (Envigo Research Limited, 2017a), the test material (Rosin, esters with ethylene glycol; CAS# 68512-65-2) was administered by continuous dietary admixture to three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 205.7, 506.6 and 1202.5 mg/kg bw/day for males and 243.2, 594.4 and 1377.8 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet only.

  

Based on the results of this ninety-day study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000 ppm (equivalent to 1202.5 mg/kg bw/day for males and 1377.8 mg/kg bw/day for females). The No Observed Effect Level (NOEL) was considered to be 3000 ppm based on non-adverse absolute and relative liver weight changes in males at 7500 ppm and both sexes at 15000 ppm.

 

In a key Guideline (OECD 408) oral repeated dose toxicity study (Envigo Research Limited, 2017b), the test material (Rosin, Triethylene Glycol Ester; CAS# 8050-25-7) was administered by continuous dietary admixture to three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 217.6, 544.6 and 1272.8 mg/Kg bw/day for males and 240.6, 579.4 and 1453.0 mg/Kg bw/day for females). A control group of ten males and ten females were treated with basal laboratory diet.

  

Based on the results observed in this study, the No Observed Adverse Effect Level (NOAEL) for dietary administration of Rosin, Triethylene Glycol Ester (CAS# 8050-25-7) for ninety consecutive days was considered to be 18000 ppm (equivalent to a mean achieved dosage of 1272.8 mg/Kg bw/day for males and 1453.0 mg/Kg bw/day for females). The No Observed Effect Level (NOEL) was considered to be 7500 ppm (equivalent to a mean achieved dosage of 544.6 mg/Kg bw/day for males and 579.4 mg/Kg bw/day for females), based on non-adverse effects observed on absolute and relative liver (both sexes) weights and kidney (male) weights and adaptive centrilobular hypertrophy in male livers at 18000 ppm.

 

The potential for Resin acids and rosin acids, esters with ethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Envigo Research Limited., 2015a) conducted according to OECD Guideline 422. In that study, rats were treated for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No mortality or adverse treatment-related systemic toxicity effects were observed at the highest concentration tested (18000 ppm (male) and 15000 ppm (female)). Based on the results for this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm. 

 

The potential for Resin acids and rosin acids, hydrogenated, esters with triethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study Envigo Research Limited., 2015b) conducted according to OECD Guideline 422. In that study, the test material was administered to rats for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No treatment-related systemic toxicity effects were observed in the study. Based on this, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with diethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2014a) conducted according to OECD Guideline 422. In that study, the test material was administered orally to rats for about eight weeks at concentrations of 3000, 7500 and 15000/18000 ppm. No unscheduled deaths occurred during the study and no treatment-related clinical changes were observed. Microscopic changes in the liver of males and females exposed at the highest concentration and only in males exposed at the mid concentration were observed. Histopathological examination confirmed that this condition is considered to be adaptive in nature. Microscopic kidney changes were observed in one male treated at 18000 ppm and microscopic lung changes were observed in females treated at 18000/15000 ppm. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 3000 ppm for either sex. The ‘No Observed Adverse Effect Level’ (NOAEL) for either sex was therefore considered to be 18000/15000 ppm.

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and rosin acids, esters with diethylene glycol

indicates that the test material was not mutagenic towards five strains ofSalmonella typhimuriumwhen tested in the absence or presence of exogenous metabolic activation.

 

No additional key or supportingin vitrotoxicity data are available for linear esters of rosin. However, data are available from simple and bulky esters of rosin. When tested using mammalian cellsin vitro, in the absence and in the presence of S9 fraction, Resin acids and rosin acids, hydrogenated, Me esters and Resin acids and rosin acids, esters with pentaerythritol were inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in a cytogenetics assay (human lymphocytes).

 

Reproductive / developmental toxicity

Three key reproductive/developmental toxicity screening studies (OECD 422) and two key developmental toxicity studies (OECD 414) are available to evaluate the reproductive toxicity potential of Linear Rosin Esters.

 

The potential for Resin acids and rosin acids, esters with ethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015a) conducted according to OECD Guideline 422. In that study, rats were treated for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No mortality or adverse treatment-related systemic or reproductive toxicity effects were observed at the highest concentration tested (18000 ppm (male) and 15000 ppm (female)). Based on the results for this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, hydrogenated, esters with triethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015b) conducted according to OECD Guideline 422. In that study, the test material was administered to rats for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No treatment-related systemic or reproductive toxicity effects were observed in the study. Based on this, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with diethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2014a) conducted according to OECD Guideline 422. In that study, the test material was administered orally to rats for about eight weeks at concentrations of 3000, 7500 and 15000/18000 ppm. No unscheduled deaths occurred during the study and no treatment-related clinical changes were observed. Microscopic changes in the liver of males and females exposed at the highest concentration and only in males exposed at the mid concentration were observed. Histopathological examination confirmed that this condition is considered to be adaptive in nature. Microscopic kidney changes were observed in one male treated at 18000 ppm and microscopic lung changes were observed in females treated at 18000/15000 ppm. No adverse treatment-related reproductive toxicity effects were observed at the highest concentration tested. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 3000 ppm for either sex. The ‘No Observed Adverse Effect Level’ (NOAEL) for either sex was therefore considered to be 18000/15000 ppm. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 18000/15000 ppm.

 

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017c), the test material (Rosin, esters with ethylene glycol; CAS# 68512-65-2), was administered by continuous dietary admixture to three groups each of twenty-four time mated Sprague-Dawley Crl:CD®(SD) IGS BR strain rats, between gestation days 3 and 19 (inclusive) at dietary concentrations of 3250, 8750, and 18750 ppm (equivalent to a mean achieved dosage of 266.7, 715.0 and 1487.0 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

 

No mortality or signs of clinical toxicity were observed through the study period. Initial dietary exposure at 18750 ppm was associated with a mean body weight loss, thereafter body weight gain was similar to control to gestation day 14. Lower body weight gain was observed from gestation days 14 to 20. During the later stage of gestation, body weight gain in the high exposure group may have been influenced by lower foetal/litter weight, however overall body weight remained lower than control, when adjusted for the contribution of the gravid uterus. Food consumption at this dietary level was lower than control during the first two days of dietary exposure, which probably reflected an initial reluctance to eat the treated diet (due to its palatability), but subsequent food intake was similar to control.

 

For litters at 18750 ppm, there was no effect of maternal exposure on pre-implantation loss, implantation count, embryofoetal survival, litter size or sex ratio but mean foetal, litter and placental weight were all lower than control. External examination of the foetuses at necropsy and subsequent detailed skeletal evaluation did not indicate any effect of maternal exposure on foetal development. However, there was a cluster of visceral findings (kinked ureters, dilated ureters, increased renal pelvic cavitation, absent renal papilla misshapen kidneys and absent renal medulla) that indicated a treatment-related disturbance of the normal development of the kidneys and ureters. One litter at 18750 ppm showed five foetuses with gastroschisis and encephalocoele. Despite the limitation of this finding to one litter, the group mean incidence of affected foetuses was higher than both concurrent and historical control values. As this finding was observed in the highest treated group an association with treatment cannot be discounted resulting in confirmation that dietary exposure at 18750 ppm is regarded as an adverse effect level for offspring development.

 

At 3250 and 8750 ppm, there was no effect of dietary exposure on maternal body weight gain or food consumption and pre-implantation loss, implantation count, embryofoetal survival, litter size, sex ratio and mean foetal, litter and placental weight were also considered to be unaffected by maternal exposure at these dietary levels. However, at 8750 ppm, the incidence of foetuses/litters showing kinked ureters, dilated ureters, increased renal pelvic cavitation and absent renal papilla was higher than control and the historical control range, indicating a treatment-related effect on the normal development of the kidneys and ureters. At 3250 ppm, the incidences of foetuses/litters showing kinked ureters or dilated ureters were similar to control and were within the historical control range. However, the incidence of foetuses/litters showing increased renal pelvic cavitation was higher than both concurrent control and the historical control range. While this higher incidence of increased renal pelvic cavitation was only slightly higher than the historical control range, in view of the findings apparent at higher dietary levels, an association with treatment cannot be discounted. However, increased renal pelvic cavitation is frequently observed amongst neonatal and adult animals within this laboratory without any obvious adverse impact of the viability of these animals and may be regarded, to a certain extent, as a variation of the normal. As this finding occurred in the absence of any increased incidence of more significant findings with the potential to effect offspring viability, such as absent renal papilla, and in the absence of any effect on skeletal development, this dietary level could be regarded as a No Observed Adverse Effect Level (NOAEL) for foetal development.

 

Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) for the pregnant rat was considered to be 8750 ppm (equivalent to 715 mg/kg bw/day) and the NOAEL for developmental toxicity was considered to be 3250 ppm (equivalent to 266.7 mg/kg bw/day).

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016b), the test material (Resin acids and rosin acids, esters with triethylene glycol; CAS# 8050-25-7) was administered by continuous dietary admixture to three groups, each composed of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between gestation days 3 and 19 (inclusive) at dietary concentrations 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 258.4, 634.1 or 1268.4 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control. The oral administration of the test material to pregnant rats by continuous dietary admixture from gestation days 3 to 19, at dietary concentrations of 3000, 7500 and 15000 ppm did not result in any treatment related effects. The No Observed Adverse Effect Level (NOAEL) for the pregnant female was considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day).

 

All members of Category 2 with the exception of Resin acids and rosin acids, esters with ethylene glycol (CAS# 68512-65-2) are not classified for reproductive or developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

 

In the OECD 414 study with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) presented above, foetal developmental toxicity was observed at dietary exposure levels below those that resulted in maternal toxicity. This key OECD 414 study provides data to trigger Reproductive Category 2 Classification for Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) under EU CLP. However, the results of the OECD 414 with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) will not be used for read across within the category Rosin, Esters.  H4R commissioned a study to assess and compare the in vitro gut absorption and chemistry of the Ethylene Glycol (EG), Diethylene Glycol (DEG), and Triethylene Glycol (TEG) esters and decided that the appropriate read across for the linear esters developmental toxicity will be from the TEG to the DEG ester.

Following the CXR study, H4R analysed samples of Rosin EG, DEG and TEG esters with GPC.  It was observed that the EG-Rosin was clearly different in its composition from both the DEG-Rosin and TEG-Rosin, in that it had a much larger fraction rosin acids and the mono-EG ester was almost absent, compared to the DEG- and TEG-Rosin esters.  It was concluded that TEG- and DEG-Rosin esters are much more alike with respect to their mono and di-ester compositions and the EG-Rosin ester is unlike the other members of the linear esters subcategory because of the large fraction of rosin acids present.  Consequently, H4R concluded that the most appropriate read across within the linear subcategory is from TEG-Rosin ester  to DEG-Rosin ester. The rationale for this decision is provided in the 'Sameness Report' for EG, DEG, and TEG rosin esters that has been attached to Section 13.

 

Additionally, there is only one registration of Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) and the registrant had stopped production/sale of this substance in the EU.

DNEL General Population long-term-systemic via dermal route

Dose descriptor

A NOAEL of 1272.8 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

100% absorption after ingestion and 100% after skin contact are assumed.

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

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

General Population

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

10 (for general population)

Exposure duration

2 (subchronic to chronic)

Issues related to reliability of the dose-response

1

Issues related to completeness and consistency of the available data

1

 

Overall AF

200

DNEL General Population long-term dermal-systemic = 1272.8 / 200 = 6.36 mg/Kg bw/day

DNEL General Population long-term-systemic via oral route

Dose descriptor

A NOAEL of 1272.8 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

100% absorption after ingestion and 100% after skin contact are assumed.

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

 

Long-term DNEL Assessment Factors (Oral)

Assessment Factor

General Population

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

10 (for general population)

Exposure duration

2 (subchronic to chronic)

Issues related to reliability of the dose-response

1

Issues related to completeness and consistency of the available data

1

 

Overall AF

200

 

DNEL General Population long-term oral-systemic = 1272.8 / 200 = 6.36 mg/Kg bw/day