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:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
other: NOEL
DNEL value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

Converted dose in ppm to mg/Kg bw/day as follows:

 

Corrected NOEL = Rat NOELOral (10000 ppm) x 0.05 (Adult rat weight assumed to be 0.40 Kg and daily feed consumption (diet) assumed to be 20 grams)

 

Corrected NOEL = 500 mg/Kg bw/day

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)

 

                                       = 500 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

Data for 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 Bulky 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 simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me ester), linear esters of rosin (Resin acids and rosin acids, esters with diethylene glycol), and supporting data from Resin acids and rosin acids, esters with glycerol and Resin acids and rosin acids, esters with pentaerythritol 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

Data for 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 for 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 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 Bulky Rosin Esters to cause target organ toxicity following repeated exposure is well understood. Key information is available from two guideline equivalent (OECD 408) and four supporting studies that have investigated the repeated dose oral toxicity of Resin acids and Rosin acids, hydrogenated, esters with glycerol; Resin acids and Rosin acids, hydrogenated, esters with pentaerythritol; and Resin acids and Rosin acids, esters with glycerol following oral administration to rats.

 

In a key subchronic dietary toxicity study, Staybelite Ester 5 (Resin acids and rosin acids, hydrogenated, esters with glycerol) was administered to 20 rats/sex/group in diets at concentrations of 0, 2000, 5000, or 10000 ppm continuously for 90 days (WIL Research Laboratories, 1987a). An additional 5 rats/sex were administered 0, 5000, or 10000 ppm and were used for an interim sacrifice after 30 days on test. Evaluations were made for morbidity and mortality, clinical signs, food consumption, body weight and weight gain. At necropsy, a battery of hematology, clinical chemistry, and urinalysis studies were conducted; organ weights were measured, and tissues were examined both grossly and microscopically. No toxicity related to the administration of the test material occurred during the study. Statistically significant differences, when observed, were spurious in nature, did not occur in a dose-dependent manner, or were within the historical control range for animals within the test facility. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 10000 ppm for both males and females.

 

In a key subchronic dietary toxicity study, Pentalyn HD-CGR (Resin acids and rosin acids, hydrogenated, esters with pentaerythritol) was administered to groups of 20-25 rats/sex at target concentrations of 0, 0.2, 0.5, or 1.0% (w/w) continuously for up to 91 days (Tegeris Laboratories, Inc., 1985a). Five rats/sex/group were sacrificed after receiving the 0, 0.5, or 1.0 % diets for 30 days and used for an interim evaluation. No toxicity related to the administration of Pentalyn HD-CGR (Resin acids and rosin acids, hydrogenated, esters with pentaerythritol) occurred on the study. There were no significant dose-related effects on mortality, clinical signs, body weights and body weight gains, food consumption, ophthalmoscopic examination, hematology, clinical chemistry or urinalysis parameters, organ weights, or gross or microscopic examination. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1.0% (w/w) for male and female rats.

 

In a supporting subchronic dietary toxicity study, Ester Gum 8BG (Resin acids and rosin acids, esters with glycerol) was administered to 20 Fischer 344 rats/sex/group at dosage levels of 0, 625, 1250, and 2500 mg/kg diet/day for 90 days (International Research and Development Corporation, 1991a). No toxicity related to the administration of Ester Gum 8BG occurred in the study. There were no statistically significant, test substance-related effects on survival, mean body weights, organ weights, food consumption, clinical chemistry parameters, hematology parameters, or ophthalmoscopic, macroscopic or microscopic examination. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 2500 mg/kg diet/day for male and female rats.

 

In a supporting subchronic dietary toxicity study using two samples of Resin acids and rosin acids, esters with glycerol (Ester Gum CGR (Chinese Gum Rosin) or Ester Gum PCR (Portuguese Gum Rosin)), groups of 20 rats/sex were fed diets containing target concentrations of 0, 2000, 5000, and 10000 ppm test substance continuously for 90 days (WIL Research Laboratories, 1989a). An additional 5 rats/sex/group/test substance were administered 0, 5000, or 10000 ppm and were used for an interim sacrifice after 30 days of continuous test-substance treatment. No toxicity related to the administration of resin acids and rosin acids, esters with glycerol (Ester Gum-CGR or Ester Gum-PCR) occurred in the study. All significant findings were spurious in nature, did not occur in a dose-dependent manner, or were within historical control ranges of the test facility. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 10000 ppm for male and female rats.

 

In a supporting subchronic dietary toxicity study, Ester Gum 8D-SP (Resin acids and rosin acids, esters with glycerol) was administered to 15 rats/sex/group at target concentrations of 0.20, 1.0, or 5.0% (w/w) for 90 days (Adria Laboratories Inc., 1982a).  Effects related to the administration of Ester Gum 8D-SP were limited to the 5% treatment group and included initial decreased food consumption (possibly secondary to poor palatability of the test diet) lasting 3-5 weeks for both sexes, increased liver weights in females (associated with very slight or slight periportal hepatic vacuolation) and increased relative liver weight in males. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1% (w/w) for male and female rats.

 

In a supporting dietary toxicity study, Ester Gum 8D (Resin acids and rosin acids, esters with glycerol) was administered to 10 rats/sex/group at target concentrations of 0, 0.2, and 1.0% (w/w) continuously for 28 days (Adria Laboratories Inc., 1985b). No toxicity related to the administration of Ester Gum 8D occurred during the study, including no biologically or statistically significant effects on mortality, morbidity, clinical signs, food consumption, or body weight gain. There were also no treatment-related gross or microscopic changes observed at necropsy. Under the conditions of the study, the NOAEL for systemic toxicity was determined to be 1.0% (w/w) for male and female rats.

 

The potential for Rosin, glycerol ester to cause reproductive toxicity was evaluated in a reproductive and developmental toxicity screening study (Harlan Laboratories Ltd., 2014b) conducted according to OECD Guideline 422. In that study, the test material was administered by continuous dietary admixture to Wistar Han™:RccHan™:WIST rats (12/sex/dose), for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 181.1, 449.1 and 1087.3 mg/kg bw/day respectively for males and 228.5, 537.8 and 1281.1 mg/kg bw/day respectively for females during the pre-pairing phase). The dietary concentration given to the high dosage females during gestation and lactation was decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. A control group of twelve males and twelve females were treated with basal laboratory diet. No mortality was observed through the study period and no treatment-related clinical signs were observed in animals of either sex treated with 3000, 7500 or 18000/15000 ppm. Based on the lack of adverse treatment-related effects observed in this study, the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 18000/15000 ppm in the rat.

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and Rosin acids, esters with pentaerythritol indicates they were not mutagenic towards five strains of Salmonella typhimurium when tested in the absence or presence of exogenous metabolic activation. When tested using mammalian cells in vitro, in the absence and in the presence of S9 fraction 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

Two key reproductive/developmental toxicity screening studies (1 OECD 422 and 1 OECD 421) and two key developmental toxicity studies (OECD 414) are available to evaluate the reproductive and developmental toxicity potential of Bulky Rosin Esters.

 

The potential for Rosin, glycerol ester to cause reproductive toxicity was evaluated in a reproductive and developmental toxicity screening study (Harlan Laboratories Ltd., 2014b) conducted according to OECD Guideline 422. In that study, the test material was administered by continuous dietary admixture to Wistar Han™:RccHan™:WIST rats (12/sex/dose), for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 181.1, 449.1 and 1087.3 mg/kg bw/day respectively for males and 228.5, 537.8 and 1281.1 mg/kg bw/day respectively for females during the pre-pairing phase). The dietary concentration given to the high dosage females during gestation and lactation was decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. A control group of twelve males and twelve females were treated with basal laboratory diet. No mortality was observed through the study period and no treatment-related clinical signs were observed in animals of either sex treated with 3000, 7500 or 18000/15000 ppm. Oral exposure to the test material was not observed to produce any adverse effects on reproductive parameters.  Based on the lack of adverse treatment-related effects observed in this study, the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 18000/15000 ppm in the rat. The NOAEL for reproductive toxicity was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. There were no test substance-related effects on reproductive performance as measured by male and female mating indices or male and female fertility indices. There were also no adverse effects on gestation, gestation index, or mean number of implant sites per pregnancy. No deficiencies in lactation or maternal care were noted during the study. No adverse effects were observed on reproductive organs of either sex at necropsy at received doses of up to 1864 mg/kg bw/d in males and 1757 - 2054 mg/kg bw/d in females. The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity in Sprague-Dawley rats was considered to be 20000 ppm for males and females, equivalent to received doses of 1864 mg/kg bw/d and 1757 -2054 mg/kg bw/d, respectively. 

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016a), the test material (Resin acids and Rosin acids, esters with glycerol; CAS# 8050-31-5) was administered by continuous dietary exposure 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 of 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 241.0, 607.7 or 1227.5 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 or 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 1227.5 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 1227.5 mg/kg bw/day).

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016c), the test material (Resin acids and rosin acids, esters with pentaerythritol; CAS# 8050-26-8) 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 of 3000, 7500 or 15000 ppm (equivalent to a mean achieved dosage of 251.2, 609.5 or 1239.5 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 exposure during gestation days 3 to 19, at concentrations of 3000, 7500 or 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 1239.5 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1239.5 mg/kg bw/day).

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause developmental toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. For dams, no test material-related effects were noted for mean gestation lengths or the process of parturition at any exposure concentration. Mean number of pups born per litter, mean numbers of live pups per litter, birth index, live birth index, viability index, and group mean litter weights were unaffected by maternal exposure. For pups exposed in utero and during lactation, there was no clear evidence of a test substance-related effect on pup survival or development and no visible external abnormalities were observed in the pups prior to study termination. The NOAEL for effects during gestation was 20000 ppm, equivalent to 1757 mg/kg bw/day.

 

Results from repeated dose toxicity tests conducted using Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; and Resin acids and rosin acids, hydrogenated, esters with pentaerythritol revealed no gross or microscopic changes in any reproductive organ at necropsy.

DNEL Worker long-term-systemic via dermal route

Dose descriptor

A NOAEL of 500 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 = 500 / 100 = 5.0 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:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
other: NOEL
DNEL value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

Converted dose in ppm to mg/Kg bw/day as follows:

 

Corrected NOEL = Rat NOELOral (10000 ppm) x 0.05 (Adult rat weight assumed to be 0.40 Kg and daily feed consumption (diet) assumed to be 20 grams)

 

Corrected NOEL = 500 mg/Kg bw/day

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)

 

                                     = 500.0 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:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
other: NOEL
DNEL value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

Converted dose in ppm to mg/Kg bw/day as follows:

 

Corrected NOEL = Rat NOELOral(10000 ppm) x 0.05 (Adult rat weight assumed to be 0.40 Kg and daily feed consumption (diet) assumed to be 20 grams)

 

Corrected NOEL = 500 mg/Kg bw/day

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)

 

                                     = 500.0 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

Data for 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 Bulky 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 simple esters of rosin (Resin acids and rosin acids, hydrogenated, Me ester), linear esters of rosin (Resin acids and rosin acids, esters with diethylene glycol), and supporting data from Resin acids and rosin acids, esters with glycerol and Resin acids and rosin acids, esters with pentaerythritol 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

Data for 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 for 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 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 Bulky Rosin Esters to cause target organ toxicity following repeated exposure is well understood. Key information is available from two guideline equivalent (OECD 408) and four supporting studies that have investigated the repeated dose oral toxicity of Resin acids and Rosin acids, hydrogenated, esters with glycerol; Resin acids and Rosin acids, hydrogenated, esters with pentaerythritol; and Resin acids and Rosin acids, esters with glycerol following oral administration to rats.

 

In a key subchronic dietary toxicity study, Staybelite Ester 5 (Resin acids and rosin acids, hydrogenated, esters with glycerol) was administered to 20 rats/sex/group in diets at concentrations of 0, 2000, 5000, or 10000 ppm continuously for 90 days (WIL Research Laboratories, 1987a). An additional 5 rats/sex were administered 0, 5000, or 10000 ppm and were used for an interim sacrifice after 30 days on test. Evaluations were made for morbidity and mortality, clinical signs, food consumption, body weight and weight gain. At necropsy, a battery of hematology, clinical chemistry, and urinalysis studies were conducted; organ weights were measured, and tissues were examined both grossly and microscopically. No toxicity related to the administration of the test material occurred during the study. Statistically significant differences, when observed, were spurious in nature, did not occur in a dose-dependent manner, or were within the historical control range for animals within the test facility. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 10000 ppm for both males and females.

 

In a key subchronic dietary toxicity study, Pentalyn HD-CGR (Resin acids and rosin acids, hydrogenated, esters with pentaerythritol) was administered to groups of 20-25 rats/sex at target concentrations of 0, 0.2, 0.5, or 1.0% (w/w) continuously for up to 91 days (Tegeris Laboratories, Inc., 1985a). Five rats/sex/group were sacrificed after receiving the 0, 0.5, or 1.0 % diets for 30 days and used for an interim evaluation. No toxicity related to the administration of Pentalyn HD-CGR (Resin acids and rosin acids, hydrogenated, esters with pentaerythritol) occurred on the study. There were no significant dose-related effects on mortality, clinical signs, body weights and body weight gains, food consumption, ophthalmoscopic examination, hematology, clinical chemistry or urinalysis parameters, organ weights, or gross or microscopic examination. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1.0% (w/w) for male and female rats.

 

In a supporting subchronic dietary toxicity study, Ester Gum 8BG (Resin acids and rosin acids, esters with glycerol) was administered to 20 Fischer 344 rats/sex/group at dosage levels of 0, 625, 1250, and 2500 mg/kg diet/day for 90 days (International Research and Development Corporation, 1991a). No toxicity related to the administration of Ester Gum 8BG occurred in the study. There were no statistically significant, test substance-related effects on survival, mean body weights, organ weights, food consumption, clinical chemistry parameters, hematology parameters, or ophthalmoscopic, macroscopic or microscopic examination. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 2500 mg/kg diet/day for male and female rats.

 

In a supporting subchronic dietary toxicity study using two samples of Resin acids and rosin acids, esters with glycerol (Ester Gum CGR (Chinese Gum Rosin) or Ester Gum PCR (Portuguese Gum Rosin)), groups of 20 rats/sex were fed diets containing target concentrations of 0, 2000, 5000, and 10000 ppm test substance continuously for 90 days (WIL Research Laboratories, 1989a). An additional 5 rats/sex/group/test substance were administered 0, 5000, or 10000 ppm and were used for an interim sacrifice after 30 days of continuous test-substance treatment. No toxicity related to the administration of resin acids and rosin acids, esters with glycerol (Ester Gum-CGR or Ester Gum-PCR) occurred in the study. All significant findings were spurious in nature, did not occur in a dose-dependent manner, or were within historical control ranges of the test facility. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 10000 ppm for male and female rats.

 

In a supporting subchronic dietary toxicity study, Ester Gum 8D-SP (Resin acids and rosin acids, esters with glycerol) was administered to 15 rats/sex/group at target concentrations of 0.20, 1.0, or 5.0% (w/w) for 90 days (Adria Laboratories Inc., 1982a).  Effects related to the administration of Ester Gum 8D-SP were limited to the 5% treatment group and included initial decreased food consumption (possibly secondary to poor palatability of the test diet) lasting 3-5 weeks for both sexes, increased liver weights in females (associated with very slight or slight periportal hepatic vacuolation) and increased relative liver weight in males. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1% (w/w) for male and female rats.

 

In a supporting dietary toxicity study, Ester Gum 8D (Resin acids and rosin acids, esters with glycerol) was administered to 10 rats/sex/group at target concentrations of 0, 0.2, and 1.0% (w/w) continuously for 28 days (Adria Laboratories Inc., 1985b). No toxicity related to the administration of Ester Gum 8D occurred during the study, including no biologically or statistically significant effects on mortality, morbidity, clinical signs, food consumption, or body weight gain. There were also no treatment-related gross or microscopic changes observed at necropsy. Under the conditions of the study, the NOAEL for systemic toxicity was determined to be 1.0% (w/w) for male and female rats.

 

The potential for Rosin, glycerol ester to cause reproductive toxicity was evaluated in a reproductive and developmental toxicity screening study (Harlan Laboratories Ltd., 2014b) conducted according to OECD Guideline 422. In that study, the test material was administered by continuous dietary admixture to Wistar Han™:RccHan™:WIST rats (12/sex/dose), for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 181.1, 449.1 and 1087.3 mg/kg bw/day respectively for males and 228.5, 537.8 and 1281.1 mg/kg bw/day respectively for females during the pre-pairing phase). The dietary concentration given to the high dosage females during gestation and lactation was decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. A control group of twelve males and twelve females were treated with basal laboratory diet. No mortality was observed through the study period and no treatment-related clinical signs were observed in animals of either sex treated with 3000, 7500 or 18000/15000 ppm. Based on the lack of adverse treatment-related effects observed in this study, the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 18000/15000 ppm in the rat.

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and Rosin acids, esters with pentaerythritol indicates they were not mutagenic towards five strains of Salmonella typhimurium when tested in the absence or presence of exogenous metabolic activation. When tested using mammalian cells in vitro, in the absence and in the presence of S9 fraction 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

Two key reproductive/developmental toxicity screening studies (1 OECD 422 and 1 OECD 421) and two key developmental toxicity studies (OECD 414) are available to evaluate the reproductive and developmental toxicity potential of Bulky Rosin Esters.

 

The potential for Rosin, glycerol ester to cause reproductive toxicity was evaluated in a reproductive and developmental toxicity screening study (Harlan Laboratories Ltd., 2014b) conducted according to OECD Guideline 422. In that study, the test material was administered by continuous dietary admixture to Wistar Han™:RccHan™:WIST rats (12/sex/dose), for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to a mean achieved dosage of 181.1, 449.1 and 1087.3 mg/kg bw/day respectively for males and 228.5, 537.8 and 1281.1 mg/kg bw/day respectively for females during the pre-pairing phase). The dietary concentration given to the high dosage females during gestation and lactation was decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. A control group of twelve males and twelve females were treated with basal laboratory diet. No mortality was observed through the study period and no treatment-related clinical signs were observed in animals of either sex treated with 3000, 7500 or 18000/15000 ppm. Oral exposure to the test material was not observed to produce any adverse effects on reproductive parameters.  Based on the lack of adverse treatment-related effects observed in this study, the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 18000/15000 ppm in the rat. The NOAEL for reproductive toxicity was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. There were no test substance-related effects on reproductive performance as measured by male and female mating indices or male and female fertility indices. There were also no adverse effects on gestation, gestation index, or mean number of implant sites per pregnancy. No deficiencies in lactation or maternal care were noted during the study. No adverse effects were observed on reproductive organs of either sex at necropsy at received doses of up to 1864 mg/kg bw/d in males and 1757 - 2054 mg/kg bw/d in females. The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity in Sprague-Dawley rats was considered to be 20000 ppm for males and females, equivalent to received doses of 1864 mg/kg bw/d and 1757 -2054 mg/kg bw/d, respectively. 

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016a), the test material (Resin acids and Rosin acids, esters with glycerol; CAS# 8050-31-5) was administered by continuous dietary exposure 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 of 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 241.0, 607.7 or 1227.5 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 or 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 1227.5 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 1227.5 mg/kg bw/day).

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016c), the test material (Resin acids and rosin acids, esters with pentaerythritol; CAS# 8050-26-8) 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 of 3000, 7500 or 15000 ppm (equivalent to a mean achieved dosage of 251.2, 609.5 or 1239.5 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 exposure during gestation days 3 to 19, at concentrations of 3000, 7500 or 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 1239.5 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1239.5 mg/kg bw/day).

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause developmental toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. For dams, no test material-related effects were noted for mean gestation lengths or the process of parturition at any exposure concentration. Mean number of pups born per litter, mean numbers of live pups per litter, birth index, live birth index, viability index, and group mean litter weights were unaffected by maternal exposure. For pups exposed in utero and during lactation, there was no clear evidence of a test substance-related effect on pup survival or development and no visible external abnormalities were observed in the pups prior to study termination. The NOAEL for effects during gestation was 20000 ppm, equivalent to 1757 mg/kg bw/day.

 

Results from repeated dose toxicity tests conducted using Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; and Resin acids and rosin acids, hydrogenated, esters with pentaerythritol revealed no gross or microscopic changes in any reproductive organ at necropsy.

DNEL General Population long-term-systemic via dermal route

Dose descriptor

A NOAEL of 500.0 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 = 500 / 200 = 2.5 mg/Kg bw/day

DNEL General Population long-term-systemic via oral route

Dose descriptor

A NOAEL of 500.0 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 = 500 / 200 = 2.5 mg/Kg bw/day