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:
7.77 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:
777 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
777 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)

 

                                       = 777 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 available for Resin acids and rosin acids, hydrogenated, Me esters demonstrate that Simple 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, hydrogenated, Me esters, 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 available for Resin acids and rosin acids, hydrogenated, Me esters demonstrates that Simple Rosin Esters were not irritating to skin or eye. Other information for Resin acids and rosin acids, hydrogenated, Me esters, indicates that Simple Rosin Esters are not

sensitising in humans or guinea pig (Maximization Test).

 

Repeated dose toxicity

 

The potential for the members of the Simple Rosin Esters sub-category to cause target organ toxicity following repeated exposure is well understood. Key information is available from two Klimisch 1 Guideline equivalent studies that have investigated the repeated

dose oral toxicity of Resin acids and Rosin acids, hydrogenated, Me esters following oral administration to rats.

 

In a key study, performed using two samples of Resin acids and rosin acids, hydrogenated, Me esters having the same composition but manufactured using different processes, groups of 20 male and 20 female rats were given diets containing 0, 100, 500, 2000

and 10000 ppm test substance for up to 13 weeks (Toxicol Laboratories Ltd, 1994a,b). This resulted in received doses of 8-9, 39-45, 155-178 and 782-871 mg/kg bw/d for the sample Hercolyn DR, and 8-9, 39-43, 154-177 and 777-901 mg/kg bw/d for the second sample, Hercolyn DE. There were no significant treatment-related dose-dependent effects on mortality, clinical signs, food consumption, food efficiency, ophthalmoscopic examination, hematology, or urinalysis. Reductions in food consumption in both sexes in the high-dose groups, with a corresponding decrease in mean body weights, were attributed to poor palatability of the test substances. Treatment-related changes occurred primarily in the liver, where increased liver weights were seen in one or both sexes at a dietary concentration of 2000 or 10000 ppm for both test materials. Macroscopic findings included an increase in abnormally shaped livers, which were reported at an incidence of 17-27% in controls (both sexes) versus 45-50% in animals receiving 10000 ppm Hercolyn DR and 50-75% after sub-chronic treatment with 10000 ppm Hercolyn DE. There was also a dose-dependent increase in the incidence of hepatocyte hypertrophy in groups receiving dietary concentrations of 2000 ppm (5% incidence, both samples) or 10000 ppm (50-65% incidence Hercolyn DR; 75% incidence Hercolyn DE) test substance. Except for variations in mean plasma gamma glutamyl transferase levels in high-exposure group females, all other clinical and hematological changes were slight or within the historical control values. The only other microscopic finding of note was thyroid follicular epithelial hypertrophy, which was present at an overall incidence of 12.5% (males and females combined) in animals given 10000 ppm Hercolyn DR or 10000 ppm Hercolyn DE (lower treatment levels unaffected). The authors of the report considered this high-dose finding secondary to perturbation of the pituitary/thyroid axis caused by changes in the liver. All other histological parameters were within the normal range of background changes routinely present in untreated rats of this age and strain. Under the conditions of these studies, the no-effect level for systemic effects was 500 ppm for both test samples. For Hercolyn DR this was equivalent to a NOEL of 39 mg/kg bw/day for males and 45 mg/kg bw/day for females, and equivalent to 39 mg/kg bw/day for males and 43 mg/kg bw/day for females given Hercolyn DE. However, given the minimal histopathological findings together with the small numbers of animals responding at this dietary level, the sub-chronic NOEL for Resin acids and rosin acids, hydrogenated, Me esters is probably closer to 2000 ppm, equivalent to 154-155 mg/kg bw/day for males and 177-178 mg/kg bw/day for females. The no-effect level is considered a NOEL (rather than a NOAEL) since the findings (hepatocyte hypertrophy, thyroid follicular epithelial hypertrophy) appeared adaptive rather than adverse (ECHA, 2012) and therefore of doubtful relevance to humans. The NOAEL for repeated dose toxicity was 777- 901 mg/kg bw/d, the highest dose tested.

 

In a supporting short-term toxicity study (Adria Laboratories Inc, 1985a), Resin acids and rosin acids, hydrogenated, Me esters was administered via the diet to groups of 10 male and 10 female Sprague-Dawley rats at dose levels of 0, 0.2, and 1.0% (10

rats/sex/group) for 28 days (equivalent to received doses of 177-183 mg/kg bw/d and 877-918 mg/kg bw/d, respectively). The study is assigned Rel. 4 since physico-chemical characterization showed that the sample had an atypical softening point, and it is unclear if the sample tested was truly representative of the registered substance. Nonetheless, the study is included for completeness. Clinical findings were sporadic in nature and were not attributed to test substance exposure. A decrease in male body weight gain in animals exposed to 1.0% test material was noted during the first week of exposure but thereafter body weight gains in all test substance-exposed animals were similar to controls, and final body weights were similar among groups. No effects were noted in food consumption or during gross necropsy of any animal in any group.  A slight increase in the size of the zona glomerulosa cells of the adrenal cortex was observed in rats exposed to the test substance at 1.0%, but the change may occur spontaneously, as was seen in one of the control females, and was not determined to be associated with any necrotic, degenerative, or hyperplastic response. Under the conditions of this study, the oral subacute NOAEL for Resin acids and rosin acids, hydrogenated, Me esters in male and female rats was 1.0% in diet, equivalent to a received dose of 877 -918 mg/kg bw/day.

 

In a reproductive/developmental toxicity screening study (Inveresk Research Laboratories, 2003a), 10 rats/sex/group were exposed to Rosin acids and rosin acids, hydrogenated, Me esters (CAS# 8050-15-5) at dose concentrations of 0, 5000, 10000, or 20000 ppm

for 57-59 days (females) or 28 days (males) in the diet. 

 

While mortality occurred in two dams in the 5000 and 10000 ppm treatment groups, the deaths were attributed to problems during parturition. Poor maternal performance was observed in five dams treated with 20000 ppm, and four of the five dams were euthanized

in extremis due to poor overall health. There was a reduction in body weight and food consumption in all groups during the first week of treatment; the reductions remained for animals in the 10000 and 20000 ppm groups. A dose related increase in liver weights in both sexes was associated with an increase in the incidence of hepatocellular hypertrophy across all treatment groups. The authors believe that these findings were considered most likely to reflect an adaptive change in liver metabolism since there was no evidence of cell damage, cholestasis or changes to lipid metabolism revealed by histological examination. It was suggested that this would support the slight increases in alanine transferase, bilirubin and cholesterol levels, although these changes may have been related to increased workload of the liver. The NOAEL for subacute toxicity was considered to be less than 5000 ppm for males (eq. to <405 mg/Kg bw/d) and females (eq. to <476 mg/Kg bw/d).

 

In addition to the studies discussed above, Benchmark Dose Modelling (ICF, 2012) was performed on findings of hepatocyte hypertrophy from the sub-chronic study conducted by Toxicol Laboratories Ltd (1994a,b) and the BMDL (reflecting the 95% lower confidence

limit on the benchmark dose) calculated. BMDL values for males and females given Resin acids and rosin acids, hydrogenated, Me esters via fed were in a range 93.9-222 mg/kg bw/d, equivalent to a mean of 151.7 (SD 52.9) mg/kg bw/d. Reference: ECHA (2012) Guidance on the Application of the CLP Criteria: guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, version 2. European Chemicals Agency, April 2012. 

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and rosin acids, hydrogenated, Me esters indicates they were not mutagenic towards strains of Salmonella typhimurium and strain WP2 of Escherichia coli 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, hydrogenated, Me esters were inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in an in vitromammalian chromosome aberration test (Chinese Hamster Ovary (CHO) cells).

 

Reproductive / developmental toxicity

One key reproductive/developmental toxicity screening study (OECD 422) and one key developmental toxicity study (OECD 414) is available to evaluate the reproductive and developmental toxicity potential of Simple Rosin Esters.

 

In reproductive/developmental toxicity screening study (Inveresk Research Laboratories, 2003a), 10 rats/sex/group were exposed to Rosin acids and rosin acids, hydrogenated, Me esters at dose concentrations of 0, 5000, 10000, or 20000 ppm for 57-59 days

(females) or 28 days (males) in the diet.

 

There were no test material-related effects on mating performance, fertility (as measured by fertility indices), duration of gestation, or reproductive organs in a reproduction and developmental toxicity screening test in which adult male and female rats were exposed

via the diet to target concentrations of 0, 5000, 10000 or 20000 ppm during premating, mating, gestation, and lactation for a total of 28 exposure days for males and 57-59 exposure days for females. At 20000 ppm, there was a slight decrease in the mean number of implant sites per pregnancy, although there were no effects on litter size at birth when compared to the control. There were no effects on the number of live young born at any of the dose levels, or on the number of implants at the lower doses. There were no gross externally visible malformations noted at pup postmortem examinations. 

 

For females in the 20000 and 10000 ppm treatment groups, there was a reduction in food consumption from the start of treatment through study termination and food consumption was markedly reduced during Days 0-4 of lactation. At 5000 ppm, there was also a

slight reduction in food consumption during the pre-mating period, the first two weeks of gestation, and lactation. There was also a dose-dependent reduction in female body weights. Four of the ten 20000 ppm females were sacrificed with their litters on Days 3-4 of lactation as a result of poor maternal performance and the poor performance of their offspring. A fifth animal was not euthanized at this time but also showed poor maternal and pup performance. In the remaining 5 litters at 20000 ppm, pup survival was 100% and, although lower than controls, the mean pup and litter weights increased between Day 1 and 4 of lactation. Mean pup weights and mean litter weights were also lower than the control at 5000 and 10000 ppm. Single deaths in the 5000 and 10000 ppm female dose groups were attributed to problems at parturition and not to test-related toxicity. There was a dose related increase in liver weight in both sexes at all dose levels. Lower weights for a number of other organs in the female exposure groups were considered to reflect the lower body weights of the females. Hepatocyte hypertrophy was observed in all animals treated at mid- and high-exposure levels and in a single animal of each sex at the 5000 ppm exposure level. Thymic atrophy was observed in 3 of the females sacrificed in extremis.

 

Based on previous studies conducted by the same testing facility with other oils and rosins which found that the animals preferred not to eat diet containing these materials, the decrease in food consumption and subsequent decrease in maternal weight may be

indicative of a palatability issue. The dose related increase in liver weights in both sexes was associated with an increase in the incidence of hepatocyte hypertrophy across all exposure groups. These findings were considered by the study authors to reflect an adaptive change in liver metabolism since there was no evidence of cell damage, cholestasis or changes to lipid metabolism that would support the slight increases observed in alanine transferase, bilirubin and cholesterol levels. The poor maternal performance of the adult females treated at 20000 ppm was attributed to reduced body weight and food consumption, and increased metabolic workload during gestation, parturition and lactation. The five females whose litters increased in weight over Days 1 to 4 of lactation had increased liver weights compared to those who didn’t.

 

The NOAEL for reproductive toxicity for males was considered to be 20000 ppm, based on an absence of adverse effects on mating performance or reproductive organs. The NOAEL for reproductive toxicity for females was considered to be 10000 ppm, based on a

slight decrease in the mean number of implant sites per pregnancy in the 20000 ppm exposure group. The NOAEL for developmental toxicity was considered to be <5000 ppm, based on an initial reduction in mean pup weights and mean litter weights in all test groups relative to the controls. This was likely due to maternal toxicity.  

 

Even though some effects were noted with respect to reproductive and developmental parameters, the likely cause of the toxicity is palatability of the test substance in the diet. Under the conditions of the study, the test material is not classified for Reproductive

Toxicity according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. The test material is also not selectively toxic to the developing fetus and is not classified for Developmental Toxicity according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. 

 

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017b), the test material (Resin acids and Rosin acids, methyl ester; CAS# 68186-14-1) 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 3000, 7500, and 15000 ppm. A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

 

No mortality was observed through the study period. Maternal dietary exposure to 15000 ppm of the test material during gestation was associated with lower body weight gain and food consumption compared to control, with differences being particularly marked

during the initial two days of dietary exposure. Although lower litter weight due to reduced foetal weight would have contributed to the lower final body weight and overall weight gain, an underlying effect on the pregnant dam was still clearly present when these values were adjusted for the contribution of the gravid uterus. Despite these marked effects on body weight and food intake, in utero survival of the developing conceptus appeared to be unaffected by maternal exposure to the test item at this dietary level although there was a clear reduction in foetal weight, which resulted in lower litter weight compared to control. The lower foetal weight at 15000 ppm of the test item is suggestive of a retardation of foetal growth and was supported by a slightly increased incidence of small foetuses compared to control.

 

Skeletal examination of the foetuses also revealed statistically significant differences from control for a number of skeletal parameters (increased foetal incidences of unossified areas of the occipital bone, incomplete ossification of the thoracic centrum and less than

four ossified pre-sacral vertebrae and decreased foetal incidence of ossification present in ventral arch of vertebra 1 and one or more forepaw phalanges ossified) consistent with such a retardation of growth. However, lower foetal incidence of incomplete ossification of the parietal, intraparietal and jugal bones, the pubis and the femur also attained statistical significance compared to control: this was considered contradictory to a delay in foetal maturation. Overall, the differences from control for foetal parameters showed a non-specific and inconsistent pattern of delayed ossification.

 

Maternal dietary exposure to 7500 ppm of the test material during gestation was generally well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this most probably reflects an initial reluctance to

eat the diet as subsequent body weight gain was essentially similar to control. Food consumption was statistically significantly lower than control until gestation day 14, although differences were most notable during the first two days of dietary exposure. There was no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

Maternal dietary exposure to 3000 ppm of the test material during gestation was well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this was considered to be of no toxicological significance in

the absence of any effect on overall body weight gain during gestation compared to control. There was no obvious effect of maternal exposure to the test item at a concentration of 3000 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

At 7500 ppm, food consumption was lower than control throughout much of gestation and this lower food intake was associated with lower cumulative body weight gains during gestation. The clear NOAEL was considered to be 3000 ppm (equivalent to 237.3 mg/kg

bw/day). There was no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control. Therefore, 7500 ppm (equivalent to 554.4 mg/kg bw/day) was considered to be the NOAEL for the survival, growth and development of the offspring.

DNEL Worker long-term-systemic via dermal route

Dose descriptor

A NOAEL of 777.0 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

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 = 777.0 / 100 = 7.77 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:
3.885 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:
7.77 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
7.77 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)

 

                                     = 777.0 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:
3.885 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:
777 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
777 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)

 

                                     = 777.0 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 available for Resin acids and rosin acids, hydrogenated, Me esters demonstrate that Simple 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, hydrogenated, Me esters, 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 available for Resin acids and rosin acids, hydrogenated, Me esters demonstrates that Simple Rosin Esters were not irritating to skin or eye. Other information for Resin acids and rosin acids, hydrogenated, Me esters, indicates that Simple Rosin Esters are not

sensitising in humans or guinea pig (Maximization Test).

 

Repeated dose toxicity

The potential for the members of the Simple Rosin Esters sub-category to cause target organ toxicity following repeated exposure is well understood. Key information is available from two Klimisch 1 Guideline equivalent studies that have investigated the repeated

dose oral toxicity of Resin acids and Rosin acids, hydrogenated, Me esters following oral administration to rats.

 

In a key study, performed using two samples of Resin acids and rosin acids, hydrogenated, Me esters having the same composition but manufactured using different processes, groups of 20 male and 20 female rats were given diets containing 0, 100, 500, 2000

and 10000 ppm test substance for up to 13 weeks (Toxicol Laboratories Ltd, 1994a,b). This resulted in received doses of 8-9, 39-45, 155-178 and 782-871 mg/kg bw/d for the sample Hercolyn DR, and 8-9, 39-43, 154-177 and 777-901 mg/kg bw/d for the second

sample, Hercolyn DE. There were no significant treatment-related dose-dependent effects on mortality, clinical signs, food consumption, food efficiency, ophthalmoscopic examination, hematology, or urinalysis. Reductions in food consumption in both sexes in the high-dose groups, with a corresponding decrease in mean body weights, were attributed to poor palatability of the test substances. Treatment-related changes occurred primarily in the liver, where increased liver weights were seen in one or both sexes at a dietary concentration of 2000 or 10000 ppm for both test materials. Macroscopic findings included an increase in abnormally shaped livers, which were reported at an incidence of 17-27% in controls (both sexes) versus 45-50% in animals receiving 10000 ppm Hercolyn DR and 50-75% after sub-chronic treatment with 10000 ppm Hercolyn DE. There was also a dose-dependent increase in the incidence of hepatocyte hypertrophy in groups receiving dietary concentrations of 2000 ppm (5% incidence, both samples) or 10000 ppm (50-65% incidence Hercolyn DR; 75% incidence Hercolyn DE) test substance. Except for variations in mean plasma gamma glutamyl transferase levels in high-exposure group females, all other clinical and hematological changes were slight or within the historical control values. The only other microscopic finding of note was thyroid follicular epithelial hypertrophy, which was present at an overall incidence of 12.5% (males and females combined) in animals given 10000 ppm Hercolyn DR or 10000 ppm Hercolyn DE (lower treatment levels unaffected). The authors of the report considered this high-dose finding secondary to perturbation of the pituitary/thyroid axis caused by changes in the liver. All other histological parameters were within the normal range of background changes routinely present in untreated rats of this age and strain. Under the conditions of these studies, the no-effect level for systemic effects was 500 ppm for both test samples. For Hercolyn DR this was equivalent to a NOEL of 39 mg/kg bw/day for males and 45 mg/kg bw/day for females, and equivalent to 39 mg/kg bw/day for males and 43 mg/kg bw/day for females given Hercolyn DE. However, given the minimal histopathological findings together with the small numbers of animals responding at this dietary level, the sub-chronic NOEL for Resin acids and rosin acids, hydrogenated, Me esters is probably closer to 2000 ppm, equivalent to 154-155 mg/kg bw/day for males and 177-178 mg/kg bw/day for females. The no-effect level is considered a NOEL (rather than a NOAEL) since the findings (hepatocyte hypertrophy, thyroid follicular epithelial hypertrophy) appeared adaptive rather than adverse (ECHA, 2012) and therefore of doubtful relevance to humans. The NOAEL for repeated dose toxicity was 777- 901 mg/kg bw/d, the highest dose tested.

 

In a supporting short-term toxicity study (Adria Laboratories Inc, 1985a), Resin acids and rosin acids, hydrogenated, Me esters was administered via the diet to groups of 10 male and 10 female Sprague-Dawley rats at dose levels of 0, 0.2, and 1.0% (10

rats/sex/group) for 28 days (equivalent to received doses of 177-183 mg/kg bw/d and 877-918 mg/kg bw/d, respectively). The study is assigned Rel. 4 since physico-chemical characterization showed that the sample had an atypical softening point, and it is unclear if

the sample tested was truly representative of the registered substance. Nonetheless, the study is included for completeness. Clinical findings were sporadic in nature and were not attributed to test substance exposure. A decrease in male body weight gain in animals exposed to 1.0% test material was noted during the first week of exposure but thereafter body weight gains in all test substance-exposed animals were similar to controls, and final body weights were similar among groups. No effects were noted in food consumption or during gross necropsy of any animal in any group.  A slight increase in the size of the zona glomerulosa cells of the adrenal cortex was observed in rats exposed to the test substance at 1.0%, but the change may occur spontaneously, as was seen in one of the control females, and was not determined to be associated with any necrotic, degenerative, or hyperplastic response. Under the conditions of this study, the oral subacute NOAEL for Resin acids and rosin acids, hydrogenated, Me esters in male and female rats was 1.0% in diet, equivalent to a received dose of 877 -918 mg/kg bw/day.

 

In a reproductive/developmental toxicity screening study (Inveresk Research Laboratories, 2003a), 10 rats/sex/group were exposed to Rosin acids and rosin acids, hydrogenated, Me esters (CAS# 8050-15-5) at dose concentrations of 0, 5000, 10000, or 20000 ppm

for 57-59 days (females) or 28 days (males) in the diet. 

 

While mortality occurred in two dams in the 5000 and 10000 ppm treatment groups, the deaths were attributed to problems during parturition. Poor maternal performance was observed in five dams treated with 20000 ppm, and four of the five dams were euthanized

in extremis due to poor overall health. There was a reduction in body weight and food consumption in all groups during the first week of treatment; the reductions remained for animals in the 10000 and 20000 ppm groups. A dose related increase in liver weights in both sexes was associated with an increase in the incidence of hepatocellular hypertrophy across all treatment groups. The authors believe that these findings were considered most likely to reflect an adaptive change in liver metabolism since there was no evidence

of cell damage, cholestasis or changes to lipid metabolism revealed by histological examination. It was suggested that this would support the slight increases in alanine transferase, bilirubin and cholesterol levels, although these changes may have been related to increased workload of the liver. The NOAEL for subacute toxicity was considered to be less than 5000 ppm for males (eq. to <405 mg/Kg bw/d) and females (eq. to <476 mg/Kg bw/d).

 

In addition to the studies discussed above, Benchmark Dose Modelling (ICF, 2012) was performed on findings of hepatocyte hypertrophy from the sub-chronic study conducted by Toxicol Laboratories Ltd (1994a,b) and the BMDL (reflecting the 95% lower confidence

limit on the benchmark dose) calculated. BMDL values for males and females given Resin acids and rosin acids, hydrogenated, Me esters via fed were in a range 93.9-222 mg/kg bw/d, equivalent to a mean of 151.7 (SD 52.9) mg/kg bw/d. Reference: ECHA (2012)

Guidance on the Application of the CLP Criteria: guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, version 2. European Chemicals Agency, April 2012. 

 

Genetic toxicity

Results from genetic toxicity testing of Resin acids and rosin acids, hydrogenated, Me esters indicates they were not mutagenic towards strains of Salmonella typhimurium and strain WP2 of Escherichia coli 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, hydrogenated, Me esters were inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in an in vitro mammalian chromosome aberration test (Chinese Hamster Ovary (CHO) cells).

 

Reproductive / developmental toxicity

One key reproductive/developmental toxicity screening study (OECD 422) and one key developmental toxicity study (OECD 414) is available to evaluate the reproductive and developmental toxicity potential of Simple Rosin Esters.

 

In reproductive/developmental toxicity screening study (Inveresk Research Laboratories, 2003a), 10 rats/sex/group were exposed to Rosin acids and rosin acids, hydrogenated, Me esters at dose concentrations of 0, 5000, 10000, or 20000 ppm for 57-59 days

(females) or 28 days (males) in the diet.

 

There were no test material-related effects on mating performance, fertility (as measured by fertility indices), duration of gestation, or reproductive organs in a reproduction and developmental toxicity screening test in which adult male and female rats were exposed

via the diet to target concentrations of 0, 5000, 10000 or 20000 ppm during premating, mating, gestation, and lactation for a total of 28 exposure days for males and 57-59 exposure days for females. At 20000 ppm, there was a slight decrease in the mean number of

implant sites per pregnancy, although there were no effects on litter size at birth when compared to the control. There were no effects on the number of live young born at any of the dose levels, or on the number of implants at the lower doses. There were no gross externally visible malformations noted at pup postmortem examinations. 

 

For females in the 20000 and 10000 ppm treatment groups, there was a reduction in food consumption from the start of treatment through study termination and food consumption was markedly reduced during Days 0-4 of lactation. At 5000 ppm, there was also a

slight reduction in food consumption during the pre-mating period, the first two weeks of gestation, and lactation. There was also a dose-dependent reduction in female body weights. Four of the ten 20000 ppm females were sacrificed with their litters on Days 3-4 of

lactation as a result of poor maternal performance and the poor performance of their offspring. A fifth animal was not euthanized at this time but also showed poor maternal and pup performance. In the remaining 5 litters at 20000 ppm, pup survival was 100% and, although lower than controls, the mean pup and litter weights increased between Day 1 and 4 of lactation. Mean pup weights and mean litter weights were also lower than the control at 5000 and 10000 ppm. Single deaths in the 5000 and 10000 ppm female dose groups were attributed to problems at parturition and not to test-related toxicity. There was a dose related increase in liver weight in both sexes at all dose levels. Lower weights for a number of other organs in the female exposure groups were considered to reflect the lower body weights of the females. Hepatocyte hypertrophy was observed in all animals treated at mid- and high-exposure levels and in a single animal of each sex at the 5000 ppm exposure level. Thymic atrophy was observed in 3 of the females sacrificed in extremis.

 

Based on previous studies conducted by the same testing facility with other oils and rosins which found that the animals preferred not to eat diet containing these materials, the decrease in food consumption and subsequent decrease in maternal weight may be

indicative of a palatability issue. The dose related increase in liver weights in both sexes was associated with an increase in the incidence of hepatocyte hypertrophy across all exposure groups. These findings were considered by the study authors to reflect an adaptive change in liver metabolism since there was no evidence of cell damage, cholestasis or changes to lipid metabolism that would support the slight increases observed in alanine transferase, bilirubin and cholesterol levels. The poor maternal performance of

the adult females treated at 20000 ppm was attributed to reduced body weight and food consumption, and increased metabolic workload during gestation, parturition and lactation. The five females whose litters increased in weight over Days 1 to 4 of lactation had increased liver weights compared to those who didn’t.

 

The NOAEL for reproductive toxicity for males was considered to be 20000 ppm, based on an absence of adverse effects on mating performance or reproductive organs. The NOAEL for reproductive toxicity for females was considered to be 10000 ppm, based on a

slight decrease in the mean number of implant sites per pregnancy in the 20000 ppm exposure group. The NOAEL for developmental toxicity was considered to be <5000 ppm, based on an initial reduction in mean pup weights and mean litter weights in all test

groups relative to the controls. This was likely due to maternal toxicity.  

 

Even though some effects were noted with respect to reproductive and developmental parameters, the likely cause of the toxicity is palatability of the test substance in the diet. Under the conditions of the study, the test material is not classified for Reproductive

Toxicity according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. The test material is also not selectively toxic

to the developing fetus and is not classified for Developmental Toxicity according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. 

 

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017b), the test material (Resin acids and Rosin acids, methyl ester; CAS# 68186-14-1) 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 3000, 7500, and 15000 ppm. A further group of twenty-four time mated females was treated with basal laboratory diet to

serve as a control.

 

No mortality was observed through the study period. Maternal dietary exposure to 15000 ppm of the test material during gestation was associated with lower body weight gain and food consumption compared to control, with differences being particularly marked

during the initial two days of dietary exposure. Although lower litter weight due to reduced foetal weight would have contributed to the lower final body weight and overall weight gain, an underlying effect on the pregnant dam was still clearly present when these values

were adjusted for the contribution of the gravid uterus. Despite these marked effects on body weight and food intake, in utero survival of the developing conceptus appeared to be unaffected by maternal exposure to the test item at this dietary level although there was a clear reduction in foetal weight, which resulted in lower litter weight compared to control. The lower foetal weight at 15000 ppm of the test item is suggestive of a retardation of foetal growth and was supported by a slightly increased incidence of small foetuses compared to control.

 

Skeletal examination of the foetuses also revealed statistically significant differences from control for a number of skeletal parameters (increased foetal incidences of unossified areas of the occipital bone, incomplete ossification of the thoracic centrum and less than

four ossified pre-sacral vertebrae and decreased foetal incidence of ossification present in ventral arch of vertebra 1 and one or more forepaw phalanges ossified) consistent with such a retardation of growth. However, lower foetal incidence of incomplete

ossification of the parietal, intraparietal and jugal bones, the pubis and the femur also attained statistical significance compared to control: this was considered contradictory to a delay in foetal maturation. Overall, the differences from control for foetal parameters showed a non-specific and inconsistent pattern of delayed ossification.

 

Maternal dietary exposure to 7500 ppm of the test material during gestation was generally well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this most probably reflects an initial reluctance to

eat the diet as subsequent body weight gain was essentially similar to control. Food consumption was statistically significantly lower than control until gestation day 14, although differences were most notable during the first two days of dietary exposure. There was

no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

Maternal dietary exposure to 3000 ppm of the test material during gestation was well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this was considered to be of no toxicological significance in

the absence of any effect on overall body weight gain during gestation compared to control. There was no obvious effect of maternal exposure to the test item at a concentration of 3000 ppm on in utero survival of the developing conceptus, foetal litter or placental

weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

At 7500 ppm, food consumption was lower than control throughout much of gestation and this lower food intake was associated with lower cumulative body weight gains during gestation. The clear NOAEL was considered to be 3000 ppm (equivalent to 237.3 mg/kg

bw/day). There was no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to

control. Therefore, 7500 ppm (equivalent to 554.4 mg/kg bw/day) was considered to be the NOAEL for the survival, growth and development of the offspring.

DNEL General Population long-term-systemic via dermal route

Dose descriptor

A NOAEL of 777.0 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 = 777.0 / 200 = 3.885 mg/Kg bw/day

DNEL General Population long-term-systemic via oral route

Dose descriptor

A NOAEL of 777.0 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 = 777.0 / 200 = 3.885 mg/Kg bw/day