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Administrative data

Description of key information

Information is available on the oral repeated dose toxicity of Rosin esters (simple, linear, and bulky). No treatment-related or biologically relevant findings were apparent in rats following oral sub-chronic dietary exposure to Resin acids and rosin acids, esters with glycerol, Resin acids and rosin acids, esters with ethylene glycol, Resin acids and rosin acids, esters with triethylene glycol, Resin acids and rosin acids, hydrogenated, esters with glycerol and Resin acids and rosin acids, hydrogenated, esters with pentaerythritol.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Adequate information is available to characterise the oral repeated dose toxicity of Rosin esters (simple, linear, and bulky).

Simple Rosin Esters

 

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 subacute 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. 

 

Linear Rosin Esters

 

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

 

Clinical signs, functional observations, bodyweight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on control group and high dose animals before the start of treatment and during Week 12 of the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of tissues from high dose and control animals was performed.

 

The continuous oral (dietary) administration of the test material in the diet for ninety consecutive days was well tolerated and was not associated with any obvious signs of systemic toxicity for animals of either sex. There were no effects of dietary exposure indicated by body weight performance, food and water consumption, food conversion efficiency, functional observations or ophthalmic examinations. Hematological investigations did not reveal any adverse effect of treatment; however, blood chemical evaluations did reveal a number of statistically significant intergroup differences. Males fed diet containing 18000 ppm showed lower albumin and total protein and higher cholesterol and bilirubin levels. The effect on albumin was also evident in males fed diet containing 7500 ppm. Higher bilirubin levels were also evident in females fed diet containing 18000 ppm. In animals of either sex fed diet containing 18000 ppm and males fed diet containing 7500 ppm, liver weights both absolute and relative to terminal body weight were higher than controls. These intergroup differences in blood chemistry and organ weights may be a consequence of enhanced hepatic metabolism and turnover as a by-product of xenobiotic metabolism. However, due to the lack of pathological changes in the liver, these intergroup differences may represent altered metabolic function but these occurred in the absence of adverse gross or microscopic hepatic effects after ninety consecutive days of dietary exposure.

 

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

 

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

 

Clinical signs, functional observations, bodyweight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on control group and high dietary level animals before the start of treatment and during Week 12 of the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of tissues from high dose and control animals was performed.

 

No mortality was observed through the study period and dietary exposure to the test material for a period of ninety consecutive days at 3000, 7500 or 18000 ppm was well tolerated and was not associated with any obvious signs of adverse systemic toxicity in rats of either sex.

 

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

 

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

 

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

 

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

 

Bulky Rosin Esters

 

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 subacute 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.

Justification for classification or non-classification

Not classified for specific target organ toxicity – repeated exposure according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).