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Description of key information

Several key Guideline (OECD 408, 414, 421, & 422) studies that investigated the repeated dose toxicity potential of Rosin Adduct Esters following oral dietary exposure in rats are available. The results are summarized below:

 

OECD 408

1) Rosin acids and resin acids, maleated, esters with pentaerythritol (CAS# 94581-17-6): The systemic toxicity NOAEL was determined to be 3000 ppm (equivalent to mean achieved dosages of 209.1 mg/Kg bw/day for males and 248.7 mg/Kg bw/day for females), based on histopathological changes apparent in both the liver and urinary bladder in animals exposed at the 6000 ppm and 12000/15000 ppm concentration levels.

 

2) Resin acids and Rosin acids, fumarated, esters with pentaerythitol (CAS# 94581-15-4): The NOAEL for systemic toxicity was considered to be 18000 ppm (equivalent to a mean achieved dosage of 1090.0 mg/Kg bw/day for males and 1298.9 mg/Kg bw/day for females), based on based on the lack of adverse treatment-related effects observed through the study period.

 

3) RARA, fumarated, esters with glycerol (CAS# 97489-11-7): The NOAEL for systemic toxicity was determined to be 18000 ppm for female rats (equivalent to mean achieved dosages of 1482.2 mg/Kg bw/day) and 7500 ppm (equivalent to mean achieved dosages of 574.0 mg/Kg bw/day) for male rats, based on treatment-related effects observed in male rats exposed at 18000 ppm.

OECD 422

 

1) Resin acids and rosin acids, maleated, esters with pentaerythritol (CAS# 94581-17-6): The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 3000 ppm (equivalent to a mean achieved dosage of 179.3 mg/Kg bw/day in males and 221.5 mg/Kg bw/day in females), based on effects on body weight gain, food consumption and adverse histopathological changes in the kidney and urinary bladder at 7500 ppm and 18000/12000 ppm.

 

2) Resin acids and rosin acids, fumarated, esters with glycerol (CAS# 97489-11-7): The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 7500 ppm for either sex (equivalent to a mean achieved dosage of 432.2 mg/Kg bw/day in males and 544.4 mg/Kg bw/day in females), based on microscopic lung changes in animals of either sex treated with 18000/15000 ppm, microscopic urinary bladder changes in females treated with 18000/15000 ppm and microscopic prostate changes in males treated with 18000 or 7500 ppm.

 

3) Resin acids and rosin acids, fumarated, esters with pentaerythritol (CAS# 94581-15-4): The No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was established to be 300 mg/Kg/day, based on evidence of limited systemic effects (microscopic changes in the urinary bladder) observed in animals in the 1000 mg/Kg bw/day dose group.

 

4) Rosin, fumarated (CAS# 65997-04-8): The No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was established to be 3000 ppm (equivalent to 221-288 mg/Kg bw/d in males, and 196-292 mg/Kg bw/d in females), based on decreased food consumption and mean body weights in parental animals of both sexes at 10,000 ppm and 3000 ppm, with high dose animals also showing an increase in total bilirubin (both sexes) and decreased adrenal weight (females only).

 

OECD 421

 

1) Resin acids and rosin acids, esters with pentaerythritol (CAS# 8050-26-8): The NOAEL was determined to be 20000 ppm (equivalent to received doses of 1864 mg/Kg bw/d in males and 1757 -2054 mg/Kg bw/d in females, respectively), based on lack of adverse treatment-related effects observed on reproductive performance or other parameters evaluated in the study.

 

2) Rosin (CAS# 8050-09-7): The NOAEL for systemic toxicity was considered to be 1000 ppm in males (equivalent to 84 mg/Kg bw/day) and 3000 ppm in females (equivalent to 309 mg/Kg bw/day), based on reduced feed consumption and lower weight gain in animals consuming higher dietary concentrations of the test material. 

 

OECD 414

 

1) Resin acids and rosin acids, fumarated esters with glycerol (CAS# 97489-11-7): The systemic toxicity NOAEL was determined to be 7500 ppm (equivalent to a mean achieved dosage of 622.2 mg/kg bw/day), based on lower maternal body weight gain during gestation and an initial effect on food consumption observed in animals treated at the 15000 ppm concentration level.

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

Information exists to characterise the repeated dose toxicity of Rosin adduct esters. These are formed after modification of rosin with either fumaric acid or maleic anhydride followed by esterification with glycerol and/or pentaerythritol, and hence the adduct ester products therefore exhibit close structural similarities. The available data includes results obtained from testing Resin acids and rosin acids, fumarated, esters with glycerol; Resin acids and rosin acids, fumarated, esters with pentaerythritol; and Resin acids and rosin acids, maleated, esters with pentaerythritol with supporting information on Rosin, fumarated (precursor substance). This information is summarised below.

In a key oral repeated dose toxicity test conducted according to OECD Guideline 408 (Envigo Research Limited, 2017a), the test material (Resin acids and Rosin-acids, maleated, esters with pentaerythritol’ CAS# 94581-17-6) was administered in the diet 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, 6000 or 12000/15000 ppm (equivalent to mean achieved dosages of 209.1, 413.2 or 903.7 mg/Kg bw/day for males and 248.7, 436.7 or 1069.4 mg/Kg bw/day for females). The highest dietary level was increased from 12000 ppm to 15000 ppm after four weeks of treatment to maximise the achieved dosage for this dose group as the study progressed. A control group composed of ten males and ten females was fed basal laboratory diet.

 

Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Haematology 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 dietary concentration and control animals was performed. Histopathological evaluations were extended to lower dietary concentration for selected tissues.

 

No unscheduled mortality was observed through the study period and there were no obvious clinical effects of dietary exposure to test material at concentrations of 3000, 6000 or 12000/15000 ppm for either sex. Behavioural assessment, functional performance, and sensory reactivity assessments remained unaffected post treatment with the test material and there were no effects observed on food conversion efficiency, water consumption, or ophthalmoscopic parameters evaluated in animals of either sex. 

 

Dietary exposure to the test material at a concentration of 12000/15000 ppm was associated with adverse histopathological findings in the liver and urinary bladder. At a dietary exposure level of 6000 ppm, similar histopathological changes were apparent in both the liver and urinary bladder and, although the incidence was lower than observed at 12000/15000 ppm, these findings were considered to be adverse. At the 3000 ppm dietary exposure level, the adverse histopathological changes observed at higher exposure levels were not apparent and histopathological changes were limited to a low incidence of increased adipose tissue in the sternum bone marrow, which was considered to reflect individual variation and to be of no toxicological significance. Although occasional differences from control were observed for some blood chemistry parameters at the 3000 ppm level they were not regarded as adverse effects. Consequently, the No Observed Adverse Effect Level (NOAEL) of RARA, maleated, esters with pentaerythritol when administered via the diet for 90 consecutive days was considered to be 3000 ppm (equivalent to mean achieved dosages of 209.1 mg/kg bw/day for males and 248.7 mg/kg bw/day for females).

 

In a second key oral sub-chronic toxicity study (Envigo Research Limited, 2016a), the test material (Resin acids and Rosin acids, fumarated, esters with pentaerythitol; CAS# 94581-15-4) was administered by continuous dietary exposure to Wistar Han™:RccHan™:WIST strain rats (10/sex/concentration), for ninety consecutive days, at dietary concentrations of 3000 and 6000 ppm for the low and intermediate concentration groups (equivalent to a mean achieved dosage of 210.0 and 414.1 mg/Kg bw/day for males and 262.4 and 511.2 mg/Kg bw/day for females). For the high concentration group, rats were initially fed diet containing 12000 ppm for two weeks followed by 15000 ppm for four weeks and subsequently 18000 ppm for the remainder of the study (equivalent to a mean achieved dosage of 1090.0 mg/Kg bw/day for males and 1298.9 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. Haematology 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 study week 12. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of tissues from high concentration and control animals was also performed.

 

The continuous oral (dietary) administration of the test material for ninety consecutive days, did not result in any toxicologically significant effects. Therefore, based on the lack of adverse treatment-related effects observed through the study period, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity for both sexes was determined to be 18000 ppm (equivalent to a mean achieved dosage of 1090.0 mg/Kg bw/day for males and 1298.9 mg/Kg bw/day for females).

 

In another key oral sub-chronic toxicity study (Envigo Research Limited, 2015a), the test material (RARA, fumarated, esters with glycerol; CAS# 97489-11-7) was administered by continuous dietary admixture Wistar Han™:RccHan™:WIST strain rats (10/sex/concentration), for ninety consecutive days, at nominal dietary concentrations of 3000, 7500 and 18000 ppm (equivalent to mean achieved dosages of 211.9, 574.0 and 1296.1 mg/Kg bw/day for males and 248.1, 598.9 and 1482.2 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, body weight change, food 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 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.

 

Continuous oral dietary administration of the test material resulted in reduced body weight gain in males treated with 18000 ppm. There were no clinical signs evident for animals of either sex treated with 3000, 7500 or 18000 ppm. The body weight development of high dose males was reduced relative to controls during Weeks 1, 3, 4 and 7 of treatment. Subsequently a 10% reduction in overall body weight gain was evident in these males. No consistent effect on body weight gain was evident in females and no adverse effect was evident in food consumption for either sex. Therefore, the effect on body weight gain in males was most likely associated with test item toxicity rather than a palatability effect.

 

Some statistically significant differences in hematological and blood chemistry parameters were observed in treated animals relative to controls. However, majority of individual values were within the expected normal ranges for rats of the strain and age used. Therefore, these differences were not considered to be toxicologically significant. Macroscopic and microscopic examinations did not reveal any treatment related effects in treated animals.

 

Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) for RARA, fumarated, esters with glycerol was determined to be 18000 ppm for female rats and 7500 ppm for male rats.

Resin acids and rosin acids, maleated, esters with pentaerythritol (CAS# 94581-17-6) was administered in the diet to three groups, each composed of twelve male and twelve female Wistar Han™:RccHan™ WIST strain rats, 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 (Envigo Research Limited, 2017b). The dietary concentration given to the high dietary concentration females during gestation and lactation was initially decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. However, due to adverse toxicity, the high dietary concentration was reduced to 12000 ppm for both sexes on study day 22. The NOAEL for systemic toxicity was considered to be 3000 ppm, principally due to effects on body weight gain, food consumption and adverse histopathological changes in the kidney and urinary bladder at 7500 ppm and 18000/12000 ppm.

Resin acids and rosin acids, fumarated, esters with glycerol (CAS# 97489-11-7) was administered to rat by gavage at concentrations of 3000, 7500, or 18000/15000 ppm (Harlan Laboratories Ltd., 2014). The result of the study showed microscopic lung changes in animals of either sex treated with 18000/15000 ppm, microscopic urinary bladder changes in females treated with 18000/15000 ppm and microscopic prostate changes in males 18000 or 7500 ppm. The ‘No Observed Effect Level (NOEL) for systemic toxicity was considered to be 7500 ppm for either sex. 

 

Resin acids and rosin acids, fumarated, esters with pentaerythritol was administered by oral gavage to male and female rats at treatments levels of 0, 30, 300 or 1000 mg/Kg bw/g for approximately 6-7 weeks (Harlan Laboratories Ltd, 2010b). Treatment-related changes in bladder (comprising epithelial hyperplasia, ulceration and erosion with associated subepithelial oedema and inflammation) seen at 1000 mg/Kg/day but not at any other treatment level. The condition was more prevalent among females. A NOAEL of 300 mg/Kg/day for systemic toxicity was established by this study.

In a supporting study, Rosin, fumarated (the precursor of Rosin, fumarated, esters with pentaerythritol) was administered in the diet to male and female rats at concentrations of 0, 1000 ppm, 3000 ppm and 10000 ppm for approximately 6-7 weeks (Inveresk Research, 2004). Food consumption and mean body weights were decreased in both sexes at 10000 ppm and 3000 ppm, with high dose animals also showing an increase in total bilirubin (both sexes) and decreased adrenal weight (females only).  The lower of these two values will be used as the NOAEL for the repeated dose toxicity. This is considered a scientifically defensible since, apart from poor palatability and associated body weight reduction following exposure to 10000 ppm test substance, no clearly adverse effects were apparent. The NOAEL for repeated dose toxicity of Rosin, fumarated is therefore 221-228 mg/Kg bw/d for males and 196-292 mg/Kg bw/d for females.

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 orUN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).