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Description of key information

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

 

OECD 408

 

1) Rosin, Maleated (CAS# 8050-28-0): The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 1500 ppm (equivalent to a mean achieved dosage of 99.5 and 120.4 mg/Kg bw/day for males and females respectively due to reduced bodyweight gains and food consumption and adverse histopathological changes in the urinary bladder of both sexes exposed to a dietary concentration of 3000 ppm of the test material.

 

2) Rosin, Fumarated (CAS# 65997-04-8): The No Observed Adverse Effect Level (NOAEL) for systemic toxicity for both sexes was determined to be 10000 ppm (equivalent to a mean achieved dosage of 704.6 mg/kg bw/day for males and 843.4 mg/kg bw/day for females), based on a lack of adverse treatment-related effects observed at the highest concentration tested.

 

OECD 422

 

1) Rosin, Maleated (CAS# 8050-28-0): The No Observed Adverse Effect Level (NOAEL) for systemic toxicity for both sexes was considered to be 3500 ppm, based on effects on food consumption, food efficiency, body weight, and body weight gain observed at 7000 ppm.

 

2) Rosin, Fumarated (CAS# 65997-04-8): The No Observed Effect Level (NOEL) for systemic toxicity for both sexes was determined to be 1000 ppm (males 72 -97 mg/Kg bw/d; females 79 -108 mg/Kg bw/d), based on toxicity observed at levels of 3000 and 10000 ppm, with a decrease in mean body weight at both doses and sexes, an increase in total bilirubin in both sexes at 10000 ppm and a decrease in adrenal gland weight in females at 10000 ppm.

 

OECD 414 

 

1) Rosin, Maleated (CAS# 8050-28-0): The No Observed Effect Level (NOEL) for the pregnant dam was determined to be 500 ppm (equivalent to an achieved dosage of approximately 41.2 mg/Kg bw/day of the test material). The No Observed Adverse Effect Level (NOAEL) for the pregnant dam was considered to be a dietary exposure to 1500 ppm (equivalent to an achieved dosage of approximately 122.9 mg/Kg bw/day of the test material), based on effects observed on body weight gain and food consumption at a dietary concentration of 3000 ppm.

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 Adducts and Rosin Adducts Salts. These are formed when rosin reacts with maleic anhydride (or maleic acid) or fumaric acid yielding a maleated rosin adduct or a fumarated rosin adduct, respectively; the rosin adduct salts are simply the rosin adducts that have been reacted with an appropriate base. The available data includes results obtained from testing Rosin, maleated and Rosin, fumarated and is summarised below.

In a key Guideline (OECD 408) sub-chronic repeated dose oral toxicity study (Envigo Research Laboratories, 2017a), the test material (Rosin, maleated; CAS# 8050-28-0) was administered by continuous dietary admixture to three groups, each composed of ten male and ten female WistarHan™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 500, 1500 and 3000 ppm (equivalent to mean achieved dosages of 33.7, 99.5 or 195.0 mg/Kg bw/day for males and 37.1, 120.4 or 241.7 mg/Kg bw/day for females, respectively). A control group of ten males and ten females were fed basal laboratory diet.

 

Clinical signs, functional observations, body weight change, diet 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 examinations were also performed on animals from the control and high exposure groups 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 level and control animals was performed. Histopathology examinations were also extended to include the urinary bladders from animals in the low and intermediate dietary levels.

 

No mortality or adverse signs of clinical toxicity were observed through the study period. Neurobehavioral parameters, water consumption, ophthalmoscopic parameters, hematological and clinical chemistry parameters remained unaffected by exposure to the test material at concentrations up to 3000 ppm. Gross necropsy did not reveal any remarkable effects and absolute or relative (to body weight) organ weights were not affected by treatment. Males exposed to a dietary concentration of 3000 ppm of the test material generally showed lower mean body weight gain (Weeks 1, 3 and 11, p<0.01: Weeks 5 and 6, p<0.05) throughout the study and statistically significant lower overall mean body weight gain (p<0.01) compared to control. Statistically significant lower mean body weight (p<0.05) was apparent on Days 8, 22 and from Day 36 to termination compared with control. Females exposed to a dietary concentration of 3000 ppm of the test material, showed statistically significant lower overall mean body weight gain (p<0.05) compared to control and statistically significant lower mean body weights were apparent from Day 29 to termination (p<0.05 to p<0.01). Males exposed to a dietary concentration of 1500ppm showed statistically significant lower mean body weight gain (p<0.05) during the first week of the study compared with control. Statistically significant lower mean body weight gain (p<0.01) was also observed during week 11 (Days 71-78). Overall mean body weight gain was slightly, but not statistically significantly lower than control (91% of control). Mean body weights, weekly body weight gains and overall body weight gain for both sexes exposed to a dietary concentration of 500 ppm and females exposed to a dietary concentration of 1500 ppm showed no statistically significant differences from control throughout the study.

 

Males exposed to a dietary concentration of 3000 ppm showed lower food consumption throughout the study compared to control. Females exposed to a dietary concentration of 3000 ppm showed lower food consumption from Week 2, with differences from control being most pronounced during Weeks 2 to 5 and 7 to 9. Males exposed to a dietary concentration of 1500 ppm showed lower food consumption throughout the study, with differences from control being most pronounced from Week 7 onwards. For females exposed to a dietary concentration of 1500 ppm of the test material, food consumption also tended to be lower than control from Week 2, but a clear association with dietary exposure was not proven. For both sexes exposed to a dietary concentration of 500 ppm, food consumption was considered to be unaffected by treatment. Food conversion efficiency was unaffected by exposure to the test material at concentrations up to 3000 ppm.

 

Minimal to moderate urothelial hyperplasia was present in 3/8 males and 6/9 females exposed to a dietary concentration of 3000 ppm of the test item, with accompanying minimal to mild inflammatory changes also being present in 5/9 females.

 

Based on the results of this ninety-day study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity of Rosin, maleated was considered to be 1500 ppm (equivalent to a mean achieved dosage of 99.5 and 120.4 mg/Kg bw/day for males and females respectively due to reduced bodyweight gains and food consumption and adverse histopathological changes in the urinary bladder of both sexes exposed to a dietary concentration of 3000 ppm of the test material.

 

In another Key Guideline (OECD 408) sub-chronic repeated dose toxicity study (Envigo Research Laboratories, 2016a), the test material (Rosin, Fumarated; CAS# 65907-04-8) was administered continuously 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 5000, 7500 and 10000 ppm (equivalent to mean achieved dosages of 356.3, 527.4 or 704.6 mg/Kg bw/day for males and 416.9, 593.9 or 843.4 mg/Kg bw/day for females). A control group 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 exposure 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. Oral administration of the test material to rats by continuous dietary admixture resulted in an initial reduction in body weight gain for both sexes at all exposure levels during the first week of treatment. Although overall body weight gain for females in the high exposure group was lower than control females, recovery was evident in males from all exposure levels and in females exposed to 7500 or 5000 ppm of the test item. In the absence of any toxicologically significant effects detected in the haematological or blood chemical parameters examined, organ weights measured or any histopathological changes the effect on body weight was not considered to represent an adverse effect of treatment (Lewis et al., 2002).

 

The No Observed Adverse Effect Level (NOAEL) for systemic toxicity for both sexes was therefore determined to be 10000 ppm (equivalent to a mean achieved dosage of 704.6 mg/Kg bw/day for males and 843.4 mg/Kg bw/day for females).

In a Guideline (OECD 422) combined repeated dose, reproductive/developmental toxicity screening study (Harlan Laboratories Ltd, 2015a), the test material (Rosin, maleated; CAS# 8050-28-0) was administered daily in dietary mixtures at concentrations of 0, 1750, 3500 or 7000 ppm to male rats for 43 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.

  

Adverse toxic effects were observed in females in group 4 (7000 ppm) during the pre-pairing period. A severe reduction in food consumption resulting in body weight loss, significantly reduced body weights and significantly reduced food conversion efficiency were recorded. Further, clinical signs indicating worsening of the animal condition like stiff gate, hunched posture and ruffled fur were observed in most females in this group between days 12 and 14 of the pre-pairing period. Four females were found dead between day 12 and 14 and remaining females were terminated for ethical reasons on day 14 of the pre-pairing period. During necropsy, reddish discoloration of the cecum was observed in one female. This finding was histologically correlated with moderate submucosal edema/congestion. In one further female, pale discoloration of kidney and pelvic dilation was observed during the necropsy and histopathological examination confirmed kidney as a target organ in the females in the high concentration group. The pathogenesis of these changes was uncertain; however an acute/subacute impairment of the urinary outflow was suspected. The kidney findings did not appear to be linked to the cause of death as its grade severity was higher in animals killed in extremis when compared to animals found dead. Starvation caused by the aversion to test item containing food possibly contributed to the effects on body weights. However, there was no clear evidence that the food aversion was the immediate reason of the severity of the effects and bad condition of females. Thus, the reason for the mortality of females in the high-dose group remained unclear.

 

Treatment-related reduction in food consumption, food conversion efficiency, water consumption, body weight gain and body weights were also observed in males in the high concentration group (7000 ppm), however, less severe than in females. Although food and water consumption remained also slightly lower during the entire study, they recovered after the significant reduction observed at the beginning of the treatment. A body weight loss was observed at the beginning of the treatment followed by a reduced body weight gain. This resulted in reduced body weights observed until the end of the study.

 

During necropsy of males in the high concentration group, reduced adrenal weights were recorded but no other macroscopic findings. Histopathological examination revealed minimal decreased lymphocytes in the spleen and mesenteric lymph nodes which was considered to be a result of a non-specific stress.

 

In group 3 (3500 ppm), a slight and reversible reduction in food consumption and food conversion efficiency was observed in males and females. This resulted in a slight and reversible reduction in body weights, however without an effect on absolute body weights. A slight reduction in water consumption was recorded in males. During necropsy, reduced adrenal weights were recorded in females. Histopathological examination revealed no test item-related findings in any gender. No further test item-related effects were observed in any group. No test item-related findings were recorded in group 2 (1750 ppm).

 

Based on the results of this study, a NOAEL (No Observed Adverse Effect Level) for systemic toxicity was established at the dose level of 3500 ppm.

 

In a Guideline (OECD 422) combined repeated dose reproductive/developmental toxicity study (Inveresk Research, 2004a), Rosin fumarated was administered in the diet to rats at concentrations of 0, 1000ppm (males 72 -89 mg/Kg bw/d; females 79 -108 mg/Kg bw/d), 3000 ppm (males 221 -288 mg/Kg bw/d; females 196 -292 mg/Kg bw/d), and 10000 ppm (males 651 -889 mg/Kg bw/d; females 449 -995 mg/Kg bw/d). The males were treated for 2 weeks prior to mating, through until necropsy after 4 weeks of treatment. The females were treated for 2 weeks prior to mating, then through mating, gestation and until termination on at least Day 4 of lactation.

 

Under the conditions of this study, parental toxicity was exhibited at levels of 3000 and 10000 ppm, with a decrease in mean body weight at both doses and sexes, an increase in total bilirubin in both sexes at 10000 ppm and decrease in adrenal gland weight in females at 10000 ppm, but there were no clear effects of toxicity at 1000 ppm. Therefore, the parental NOEL was considered to be 1000 ppm (males 72 -97 mg/Kg bw/d; females 79 -108 mg/Kg bw/d). For reproductive parameters, the NOEL was considered to be 3000 ppm (females: 196 -268 mg/Kg bw/d).

In a key Guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Laboratories, 2017b), the test material (Rosin, maleated; CAS# 8050-28-0) was administered by continuous dietary admixture to three groups each composed of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between gestation days 3 and 19 (inclusive) at dietary concentrations of 500, 1500, and 3000 ppm equivalent to mean achieved dosages of approximately 41.2, 122.9 and 217.4 mg/Kg bw/day. A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

  

No mortality was and no clinical signs were apparent for adult females throughout the study at dietary concentrations of 500, 1500 or 3000 ppm of the test material.

 

At a dietary concentration of 3000 ppm of the test material, marginal mean body weight loss was apparent during the first day of dietary exposure and subsequent bodyweight gains were often statistically significantly lower than control animals throughout gestation. Cumulative body weight gain from the start of treatment was statistically significantly lower than control animals from gestation day 5 and overall body weight gain, when adjusted for the contribution of the gravid uterus, remained statistically significantly lower than control. In rats exposed to 1500 ppm of the test material, statistically significantly lower body weight gain was apparent during gestation days 17 to 20. Prior to this, no statistically significant difference in body weight gain had been apparent and there were no statistically significant differences from control animals apparent for cumulative body weight gain, including overall body weight gain when adjusted for the contribution of the gravid uterus. No statistically significant differences in body weight gain during gestation were apparent for females that received 500 ppm of the test material. Food consumption throughout gestation was statistically significantly lower in rats exposed to the test material at 3000 ppm when compared with control animals. No obvious effects on food consumption during gestation were observed in animals exposed to the test material at 500 or 1500 ppm. Gross necropsy on Gestation Day 20, did not reveal any remarkable findings (macroscopic abnormalities) in adult animals in any of the treatment groups.

  

Based on the results of this study, dietary exposure to 500 ppm of the test material (equivalent to an achieved dosage of approximately 41.2 mg/Kg bw/day of the test material) was considered to be a clear No Observed Effect Level (NOEL) for the pregnant dam. The No Observed Adverse Effect Level (NOAEL) for the pregnant dam was considered to be a dietary exposure to 1500 ppm of the test item (equivalent to an achieved dosage of approximately 122.9 mg/Kg bw/day of the test material), due to effects on body weight gain and food consumption apparent at a dietary level of 3000 ppm.

 

In a supporting dose range-finding toxicity study, the test material (Rosin, Maleated, CAS # 8050-28-0) was administered to four groups of 3 males and 3 female rats at dose levels of 0, 5000, 10000 and 20000 ppm.

 

The results of the study show a dose-dependent reduction in food consumption resulting in effects on body weights and body weight gain. Water consumption was also slightly reduced in all dose-groups. At the high dose levels, adverse effects on food consumption and body weight gain were observed in both genders. Body weight loss was recorded in both sexes from treatment start until termination of this group. In addition, ruffled fur was observed in males and females at high-dose level. Due to these observations males and females were terminated for ethical reasons prior to schedule. In group 3, animals recovered in food consumption followed by a slight reduction at the end of the treatment.

 

Reduction of food consumption was accompanied by body weight loss in both sexes. In group 2, reduction in food consumption was less pronounced and reversible, although also in this group values remained slightly lower than control values until the end of the study. Reduced body weight gain and reduced body weights were recorded in males and females during the entire study period with slight body weight loss at the beginning of the treatment. These values recovered partially during the study, although remained lower than control values until the end of the study.

 

Based on the results of the study, the dose level selected for the OECD 422 screening study to be conducted on the test material Rosin maleated are 0, 1750, 3500 and 7000 ppm.

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).