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Administrative data

Description of key information

Key data is available for Fatty acids, tall oil, oligomeric reaction products with maleaic anhydride and rosin, calcium, magnesium, zinc salts from a Guideline (OECD 422) combined repeated dose, reproductive/developmental toxicity screening study. Additionally, key Guideline (OECD 408, & 414) studies that investigated the repeated dose toxicity potential of Rosin, maleated, a structural analogue 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.

 

OECD 422

 

1) Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium, magnesium, zinc salts (CAS# 160901-14-4): The NOAEL (No Observed Adverse Effect Level) for systemic toxicity was established at a concentration of 15000 ppm (equivalent to mean achieved dosages of 761.3 mg/Kg bw/day (pre-pairing) and 769.9 mg/Kg bw/day (post-pairing) in males and 746.7 mg/Kg bw/day (pre-pairing); 1141.2 mg/Kg bw/day (Gestation); and 1418.2 mg/Kg bw/day (Lactation) in females). The NOEL (No Observed Effect Level) was established at a concentration of 1000 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: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
99.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Adverse histopathological changes in the urinary bladder of both sexes exposed to a dietary concentration of 3000 ppm (equivalent to mean achieved dosages of 195.0 mg/Kg bw/day for males and 241.7 mg/Kg bw/day for females) of the test material.
System:
urinary
Organ:
bladder

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

Key data is available for Fatty acids, tall oil, oligomeric reaction products with maleaic anhydride and rosin, calcium, magnesium salts from a Guideline (OECD 422) combined repeated dose, reproductive/developmental toxicity screening study. Additionally, key Guideline (OECD 408 & 414) studies that investigated the repeated dose toxicity potential of Rosin, maleated, a structural analogue following oral dietary exposure in rats are available. The results are summarized below:

In a key combined repeated dose, reproductive/developmental toxicity study (Harlan Laboratories Ltd., 2015a), the test material (Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium, magnesium, zinc salts (TOFA / rosin and rosin adduct and salts; CAS no. 160901-14-4)) was administered orally in the feed to male rats (12/concentration) for 42 days and to female rats (12/concentration) for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post-partum at concentrations of 0, 1000, 5000, or 15000 ppm.

 

In group 4, slight reductions in food consumption and water consumption and low body weight and body weight gain recorded in males and females were likely due to reduced palatability of the diet at the higher concentration. In addition, differences in bilirubin, cholesterol, creatinine and triglyceride values noted in group 4 were considered not to be adverse in the absence of any histopathological or other related changes. The general lipemic trend (increased cholesterol and triglycerides) in the females of group 4 was not reflected in males and, although the toxicological relevance of this finding is unclear, a possible relationship with the treatment of the test item cannot be excluded.

  

Microscopic findings of minimal hypertrophy/vacuolation of the zona glomerulosa were observed in the adrenal glands of some males and females of group 4. The pathogenesis of this change is uncertain. The zona glomerulosa is the site of synthesis of aldosterone a mineralocorticoid which is mainly involved in the control of salt and water balance in the body. Secretion of aldosterone is controlled through the renin-angiotensin system and hypertrophy of the zona glomerulosa is generally considered to be an adaptive process following stimulation of this system (Domenici Lombardo, 1990) and considered not to be adverse.

 

The decreased adrenal weights recorded at necropsy in males and females of group 4 correlated histologically with hypertrophy. These findings are suggestive of an adaptive response and considered not to be adverse. Marginally low food consumption in males and females and reduced water consumption in females were noted in group 3. No other test item-related effects were noted in males or females at any concentration.

 

Based on these data, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity was established at a concentration of 15000 ppm and the NOEL (No Observed Effect Level) was established at a concentration of 1000 ppm.

Justification for Read Across

Fatty acids, tall oil, oligomeric reaction products with maleaic anhydride and rosin, calcium, magnesium salts and Rosin, maleated are UVCB homologues formed by the reaction of levoprimaric acid present in both with maleic anhydride or maleic acid, with additional neutralisation of fatty acids present in the former to give divalent calcium, magnesium and zinc salts. The Diels-Alder reaction of levopimaric acid with maleic anhydride or male/c acid results in the formation of maleopimaric anhydride or acid and the (cis-) maleopimaric tricarboxylic acid (Soltes and Zinkel, 1989). Overall, these reactions involve Diels-Alder addition of a nucleophile such as maleic anhydride, maleic acid. The reaction products are isomer/c mixtures comprising (i) maleopimaric acid anhydride and (ii) (cis-) maleopimaric tricarboxylic acid.

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 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.

 

Additionally, key data from a Guideline OECD 422 study and supporting data from dose range-finding studies (Harlan Laboratories Ltd., 2014 and Charles River Laboratories, 2017) that were conducted on Rosin, maleated is also available. This data is available in the substance dossier for Rosin, maleated.

 

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).