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Effects on fertility

Description of key information

One key Guideline (OECD 422) study was identified for Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts.

The NOAEL for reproductive toxicity was determined to 5000 ppm (equivalent to mean achieved dosages of 327.1 mg/Kg bw/day (pre-pairing); 381.6 mg/Kg bw/day (Gestation); and 591.0 mg/Kg bw/day (Lactation) in female rats), based on lower mean number of corpora lutea and implantations per dam, number of live pups at the first litter check and living pups on day 4 post-partum observed at the 15000 ppm concentration level.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
327.1 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The NOAEL of 327.1 mg/Kg bw/day presented above is for the pre-pairing phase. The equivalent mean achieved dosages during gestation and lactation were 381.6 mg/Kg bw/day and 591.0 mg/Kg bw/day, respectively in female rats.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

One key Guideline (OECD 422) study was identified forFatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts.

In a 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 the 15000 ppm concentration group, 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 the 15000 ppm concentration group 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.

 

Reproduction parameter changes showed a lower mean number of corpora lutea and implantations per dam, number of live pups at the first litter check and living pups on day 4 post partum in the high concentration group.

 

There was also a higher incidence of red discoloured lungs in the pups at this concentration. Microscopic findings of minimal hypertrophy/vacuolation of the zona glomerulosa were observed in the adrenal glands of some males and females in the high concentration group. 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 in the 15000 ppm concentration group 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 animals exposed to the test material at 5000 ppm. 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.

 

The NOAEL and NOEL for reproductive toxicity was established at a concentration of 5000 ppm, the middle dose level used in the study.

Additionally, key data from a Guideline OECD 422 study (Harlan Laboratories Ltd., 2015) that was conducted on Rosin, maleated is also available. This data is available in the substance dossier for Rosin, maleated.

Effects on developmental toxicity

Description of key information

One key Guideline (OECD 422) reproductive/developmental toxicity study that tested Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts was identified.

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 for developmental toxicity was determined to 5000 ppm (equivalent to mean achieved dosages of 327.1 mg/Kg bw/day (pre-pairing); 381.6 mg/Kg bw/day (Gestation); and 591.0 mg/Kg bw/day (Lactation) in female rats), based on lower mean number of corpora lutea and implantations per dam, number of live pups at the first litter check and living pups on day 4 post-partum observed at the 15000 ppm concentration level.

 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
327.1 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The NOAEL of 327.1 mg/Kg bw/day presented above is for the pre-pairing phase. The equivalent mean achieved dosages during gestation and lactation were 381.6 mg/Kg bw/day and 591.0 mg/Kg bw/day, respectively in female rats.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

One key Guideline (OECD 422) reproductive/developmental toxicity study that tested Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts was identified. The data is summarized below:

In a 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 the 15000 ppm concentration group, 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 the 15000 ppm concentration group 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.

 

Reproduction parameter changes showed a lower mean number of corpora lutea and implantations per dam, number of live pups at the first litter check and living pups on day 4 post partum in the high concentration group.

 

There was also a higher incidence of red discoloured lungs in the pups at this concentration.Microscopic findings of minimal hypertrophy/vacuolation of the zona glomerulosa were observed in the adrenal glands of some males and females in the high concentration group. 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 in the 15000 ppm concentration group 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 animals exposed to the test material at 5000 ppm. 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.

 

The NOAEL and NOEL for developmental toxicity was established at a concentration of 5000 ppm, the middle dose level used in the study.

One supporting Guideline (OECD 414) developmental toxicity study (Envigo Research Laboratories, 2017b) conducted with Rosin, maleated, a structural analogue, was also identified. The results from this OECD 414 study with Rosin, maleated demonstrated that developmental effects occurred at dietary concentrations below those that produced systemic toxicity in the parental animals. However, it should be noted that this study was performed with Rosin, maleated 20% MA, and the SIP for this substance has since changed from Rosin, maleated 20% MA to Rosin, maleated 10% MA.  H4R members do not consider that the OECD 414 study conducted with Rosin, maleated 20% MA accurately reflects the developmental toxicity hazard of Rosin, maleated 10% MA, which falls within the revised SIP for this substance. In addition, H4R does not consider that the OECD 414 study conducted with Rosin, maleated 20% MA accurately reflects the developmental toxicity hazard of Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts, which is produced with 5% MA. On July 11, 2017, H4R submitted a testing proposal for an additional OECD 414 study to be conducted with Rosin, maleated 10% MA, which is pending review and approval by ECHA. Please refer to the correspondence attached to Section 13 of the Rosin, maleated dossier for details.

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.

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

Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts is not classified for reproductive or developmental toxicity 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).

 

The results from an OECD 414 study with Rosin, maleated demonstrated that developmental effects occurred at dietary concentrations below those that produced systemic toxicity in the parental animals. However, it should be noted that this study was performed with Rosin, maleated 20% MA, and the SIP for this substance has since changed from Rosin, maleated 20% MA to Rosin, maleated 10% MA.  H4R members do not consider that the OECD 414 study conducted with Rosin, maleated 20% MA accurately reflects the developmental toxicity hazard of Rosin, maleated 10% MA, which falls within the revised SIP for this substance. In addition, H4R does not consider that the OECD 414 study conducted with Rosin, maleated 20% MA accurately reflects the developmental toxicity hazard of Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts, which is produced with 5% MA. On July 11, 2017, H4R submitted a testing proposal for an additional OECD 414 study to be conducted with Rosin, maleated 10% MA, which is pending review and approval by ECHA. Please refer to the correspondence attached to Section 13 of the Rosin, maleated dossier for details.