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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
862 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Information exists to characterise the reproductive toxicity of distilled tall oil maleated.

The maleate salts are formed when the fatty acids or rosin acids react with maleic anhydride.

The available data includes results obtained from testing Rosin, fumarated and Fatty acids, C14-18 and C16-18-unsatd., maleated along with supporting data for Rosin (the precursor of all substances included in the Rosin derivatives category) and Resin acids and rosin acids, esters with pentaerythritol (a Rosin reaction product). This information is summarised below.

Rosin, fumarated was administered in the diet to rats at concentrations of 0, 1000 ppm (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 10,000 ppm (males 651-889 mg/kg bw/d; females 449-995 mg/kg bw/d) (Inveresk Research, 2004). 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. Food consumption and mean body weights were decreased 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). The lower of these two values will be used as the parental (systemic) NOAEL. This is considered 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. With regard to reproductive parameters, there was a slight decrease in the mean number of implant sites per pregnancy and a consequent slight reduction in litter size at birth in the high dose group. A slight reduction in litter size between Day1-4 of lactation at 3000 ppm was due to the loss of most pups in one litter. As there were no effects of treatment on litter survival at 10,000 ppm the findings at 3000 ppm are considered to be incidental. Based on these results, the NOAEL for reproductive parameters was considered to be 10,000 ppm (males 651-889 mg/kg bw/d; females 449-995 mg/kg bw/d).

In a key combined repeat dose reproductive/developmental toxicity study, the test material (Fatty acids, C14-18 and C16-18-unsatd., maleated) was administered daily via oral gavage at doses of 0, 100, 300, and 1000 mg/kg bw/day to Wistar rats (12/sex/dose) in a propylene glycol vehicle. Male rats were treated for a period of 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week) while female rats were treated for approximately 47 days (14 days pre-mating, for up to 7 days mating period, through gestation til PPD 4). A satellite group of nulliparous and nonpregnant female rats (5/sex/dose) was also employed in the study and treated with the test material for a period of 35 days.

No signs of mortality or clinical toxicity were observed through the study period. Body weight and food consumption remained unaffected post-treatment with the test material. There was no effect of treatment on the oestrus cycle or reproductive parameters. There was no effect of treatment noted during gestation, parturition or the post-partal period. Test material related microscopic findings were found at 1000 mg/kg bw/day (High dose) in stomach, in the form of hyper/paraceratosis of the non-glandular gastric mucosa. This minimal to mild multifocal change occurred in 4 of 5 males and 2 of 5 females. There was no evidence of test item-related histological findings in the reproductive organs. Histopathological evaluation of the male gonads as well as testicular interstitial cell structure, the spermatogenic cells representing different phases of the development and differentiation of the spermatozoons revealed normal histological pictures. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma showed similar histological structure in both control and high dose females.

There was/were no mortality or any adverse effects considered related to treatment or toxicologically significant in the F1 generation. No abnormal behaviour of the pups was noted. No external abnormalities ascribed to treatment were detected at the clinical or external macroscopic examinations of the pups. In single pups at 100, 300 and 1000 mg/kg haemorrhage was observed on PND0. The sex ratios were observed to be similar in the Control and treated groups. Body weight or body weight gain remained unaffected by treatment with fatty acids, C14-18 and C16-18-unsatd., maleated.

 

For the reproduction toxicity endpoints the NOAEL was considered to be 1000 mg/kg day. Dose levels of 1000 mg/kg body weight to Wistar rats for 35 consecutive days caused a minimal/mild hyper/paraceratosis of the nonglandular gastric mucosa in stomach in 4 of 5 males and 2 of 5 females. This finding is considered to be indicative of local irritation in a structure of the stomach that does not exist in man. Systemic effects were not observed.

Results from two supporting screening studies are presented below:

In a reproductive/developmental toxicity screening study, 10 rats/sex/group were exposed to Rosin at dose concentrations of 0, 1000, 3000, or 10000 ppm for 41-45 days (females) or 30 days (males) in the diet (Inveresk Research, 2003a). Treatment with Rosin at 10000 ppm was associated with reduced weight gain/weight loss and reduced food consumption in the parental generation and a slight decrease in the mean number of implantation sites resulting in a subsequent slight reduction in litter size. Body weight gain reductions were also observed in males exposed to 3000 ppm Rosin. Adverse effects in the F1 pups were limited to slightly reduced litter and pup weights. Based on the results of the present study, the no-observed-effect-level (NOAEL) for reproductive/developmental toxicity in Sprague-Dawley rats was considered to be 3000 ppm for males and females.

In a reproductive/developmental toxicity screening study, 10 rats/sex/group were exposed ad libitum in the diet to Rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at dose concentrations of 0, 1000, 5000, or 20000 ppm for 57-60 days (females) or 28 days (males) (Inveresk Research, 2003b). There were no test substance-related effects on reproductive performance of the parental females or on survival and development of the F1 pups. All findings occurred in a non dose-dependent manner, were spurious in nature, or were biologically irrelevant and were not considered related to rosin pentaerythritol ester consumption. The NOAEL for reproductive/developmental toxicity in Sprague-Dawley rats was considered to be 20000 ppm for males and females.

Based on these results, it would be premature to propose a 2-generation reproductive test at this time. The available information will be re-examined once results are available from a pre-natal developmental toxicity test (OECD 414) on Rosin are available, and the scientific need to propose or waive a 2-generation reproductive toxicity test will be determined and communicated to ECHA.


Short description of key information:
Two key studies were identified, one for Rosin, fumarated and one for Fatty acids, C14-18 and C16-18-unsatd., maleated. Supporting information was available for Rosin and Resin acids and rosin acids, esters with pentaerythritol . No reproductive effects were observed in any study.

Justification for selection of Effect on fertility via oral route:
Estimated NOAEL, based on results following repeated exposure of rats to the main constituents and/or related materials. Pro-rata calculation based on likely amounts of the constituents in the reaction mass.

Effects on developmental toxicity

Description of key information
Two key studies were identified, one for Rosin, fumarated and one for Fatty acids, C14-18 and C16-18-unsatd., maleated. No developmental effects were observed.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
862 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

Information exists to characterise the developmental toxicity of distilled tall oil maleated.

The maleate salts are formed when the fatty acids or rosin acids react with maleic anhydride.

The available data includes results obtained from testing Rosin, fumarated andFatty acids, C14-18 and C16-18-unsatd., maleatedalong with supporting data for Rosin (the precursor of all substances included in the Rosin derivatives category) and Resin acids and rosin acids, esters with pentaerythritol (a Rosin reaction product). This information is summarised below.

Rosin, fumarated was administered in the diet to female rats at concentrations of 0, 1000 ppm (79-108 mg/kg bw/d), 3000 ppm (196-292 mg/kg bw/d), and 10,000 ppm (449-995 mg/kg bw/d) throughout pregnancy until termination on Day 4 of lactation (Inveresk Research, 2004). Food consumption and mean body weights were decreased at 10,000 ppm and 3000 ppm, with high dose animals also showing an increase in total bilirubin and decreased adrenal weight.  The lower of these two values will be used as the maternal (systemic) NOAEL. This is considered 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. With regard to litter parameters, there was a slight decrease in the mean number of implant sites per pregnancy and a consequent slight reduction in litter size at birth in the high dose group. A slight reduction in litter size between Day1-4 of lactation at 3000 ppm was due to the loss of most pups in one litter. As there were no effects of treatment on litter survival at 10,000 ppm the findings at 3000 ppm are considered to be incidental. Based on these results, the NOAEL for developmental effects was considered to be 10,000 ppm (449-995 mg/kg bw/d).

In a key combined repeat dose reproductive/developmental toxicity study, the test material (Fatty acids, C14-18 and C16-18-unsatd., maleated) was administered daily via oral gavage at doses of 0, 100, 300, and 1000 mg/kg bw/day to Wistar rats (12/sex/dose) in a propylene glycol vehicle. Male rats were treated for a period of 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week) while female rats were treated for approximately 47 days (14 days pre-mating, for up to 7 days mating period, through gestation til PPD 4). A satellite group of nulliparous and nonpregnant female rats (5/sex/dose) was also employed in the study and treated with the test material for a period of 35 days.

No signs of mortality or clinical toxicity were observed through the study period. Body weight and food consumption remained unaffected post-treatment with the test material. There was no effect of treatment on the oestrus cycle or reproductive parameters. There was no effect of treatment noted during gestation, parturition or the post-partal period. Test material related microscopic findings were found at 1000 mg/kg bw/day (High dose) in stomach, in the form of hyper/paraceratosis of the nonglandular gastric mucosa. This minimal to mild multifocal change occurred in 4 of 5 males and 2 of 5 females. There was no evidence of test item-related histological findings in the reproductive organs. Histopathological evaluation of the male gonads as well as testicular interstitial cell structure, the spermatogenic cells representing different phases of the development and differentiation of the spermatozoons were revealed normal histological pictures. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma were similar histological structure in both Control and High Dose females.

There was/were no mortality or any adverse effects considered related to treatment or toxicologically significant in the F1 generation. No abnormal behaviour of the pups was noted. No external abnormalities ascribed to treatment were detected at the clinical or external macroscopic examinations of the pups. In single pups at 100, 300 and 1000 mg/kg haemorrhage was observed on PND0. The sex ratios were observed to be similar in the Control and treated groups. Body weight or body weight gain remained unaffected by treatment with fatty acids, C14-18 and C16-18-unsatd., maleated.

 

Daily oral gavage administration of fatty acids, C14-18 and C16-18-unsatd., maleated at dose levels of 100, 300 and 1000 mg/kg day was not associated with signs of developmental toxicity and the NOAEL was considered to be 1000 mg/kg /day.


Justification for selection of Effect on developmental toxicity: via oral route:
Estimated NOAEL, based on results following repeated exposure of rats to the main constituents and/or related materials. Pro-rata calculation based on likely amounts of the constituents in the reaction mass.

Justification for classification or non-classification

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).