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Key value for chemical safety assessment

Effects on fertility

Description of key information

Six key reproductive/developmental toxicity screening studies (5 OECD 422 and 1 OECD 421) are available to evaluate the reproductive toxicity potential of Rosin Esters. Available data indicates that oral administration of these substances does not adversely impact reproduction in rats. Additionally, results from oral repeated dose toxicity tests conducted using members of the category have revealed no gross or microscopic changes in any reproductive organ at necropsy.

Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Simple Rosin Esters

The potential for Resin and rosin acids, hydrogenated, Me esters to cause reproductive toxicity was investigated in an OECD Guideline 422 screening study (Inveresk Research Laboratories, 2003a). There were no significant test material-related effects on mating performance, fertility (as measured by fertility indices), duration of gestation, or reproductive organs in adult male and female rats exposed via the diet to target concentrations of 0, 5000, 10000 or 20000 ppm during premating, mating, gestation, and lactation. At 20000 ppm (equivalent to 1579 mg/kg bw/d for males, and an overall dose [pre-mating to lactation] of 1553 mg/kg bw/d for females), there was a slight decrease in the mean number of implant sites per pregnancy, although there were no effects on litter size at birth. There was a significant reduction in food consumption for females in the 10000 ppm (915 mg/kg bw/d) and 20000 ppm (1553 mg/kg bw/d) groups as well as a dose-dependent reduction in body weights, increased liver weights, and increased hepatocyte hypertrophy. An overall NOAEL of 1553 mg/kg bw/d (females) and 1579 mg/kg bw/d (males) for effects on fertility was obtained from this study.

Linear Rosin Esters

The potential for Resin acids and rosin acids, esters with ethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015a) conducted according to OECD Guideline 422. In that study, rats were treated for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No mortality or adverse treatment-related systemic or reproductive toxicity effects were observed at the highest concentration tested (18000 ppm (male) and 15000 ppm (female)). Based on the results for this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

The potential for Resin acids and rosin acids, hydrogenated, esters with triethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2015b) conducted according to OECD Guideline 422. In that study, the test material was administered to rats for a period of approximately seven weeks (including two weeks pre-pairing, gestation and early lactation for females at 3000, 7500 and 18000 ppm (lowered to 15000 ppm for females during gestation and lactation). No treatment-related systemic or reproductive toxicity effects were observed in the study. Based on this, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 18000/15000 ppm and the No Observed Effect Level (NOEL) for reproduction was also considered to be 18000/15000 ppm.

The potential for Resin acids and rosin acids, esters with diethylene glycol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Harlan Laboratories Ltd., 2014a) conducted according to OECD Guideline 422. In that study, the test material was administered orally to rats for about eight weeks at concentrations of 3000, 7500 and 15000/18000 ppm. No unscheduled deaths occurred during the study and no treatment-related clinical changes were observed. Microscopic changes in the liver of males and females exposed at the highest concentration and only in males exposed at the mid concentration were observed. Histopathological examination confirmed that this condition is considered to be adaptive in nature. Microscopic kidney changes were observed in one male treated at 18000 ppm and microscopic lung changes were observed in females treated at 18000/15000 ppm. No adverse treatment-related reproductive toxicity effects were observed at the highest concentration tested. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 3000 ppm for either sex. The ‘No Observed Adverse Effect Level’ (NOAEL) for either sex was therefore considered to be 18000/15000 ppm. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 18000/15000 ppm.

Bulky Rosin Esters

The potential for Rosin, glycerol ester to cause reproductive toxicity was evaluated in a reproductive and developmental toxicity screening study (Harlan Laboratories Ltd., 2014b) conducted according to OECD Guideline 422. In that study, the test material was administered by continuous dietary admixture to Wistar Han™:RccHan™:WIST rats (12/sex/dose), 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 (equivalent to a mean achieved dosage of 181.1, 449.1 and 1087.3 mg/kg bw/day respectively for males and 228.5, 537.8 and 1281.1 mg/kg bw/day respectively for females during the pre-pairing phase). The dietary concentration given to the high dosage females during gestation and lactation was decreased to 15000 ppm to lessen the expected increase in achieved intake during these phases. A control group of twelve males and twelve females were treated with basal laboratory diet. No mortality was observed through the study period and no treatment-related clinical signs were observed in animals of either sex treated with 3000, 7500 or 18000/15000 ppm. Oral exposure to the test material was not observed to produce any adverse effects on reproductive parameters.  Based on the lack of adverse treatment-related effects observed in this study, the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was determined to be 18000/15000 ppm in the rat. The NOAEL for reproductive toxicity was also considered to be 18000/15000 ppm.

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause reproductive toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. There were no test substance-related effects on reproductive performance as measured by male and female mating indices or male and female fertility indices. There were also no adverse effects on gestation, gestation index, or mean number of implant sites per pregnancy. No deficiencies in lactation or maternal care were noted during the study. No adverse effects were observed on reproductive organs of either sex at necropsy at received doses of up to 1864 mg/kg bw/d in males and 1757 - 2054 mg/kg bw/d in females. The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity in Sprague-Dawley rats was considered to be 20000 ppm for males and females, equivalent to received doses of 1864 mg/kg bw/d and 1757 -2054 mg/kg bw/d, respectively. 

 

Results from repeated dose toxicity tests conducted using Resin acids and rosin acids, esters with ethylene gycol; Resin and rosin acids, hydrogenated, Me ester; Resin acids and rosin acids, esters with glycerol; Resin acids and rosin acids, hydrogenated, esters with glycerol; and Resin acids and rosin acids, hydrogenated, esters with pentaerythritol revealed no gross or microscopic changes in any reproductive organ at necropsy.

Effects on developmental toxicity

Description of key information

Five key guideline (OECD 414) pre-natal toxicity studies and two combined reproductive/developmental toxcity screening tests (OECD 421 and OECD 422) are available to evaluate the developmental toxicity potential of Rosin Esters. Resin acids and Rosin acids, esters with glycerol; Resin acids and rosin acids, esters with triethylene glycol; and Resin acids and rosin acids, esters with pentaerythritol did not impact development in rats following oral exposure. However, Resin acids and Rosin acids, methyl ester; Rosin, esters with glycerol; and Resin acids and rosin acids, hydrogenated, Me esters have demonstrated adverse effects on development post oral exposure in 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

Simple Rosin Esters

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017b), the test material (Resin acids and Rosin acids, methyl ester; CAS# 68186-14-1) was administered by continuous dietary admixture to three groups each 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 3000, 7500, and 15000 ppm. A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

 

No mortality was observed through the study period. Maternal dietary exposure to 15000 ppm of the test material during gestation was associated with lower body weight gain and food consumption compared to control, with differences being particularly marked during the initial two days of dietary exposure. Although lower litter weight due to reduced foetal weight would have contributed to the lower final body weight and overall weight gain, an underlying effect on the pregnant dam was still clearly present when these values were adjusted for the contribution of the gravid uterus. Despite these marked effects on body weight and food intake, in utero survival of the developing conceptus appeared to be unaffected by maternal exposure to the test item at this dietary level although there was a clear reduction in foetal weight, which resulted in lower litter weight compared to control. The lower foetal weight at 15000 ppm of the test item is suggestive of a retardation of foetal growth and was supported by a slightly increased incidence of small foetuses compared to control.

 

Skeletal examination of the foetuses also revealed statistically significant differences from control for a number of skeletal parameters (increased foetal incidences of unossified areas of the occipital bone, incomplete ossification of the thoracic centrum and less than four ossified pre-sacral vertebrae and decreased foetal incidence of ossification present in ventral arch of vertebra 1 and one or more forepaw phalanges ossified) consistent with such a retardation of growth. However, lower foetal incidence of incomplete ossification of the parietal, intraparietal and jugal bones, the pubis and the femur also attained statistical significance compared to control: this was considered contradictory to a delay in foetal maturation. Overall, the differences from control for foetal parameters showed a non-specific and inconsistent pattern of delayed ossification.

 

Maternal dietary exposure to 7500 ppm of the test material during gestation was generally well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this most probably reflects an initial reluctance to eat the diet as subsequent body weight gain was essentially similar to control. Food consumption was statistically significantly lower than control until gestation day 14, although differences were most notable during the first two days of dietary exposure. There was no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

Maternal dietary exposure to 3000 ppm of the test material during gestation was well tolerated by the parent females. Although a slight mean body weight loss was apparent during the first day of treatment, this was considered to be of no toxicological significance in the absence of any effect on overall body weight gain during gestation compared to control. There was no obvious effect of maternal exposure to the test item at a concentration of 3000 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control.

 

At 7500 ppm, food consumption was lower than control throughout much of gestation and this lower food intake was associated with lower cumulative body weight gains during gestation. The clear NOAEL was considered to be 3000 ppm (equivalent to 237.3 mg/kg bw/day). There was no obvious effect of maternal exposure to the test item at a concentration of 7500 ppm on in utero survival of the developing conceptus, foetal litter or placental weights or the foetal incidence of external, visceral or skeletal findings compared to control. Therefore, 7500 ppm (equivalent to 554.4 mg/kg bw/day) was considered to be the NOAEL for the survival, growth and development of the offspring.

In a Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test (Inveresk Research, 2003a) conducted according to OECD Guideline 422, the test material (Resin acids and rosin acids, hydrogenated, Me esters) was administered to rats at dietary concentrations of 0, 5000, 10000, or 20000 ppm. Adverse effects on post-natal development, i.e., reductions in mean pup weight and mean litter weights were seen at all diet concentrations. This was associated with significant reductions in food consumption for females in the 10000 ppm (915 mg/kg bw/d) and 20000 ppm (1553 mg/kg bw/d) groups as well as a dose-dependent reduction in body weights, increased liver weights, and increased hepatocyte hypertrophy. At the highest diet concentration, four of ten dams and their pups were sacrificed in extremis before study termination. At 5000 ppm (476 mg/kg bw/d), there was also a slight reduction in food consumption during the pre-mating period as well as during the first two weeks of gestation, and lactation. Based on this study, Resin acids and rosin acids, hydrogenated, Me esters is not selectively toxic to the developing fetus; fetotoxicity was observed but always in the presence of maternal toxicity. The parental no-observed-effect-level (NOAEL) for subacute toxicity was considered to be less than 5000 ppm for males (eq. to <405 mg/kg bw/d) and females (eq. to <476 mg/kg bw/d). The reproductive toxicity NOAEL was considered to be 10000 ppm for females (eq. to 915 mg/kg bw/d) and 20000 ppm for males (eq. to 1579 mg/kg bw/d). The NOAEL for developmental toxicity was considered to be < 5000 ppm (eq. to maternal dose of <476 mg/kg bw/d).  

Linear Rosin Esters

In a key guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Limited, 2017c), the test material (Rosin, esters with ethylene glycol; CAS# 68512-65-2), was administered by continuous dietary admixture to three groups each 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 3250, 8750, and 18750 ppm (equivalent to a mean achieved dosage of 266.7, 715.0 and 1487.0 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control.

No mortality or signs of clinical toxicity were observed through the study period. Initial dietary exposure at 18750 ppm was associated with a mean body weight loss, thereafter body weight gain was similar to control to gestation day 14. Lower body weight gain was observed from gestation days 14 to 20. During the later stage of gestation, body weight gain in the high exposure group may have been influenced by lower foetal/litter weight, however overall body weight remained lower than control, when adjusted for the contribution of the gravid uterus. Food consumption at this dietary level was lower than control during the first two days of dietary exposure, which probably reflected an initial reluctance to eat the treated diet (due to its palatability), but subsequent food intake was similar to control.

 

For litters at 18750 ppm, there was no effect of maternal exposure on pre-implantation loss, implantation count, embryofoetal survival, litter size or sex ratio but mean foetal, litter and placental weight were all lower than control. External examination of the foetuses at necropsy and subsequent detailed skeletal evaluation did not indicate any effect of maternal exposure on foetal development. However, there was a cluster of visceral findings (kinked ureters, dilated ureters, increased renal pelvic cavitation, absent renal papilla misshapen kidneys and absent renal medulla) that indicated a treatment-related disturbance of the normal development of the kidneys and ureters. One litter at 18750 ppm showed five foetuses with gastroschisis and encephalocoele. Despite the limitation of this finding to one litter, the group mean incidence of affected foetuses was higher than both concurrent and historical control values. As this finding was observed in the highest treated group an association with treatment cannot be discounted resulting in confirmation that dietary exposure at 18750 ppm is regarded as an adverse effect level for offspring development.

 

At 3250 and 8750 ppm, there was no effect of dietary exposure on maternal body weight gain or food consumption and pre-implantation loss, implantation count, embryofoetal survival, litter size, sex ratio and mean foetal, litter and placental weight were also considered to be unaffected by maternal exposure at these dietary levels. However, at 8750 ppm, the incidence of foetuses/litters showing kinked ureters, dilated ureters, increased renal pelvic cavitation and absent renal papilla was higher than control and the historical control range, indicating a treatment-related effect on the normal development of the kidneys and ureters. At 3250 ppm, the incidences of foetuses/litters showing kinked ureters or dilated ureters were similar to control and were within the historical control range. However, the incidence of foetuses/litters showing increased renal pelvic cavitation was higher than both concurrent control and the historical control range. While this higher incidence of increased renal pelvic cavitation was only slightly higher than the historical control range, in view of the findings apparent at higher dietary levels, an association with treatment cannot be discounted. However, increased renal pelvic cavitation is frequently observed amongst neonatal and adult animals within this laboratory without any obvious adverse impact of the viability of these animals and may be regarded, to a certain extent, as a variation of the normal. As this finding occurred in the absence of any increased incidence of more significant findings with the potential to effect offspring viability, such as absent renal papilla, and in the absence of any effect on skeletal development, this dietary level could be regarded as a No Observed Adverse Effect Level (NOAEL) for foetal development.

 

Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) for the pregnant rat was considered to be 8750 ppm (equivalent to 715 mg/kg bw/day) and the NOAEL for developmental toxicity was considered to be 3250 ppm (equivalent to 266.7 mg/kg bw/day).

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016b), the test material (Resin acids and rosin acids, esters with triethylene glycol; CAS# 8050-25-7) 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 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 258.4, 634.1 or 1268.4 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control. The oral administration of the test material to pregnant rats by continuous dietary admixture from gestation days 3 to 19, at dietary concentrations of 3000, 7500 and 15000 ppm did not result in any treatment related effects. The No Observed Adverse Effect Level (NOAEL) for the pregnant female was considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1268.4 mg/kg bw/day).

Bulky Rosin Esters

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016a), the test material (Resin acids and Rosin acids, esters with glycerol; CAS# 8050-31-5) was administered by continuous dietary exposure 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 3000, 7500, or 15000 ppm (equivalent to a mean achieved dosage of 241.0, 607.7 or 1227.5 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control. The oral administration of the test material to pregnant rats by continuous dietary admixture from gestation Days 3 to 19, at dietary concentrations of 3000, 7500 or 15000 ppm did not result in any treatment related effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for the pregnant female was considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1227.5 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1227.5 mg/kg bw/day).

 

In a key guideline (OECD 414) developmental toxicity study (Envigo Research Limited, 2016c), the test material (Resin acids and rosin acids, esters with pentaerythritol; CAS# 8050-26-8) 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 3000, 7500 or 15000 ppm (equivalent to a mean achieved dosage of 251.2, 609.5 or 1239.5 mg/kg bw/day respectively). A further group of twenty-four time mated females was treated with basal laboratory diet to serve as a control. The oral administration of the test material to pregnant rats by continuous dietary exposure during gestation days 3 to 19, at concentrations of 3000, 7500 or 15000 ppm did not result in any treatment related effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for the pregnant female was considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1239.5 mg/kg bw/day). No treatment-related changes were detected in the offspring parameters measured or embryofoetal development. The NOAEL for developmental toxicity was therefore considered to be greater than 15000 ppm (equivalent to a mean achieved dosage of 1239.5 mg/kg bw/day).

 

The potential for Resin acids and rosin acids, esters with pentaerythritol to cause developmental toxicity was evaluated using a reproductive and developmental screening study (Inveresk Research, 2004a) conducted according to OECD Guideline 421. In that study, parental male and female Sprague-Dawley rats were exposed ad libitum in the diet to rosin pentaerythritol ester (Resin acids and rosin acids, esters with pentaerythritol) at concentrations of 0, 1000, 5000, or 20000 ppm during premating, mating, gestation and lactation for a total of 57-60 exposure days for females and 28 days for males. For dams, no test material-related effects were noted for mean gestation lengths or the process of parturition at any exposure concentration. Mean number of pups born per litter, mean numbers of live pups per litter, birth index, live birth index, viability index, and group mean litter weights were unaffected by maternal exposure. For pups exposed in utero and during lactation, there was no clear evidence of a test substance-related effect on pup survival or development and no visible external abnormalities were observed in the pups prior to study termination. The NOAEL for effects during gestation was 20000 ppm, equivalent to 1757 mg/kg bw/day.

Justification for classification or non-classification

All member of Category 2 with the exception of Resin acids and rosin acids, esters with ethylene glycol (CAS# 68512-65-2) are 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).

 

In an OECD 414 study with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2), based on the observation of foetal developmental toxicity at dietary exposure levels below those that resulted in maternal toxicity. This OECD 414 key study provides data to trigger Reproductive Category 2 Classification for Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) under EU CLP. However, the results of the OECD 414 with Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) will not be used for read across within the category Rosin, esters.  H4R commissioned a study to assess and compare the in vitro gut absorption and chemistry of the Ethylene Glycol (EG), Diethylene Glycol (DEG), and Triethylene Glycol (TEG) esters and decided that the appropriate read across for the linear esters developmental toxicity will be from the TEG to the DEG ester. The rationale for this decision is provided in the 'Sameness Report' for EG, DEG, and TEG rosin esters that has been attached to Section 13.

 

Additionally, there is only one registration of Resin acids and rosin acids, esters with ethylene glycol (CAS 68512-65-2) and the registrant had stopped production/sale of this substance in the EU.