Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
DNEL related information
DNEL derivation method:
other: ECHA Guidance. Generic ECHA recommendation for a long-term DNEL (inhalation, worker)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.131 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal NOAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans:

 

 

corrected dermal NOAEL = oral NOAEL x (ABSoral-rat / ABSderm-rat) x (ABSderm-rat / ABSderm-human)

 

                                     = oral NOAEL x (ABSoral-rat / ABSderm-human)

 

                                     = 213.1 mg/Kg bw/day x (1 / 1) 

 

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characte risation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for differences in duration of exposure:
2
Justification:
Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to c hronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for other interspecies differences:
2.5
Justification:
Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects, a default assessment factor of 5 was appli ed (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for the quality of the whole database:
1
Justification:
Default assessment factor applied for good/standard quality of the database, taking into account com pleteness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]response for human health, Version 2.1, November 2012).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified.

Irritation/Sensitisation

Rosin; Hydrogenated rosin; Rosin oligomers; and Rosin, reaction products with formaldehyde are not irritating to skin or eye. Divalent cationic salts of Rosin and Hydrogenated rosin, and trivalent cationic salts of rosin are insoluble and their irritation potential is therefore comparable to that of the parent substance. Monovalent cationic salts are soluble and alkali in solution. Test results indicate that the monovalent salts are irritating to eye but not to skin. Low vapour pressure precludes inhalation exposure.

Rosin, Hydrogenated rosin, Rosin oligomers and the salts of Resin acids and rosin acids were not sensitisers when tested in the murine Local Lymph Node assay, or when tested in guineas pigs using Maximization and/or Buehler protocols. Positive results obtained in a single Guinea Pig Maximization study with “Rosin” showed, on subsequent investigation, that the sample submitted for testing was heavily oxidized and degraded. Therefore, the positive results in this one study are erroneous and should be disregarded when reviewing the dermal sensitisation hazards of Rosin.

Repeated dose toxicity

The potential for the members of the category Rosins and their salts to cause target organ toxicity following repeated exposure is well understood. Key information is available from three guideline (OECD 408) studies that have investigated the repeated dose oral toxicity of Rosin; Rosin, hydrogenated; and Rosin, reaction products with formaldehyde following dietary administration to rats.

 

Rosin

 

In a key oral repeat dose toxicity study (Envigo Research Limited, 2017a), the test material (Rosin, CAS# 8050-09-7) was administered continuously in the diet of three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 2500, 5000 or 7500 ppm (equivalent to a mean achieved dosage of 174.1, 335.2 or 510.1 mg/kg bw/day for males and 196.4, 401.2 or 596.2 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet.

 

The continuous dietary administration of the test material to rats, at dietary concentrations of 2500, 5000 and 7500 ppm for ninety consecutive days, resulted in reduced body weight gains in animals of either sex exposed to 7500 ppm and microscopic adrenal changes in animals of either sex exposed to 7500 and 5000 ppm. The No Observed Effect Level (NOEL) for both sexes was therefore considered to be 2500 ppm (equivalent to a mean achieved dosage of 174.1 mg/kg bw/day for males and 196.4 mg/kg bw/day for females). The microscopic adrenal changes (hypertrophy of the zona glomerulosa) identified in animals of either sex exposed to 7500 or 5000 ppm were mild. The changes were not considered to have affected normal electrolyte regulation and did not appear to have an effect on homeostatic control. Therefore, they were not considered to have had adverse consequences for the organ or the body. For this reason, 5000 ppm (equivalent to a mean achieved dosage of 335.2 mg/kg bw/day for males and 401.2 mg/kg bw/day for females) was considered to be the “No Observed Adverse Effect Level” (NOAEL) systemic toxicity.

 

Rosin, hydrogenated

 

In a key sub-chronic toxicity study (Envigo Research Limited, 2016a), the test material (Rosin, Hydrogenated; CAS# 65997-06-0) was administered by continuous dietary admixture to groups of male and female WistarHan™:RccHan™:WIST strain rats(10/sex/concentration), for ninety consecutive days, at dietary concentrations of 1000 and 2000 ppm for the low and intermediate exposure groups (equivalent to mean achieved dosages of 64.5 and 133.3 mg/kg bw/day for males and 78.5 and 156.4 mg/kg bw/day for females). For the high exposure group, rats were initially fed diet containing 4000 ppm for five weeks followed by 6000 ppm for the remainder of the study (equivalent to mean achieved dosages of 334.5 mg/kg bw/day for males and 399.8 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet. The No Observed Adverse Effect Level (NOAEL) was determined to be 6000 ppm for either sex (equivalent to a mean achieved dosage of 334.5 mg/kg bw/day for males and 399.8 mg/kg bw/day for females).

 

Rosin, reaction products with formaldeyde

 

In a key sub-chronic oral repeated dose toxicity study (Envigo Research Limited, 2017b), the test item (Rosin, reaction products with formaldehyde; CAS# 91081-53-7), was administered by continuous dietary admixture to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 1000, 3000 and 7500 ppm (equivalent to a mean achieved dosage of 68.9, 213.1 and 509.2 mg/kg bw/day for males and 84.0, 255.2 and 644.6 mg/kg bw/day for females respectively). A control group of ten males and ten females were treated with basal laboratory diet.

 

Based on the effects on body weight, body weight gain and, to a lesser extent, food consumption, observed among females exposed to diets containing 7500 ppm of the test material, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity of Rosin, reaction products with formaldehyde (CAS 91081-53-7) in this Ninety Day Toxicity study was considered to be 3000 ppm (equivalent to mean achieved dosages of approximately 213.1 mg/kg bw/day or 255.2 mg/kg bw/day for males and females, respectively). As an initial transient effect on body weight and food consumption (which may reflect palatability of the diet formulations) was apparent at 1000 ppm, the No Observed Effect Level (NOEL) for systemic effects could not be established.

Genetic toxicity

Adequate information exists to characterise the genetic toxicity of the members of the category Rosin, Hydrogenated rosin, and their salts. Results of bacterial mutation assays demonstrate that Rosin, Resin acids and rosin acids, hydrogenated, potassium salts, Resin acids and rosin acids, calcium salts, Resin acids and rosin acids, magnesium salts, Resin acids and rosin acids, calcium salts, Resin acids and rosin acids, manganese salts, Resin acids and rosin acids, aluminium salts, and Resin acids and rosin acids, hydrogenated calcium salt were not mutagenic in four strains ofSalmonella typhimuriumand in strain WP2 ofEscherichia coliwhen tested in the absence or presence of exogenous metabolic activation. When tested using mammalian cells in vitro, in the absence and in the presence of S9 fraction, Rosin was inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in a cytogenetics assay (human lymphocytes).

Reproductive / developmental toxicity

Reproductive Toxicity

 

In a key combined repeated dose, reproductive/developmental OECD 422 toxicity screening study (Harlan Laboratories Ltd., 2015a), the test material (Tall oil rosin, CAS# 8050-09-7) was administered daily in dietary mixtures at concentrations of 0, 2500 ppm, 5000 ppm, or 10000 ppm to male rats for 42 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. In the high concentration group, the number of corpora lutea was reduced, which resulted in slightly, not statistically significant lower number of implantation sites and slightly, not statistically significant lower litter size at first litter check. Mean litter size at the high concentration level remained in the range of historical control values. Slightly reduced body weight and body weight gain were observed in pups during lactation. Although the reduction was only minor and predominantly not statistically significant if compared to the current control, values at the high concentration level were lower if compared to the historical control background and therefore this observation was considered to be related to the treatment with the test item. Mating performance, fertility, duration of gestation, post-implantation and post-natal loss were considered not to be affected by the treatment with the test item at any concentration level. Due to adverse effects on body weight observed in females in the high concentration group, a possibility that the reduced number of corpora lutea as well as lower pup body weight were secondary to the maternal response, should be taken into consideration. No effects on reproductive parameters were observed in animals in the 5000-ppm group. In the low concentration group (2500 ppm), no effects on reproduction were observed. For reproductive toxicity, the NOEL was established at 5000 ppm whereas the NOAEL was established at the concentration level of 10000 ppm, the highest concentration tested in the study.

 

In a key combined repeated dose, reproductive/developmental toxicity study (OECD 422), the test material (Rosin, hydrogenated; CAS# 65997-06-0) was continuously administered in feed to rats (12/sex/concentration) at concentrations of 0, 1000, 3000, and 10000 ppm. The test material was administered 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 (Harlan Laboratories Ltd., 2015b). There were no test item related microscopic findings in the reproductive organs, including the qualitative examination of the stages of spermatogenesis in the testes (no test item related abnormalities in the integrity of the various cell types present within the different stages of the sperm cycle) and the evaluation of the uterus or evaluation of follicles and corpora lutea in the ovaries. There were no test item related microscopic findings in the males or females suspected of reduced fertility. A reduction in corpora lutea count was observed in females ingroup 4 during the macroscopic evaluation at necropsy whereas histopathological evaluation of follicles and corpora lutea in the ovaries did not reveal any test item-related effect. Because no significant changes in the number of implantation sites or litter size were observed during the study, the reduction in corpora lutea count was considered not to be adverse. Further, the effect on corpora lutea count may possibly be secondary to the toxic effects in females observed in this group. Remaining reproduction parameters: mating performance, fertility, duration of gestation, post implantation and postnatal loss were not affected by the treatment with the test item at any dose level. For reproductive toxicity, the NOEL was established at the dose level of 3000 ppm whereas the NOAEL was at 10000 ppm, the highest dose level used in the study.

 

In a key reproductive/developmental toxicity study (OECD 422), the toxicological effects on rats resulting from continuous dietary oral administration of the test material (Rosin, reaction product with formaldehyde, CAS #. 91081-53-7) were evaluated (Harlan Laboratories Ltd., 2015c). The test material was administered daily in dietary mixtures at concentrations of: 0, 1000, 3000 and 10000 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. The sperm motility, morphology and sperm count, estrus cycle, mating performance, fertility, duration of gestation, corpora lutea count, implantation rate, post-implantation and postnatal loss and litter size were not affected by treatment with the test material at any concentration. Based on the result of the study, the NOAEL and NOEL for reproductive toxicity were established at a concentration of 10000 ppm, the highest concentration used in the study.

 

In another key combined repeated dose, reproductive/developmental (OECD 422) toxicity study (Harlan Laboratories Ltd., 2014a), Gum Rosin was administered to rats (12/sex/dose) in dietary mixtures at concentrations of 0, 2500, 5000, and 10000 ppm for a period of 50 days for male rats 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 (at least 36 days, up to 53 days). Mating performance, fertility index, duration of gestation, and post-implantation loss were not affected by the treatment with the test material at any dose level. In the high dose group (10000 ppm), the mean number of corpora lutea and implantations per dam as well as the mean litter size at the first litter check were decreased. The effects on reproduction were considered likely to be secondary to the effects of the treatment on food consumption and body weight development of the dams. Based on the results of this study, the NOEL and the NOAEL for reproductive toxicity were established at 5000 ppm.

 

In another key combined repeated dose, reproductive/developmental toxicity study (OECD 422), the test material (Rosin, oligomers; CAS # 65997-05-9) was administered to rats (12/sex/concentration) in dietary mixtures at concentrations of 0, 3000, 7500 and 15000 ppm (Harlan Laboratories Ltd., 2014b). The test material was continuously administered 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 (up to 55 days). No clinical signs of toxicological relevance were observed and mating performance, fertility index, and duration of gestation were not affected by the treatment at any concentration level. The mean numbers of corpora lutea and implantations per dam were decreased and the total number of post implantation losses was significantly higher in Group 4 females than in the control group. This led to a lower mean number of living pups per litter at the first litter check. These observations could be secondary to lower maternal food consumption and body weight gain in this group. The NOEL and the NOAEL for reproductive toxicity was determined to be 3000 ppm.

 

In a reproductive and developmental toxicity screening study conducted according to OECD Guideline 421 (Inveresk Research, 2003a), male and female Sprague Dawley rats were exposed to 0, 1000, 3000 or 10,000 ppm Gum Rosin (Rosin) in the diet during pre-mating, mating, gestation and lactation for a total of 30 exposure days for males and 41-45 exposure days for females. At 10,000 ppm in the diet (equivalent to 786 mg/kg bw/f for males and 869 mg/kg bw/d for females), there were no test material-related effects on mating performance, male and female fertility indices, or length of gestation and no gross or microscopic effects on reproductive organs of either sex. The mean number of implant sites per pregnancy was slightly reduced resulting in a slight reduction in litter size. Mean litter and pup weights were also slightly reduced. The effect on implantation, litter size and fetal weight may be secondary to the effects on decreased food intake and subsequent lower weight gain observed in the adult females. A NOAEL of 3000 ppm, equivalent to 248 (males) to 309 (females) mg/kg bw/d was derived from this study.

 

Additionally, in guideline repeat exposure studies (OECD 408), there were no gross or microscopic changes in reproductive organs of male or female rats exposed to Rosin; Rosin, hydrogenated; or Rosin, reaction products with formaldehyde for a period of 90 days.

 

 

Developmental toxicity

In a key pre-natal developmental toxicity study (Envigo Research Ltd., 2017c), the test material (Rosin, CAS# 8050-09-7) 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 of 2500, 5000, or 7500 ppm (equivalent to mean achieved dosages of 199.3, 387.2 or 561.1 mg/kg bw/day respectively). A further group of twenty-four time mated females was fed basal laboratory diet to serve as a control. In-utero survival of the developing conceptus was unaffected by maternal exposure at 7500 ppm, although reduced foetal and placental weights indicated an adverse effect on foetal growth. The absence of any structural defects indicated that development per se was unaffected at this dietary exposure level. At 5000 or 2500 ppm no adverse treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The ‘No Observed Adverse Effect Level’ (NOAEL) for foetal developmental toxicity was therefore considered to be 5000 ppm (equivalent to a mean achieved dosage of 387.2 mg/kg bw/day).

 

The potential for Rosin (Tall oil rosin, CAS# 8050-09-7) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered daily in dietary mixtures at concentrations of 0, 2500 ppm, 5000 ppm, or 10000 ppm to male rats for 42 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. For developmental toxicity, the NOEL was established at 5000 ppm, based on slightly reduced body weight and body weight gain observed in pups during lactation in the 10000 ppm concentration group. Although the reduction was only minor and predominantly not statistically significant if compared to the current control, values at the high concentration level were lower if compared to the historical control background and therefore this observation was considered to be related to the treatment with the test item. The NOAEL for developmental toxicity was established at the concentration level of 10000 ppm, the highest concentration tested in the study (Harlan Laboratories Ltd., 2015a). 

 

The potential for Rosin, hydrogenated (CAS# 65997-06-0) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was continuously administered in feed to rat (12/sex/concentration) at concentrations of 0, 1000, 3000, and 10000 ppm. The test material was administered 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. For developmental toxicity, the NOEL was established at the dose level of 3000 ppm, based on a slight retardation in pup body weights in the presence of adversely reduced food consumption and body weight in females in the high concentration group. No effects on development were observed during the study. The changes in pup body weights were only minor (not statistically significant if compared to the control group), and values in the high-dose group were close to the normal background range in this rat strain. The reduction in pup body weights represents a delayed growth rather than a developmental disturbance. This effect is commonly seen in the presence of maternal toxicity manifested as decreased food consumption associated with reduced body weights and it is considered to be secondary to the maternal toxicity. For these reasons, effects on pup body weights were considered not to be adverse and likely to be a secondary response. Therefore, the NOAEL for developmental toxicity was determined to be 10000 ppm, the highest dose level used in the study (Harlan Laboratories Ltd., 2015b).

 

The potential for Rosin, reaction products with formaldehyde has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered daily in dietary mixtures at concentrations of: 0, 1000, 3000 and 10000 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. No unscheduled deaths were recorded during the study period. No clinical signs were recorded. Slight reductions in food consumption and water consumption and low body weight and body weight gain was recorded in males and females of group 4. The effect was likely due to the reduced palatability of the diet at the higher concentration. Slightly low body weights and reduced water consumption were noted in males of groups 2 and 3. Minimal hypertrophy of the zona glomerulosa were observed in the adrenal glands in males and females of groups 3 and 4. The pathogenesis was considered to be an adaptive process following stimulation of this system. Increased liver weights were recorded at necropsy in males and females of group 4 and these findings are suggestive of an adaptive response to mixed function oxidase induction and considered not to be adverse. The sperm motility, morphology and sperm count, estrus cycle, mating performance, fertility, duration of gestation, corpora lutea count, implantation rate, post-implantation and postnatal loss and litter size were not affected by treatment with the test material at any concentration. There were no test material-related findings in pups noted during the first litter check, the first 4 days post-partum or during the necropsy. Based on the result of the study, the NOAEL (No Observed Adverse Effect Level) for general toxicity was established at a concentration of 10000 ppm and the NOEL (No Observed Effect Level) was established at a concentration of 1000 ppm.The NOAEL and NOEL for reproduction/ developmental toxicity were established at a concentration of 10000 ppm, the highest concentration used in the study (Harlan Laboratories Ltd., 2015c).

 

The potential for Rosin (Gum Rosin; CAS# 8050-09-7) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered to rats (12/sex/dose) in dietary mixtures at concentrations of 0, 2500, 5000, and 10000 ppm for a period of 50 days for male rats 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 (at least 36 days, up to 53 days). The NOEL and the NOAEL for developmental toxicity were established at 5000 ppm, based on mortality and body weight effects observed at the 10000 ppm concentration level (Harlan Laboratories Ltd., 2014a).

 

The potential for Rosin, oligomers (CAS# 65997-05-9) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered to rats (12/sex/concentration) in dietary mixtures at concentrations of 0, 3000, 7500 and 15000 ppm. The test material was continuously administered 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 (up to 55 days). The NOEL and the NOAEL for developmental toxicity was determined to be 3000 ppm, based on effects on pup body weight at concentrations of 7500 and 15000 ppm (Harlan Laboratories Ltd., 2014b).

 

The potential for Gum Rosin (Rosin) to cause developmental toxicity has been evaluated in a reproductive and developmental toxicity screening study conducted according to OECD Guideline 421 in which male and female Sprague Dawley rats were exposed to up to 10000 ppm test substance in the diet during premating, mating, gestation and lactation for a total of 30 exposure days for males and 41-45 exposure days for females study (Inveresk Research, 2003a). At 10000 ppm in the diet, there was a decrease in weight gain or weight loss over the first few weeks of treatment. Decreased weight gain was more severe in females, occurring during the first week on study. After this period, mean weight gain was similar to controls. Pregnant female weight gain was slightly decreased during the first half of gestation. Food consumption was significantly reduced in the 10000 ppm animals for the first 2 weeks of treatment, for both sexes. Food consumption was also slightly reduced throughout gestation and lactation. Consumption at the two lower levels was similar to that of controls. At 10000 ppm, test substance intake in the first week of treatment was lower than the second week for both sexes. There was also a decreased intake in the first week of gestation at this dietary level. For dams, no test material-related effects were noted on mean gestation length or the process of parturition at any exposure concentration. Mean litter and pup weights were slightly reduced for the 10000 ppm dams. There were no obvious external malformations noted in the pups at any of the dose levels in this study. The NOAEL was 3000 ppm, equivalent to a received dose of 288 mg/kg bw/d from GD0 to PND4.

DNEL Worker long-term dermal-systemic

Dose descriptor

A NOAEL of 213.1 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

100% absorption after ingestion and 100% after skin contact are assumed.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

5 (for workerd)

Exposure duration

2 (subchronic to chronic)

Issues related to reliability of the dose-response

1

Issues related to completeness and consistency of the available data

1

 

Overall AF

100

DNEL Worker long-term dermal-systemic = 213.1 / 100 = 2.131 mg/Kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.065 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal NOAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans:

 

 

corrected dermal NOAEL = oral NOAEL x (ABSoral-rat / ABSderm-rat) x (ABSderm-rat / ABSderm-human)

 

                                     = oral NOAEL x (ABSoral-rat / ABSderm-human)

 

                                     = 213.1 mg/Kg bw/day x (1 / 1) 

 

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characte risation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for differences in duration of exposure:
2
Justification:
Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for other interspecies differences:
2.5
Justification:
Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for intraspecies differences:
10
Justification:
For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for the quality of the whole database:
1
Justification:
Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.065 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
213.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

 

Modification of dose descriptor not required 

AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for differences in duration of exposure:
2
Justification:
Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for other interspecies differences:
2.5
Justification:
Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for intraspecies differences:
10
Justification:
For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
AF for the quality of the whole database:
1
Justification:
Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not established if no acute toxicity hazard leading to classification has been identified.

Irritation/Sensitisation

Rosin; Hydrogenated rosin; Rosin oligomers; and Rosin, reaction products with formaldehyde are not irritating to skin or eye. Divalent cationic salts of Rosin and Hydrogenated rosin, and trivalent cationic salts of rosin are insoluble and their irritation potential is therefore comparable to that of the parent substance. Monovalent cationic salts are soluble and alkali in solution. Test results indicate that the monovalent salts are irritating to eye but not to skin. Low vapour pressure precludes inhalation exposure.

Rosin, Hydrogenated rosin, Rosin oligomers and the salts of Resin acids and rosin acids were not sensitisers when tested in the murine Local Lymph Node assay, or when tested in guineas pigs using Maximization and/or Buehler protocols. Positive results obtained in a single Guinea Pig Maximization study with “Rosin” showed, on subsequent investigation, that the sample submitted for testing was heavily oxidized and degraded. Therefore, the positive results in this one study are erroneous and should be disregarded when reviewing the dermal sensitisation hazards of Rosin.

Repeated dose toxicity

The potential for the members of the category Rosins and their salts to cause target organ toxicity following repeated exposure is well understood.Key information is available from three guideline (OECD 408) studies that have investigated the repeated dose oral toxicity of Rosin; Rosin, hydrogenated; and Rosin, reaction products with formaldehyde following dietary administration to rats.

 

Rosin

 

In a key oral repeat dose toxicity study (Envigo Research Limited, 2017a), the test material (Rosin, CAS# 8050-09-7) was administered continuously in the diet of three groups, each composed of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 2500, 5000 or 7500 ppm (equivalent to a mean achieved dosage of 174.1, 335.2 or 510.1 mg/kg bw/day for males and 196.4, 401.2 or 596.2 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet.

 

The continuous dietary administration of the test material to rats, at dietary concentrations of 2500, 5000 and 7500 ppm for ninety consecutive days, resulted in reduced body weight gains in animals of either sex exposed to 7500 ppm and microscopic adrenal changes in animals of either sex exposed to 7500 and 5000 ppm. The No Observed Effect Level (NOEL) for both sexes was therefore considered to be 2500 ppm (equivalent to a mean achieved dosage of 174.1 mg/kg bw/day for males and 196.4 mg/kg bw/day for females). The microscopic adrenal changes (hypertrophy of the zona glomerulosa) identified in animals of either sex exposed to 7500 or 5000 ppm were mild. The changes were not considered to have affected normal electrolyte regulation and did not appear to have an effect on homeostatic control. Therefore, they were not considered to have had adverse consequences for the organ or the body. For this reason, 5000 ppm (equivalent to a mean achieved dosage of 335.2 mg/kg bw/day for males and 401.2 mg/kg bw/day for females) was considered to be the “No Observed Adverse Effect Level” (NOAEL) systemic toxicity.

 

Rosin, hydrogenated

 

In a key sub-chronic toxicity study (Envigo Research Limited, 2016a), the test material (Rosin, Hydrogenated; CAS# 65997-06-0) was administered by continuous dietary admixture to groups of male and female WistarHan™:RccHan™:WIST strain rats(10/sex/concentration), for ninety consecutive days, at dietary concentrations of 1000 and 2000 ppm for the low and intermediate exposure groups (equivalent to mean achieved dosages of 64.5 and 133.3 mg/kg bw/day for males and 78.5 and 156.4 mg/kg bw/day for females). For the high exposure group, rats were initially fed diet containing 4000 ppm for five weeks followed by 6000 ppm for the remainder of the study (equivalent to mean achieved dosages of 334.5 mg/kg bw/day for males and 399.8 mg/kg bw/day for females). A control group of ten males and ten females were fed basal laboratory diet. The No Observed Adverse Effect Level (NOAEL) was determined to be 6000 ppm for either sex (equivalent to a mean achieved dosage of 334.5 mg/kg bw/day for males and 399.8 mg/kg bw/day for females).

 

Rosin, reaction products with formaldeyde

 

In a key sub-chronic oral repeated dose toxicity study (Envigo Research Limited, 2017b), the test item (Rosin, reaction products with formaldehyde; CAS# 91081-53-7), was administered by continuous dietary admixture to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 1000, 3000 and 7500 ppm (equivalent to a mean achieved dosage of 68.9, 213.1 and 509.2 mg/kg bw/day for males and 84.0, 255.2 and 644.6 mg/kg bw/day for females respectively). A control group of ten males and ten females were treated with basal laboratory diet.

 

Based on the effects on body weight, body weight gain and, to a lesser extent, food consumption, observed among females exposed to diets containing 7500 ppm of the test material, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity of Rosin, reaction products with formaldehyde (CAS 91081-53-7) in this Ninety Day Toxicity study was considered to be 3000 ppm (equivalent to mean achieved dosages of approximately 213.1 mg/kg bw/day or 255.2 mg/kg bw/day for males and females, respectively). As an initial transient effect on body weight and food consumption (which may reflect palatability of the diet formulations) was apparent at 1000 ppm, the No Observed Effect Level (NOEL) for systemic effects could not be established.

Genetic toxicity

Adequate information exists to characterise the genetic toxicity of the members of the category Rosin, Hydrogenated rosin, and their salts. Results of bacterial mutation assays demonstrate that Rosin, Resin acids and rosin acids, hydrogenated, potassium salts, Resin acids and rosin acids, calcium salts, Resin acids and rosin acids, magnesium salts, Resin acids and rosin acids, calcium salts, Resin acids and rosin acids, manganese salts, Resin acids and rosin acids, aluminium salts, and Resin acids and rosin acids, hydrogenated calcium salts were not mutagenic in four strains of Salmonella typhimurium and strain WP2 of Escherichia coli when tested in the absence or presence of exogenous metabolic activation. When tested using mammalian cells in vitro, in the absence and in the presence of S9 fraction, Rosin was inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in a cytogenetics assay (human lymphocytes).

Reproductive / developmental toxicity

Reproductive Toxicity

 

In a key combined repeated dose, reproductive/developmental OECD 422 toxicity screening study (Harlan Laboratories Ltd., 2015a), the test material (Tall oil rosin, CAS# 8050-09-7) was administered daily in dietary mixtures at concentrations of 0, 2500 ppm, 5000 ppm, or 10000 ppm to male rats for 42 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. In the high concentration group, the number of corpora lutea was reduced, which resulted in slightly, not statistically significant lower number of implantation sites and slightly, not statistically significant lower litter size at first litter check. Mean litter size at the high concentration level remained in the range of historical control values. Slightly reduced body weight and body weight gain were observed in pups during lactation. Although the reduction was only minor and predominantly not statistically significant if compared to the current control, values at the high concentration level were lower if compared to the historical control background and therefore this observation was considered to be related to the treatment with the test item. Mating performance, fertility, duration of gestation, post-implantation and post-natal loss were considered not to be affected by the treatment with the test item at any concentration level. Due to adverse effects on body weight observed in females in the high concentration group, a possibility that the reduced number of corpora lutea as well as lower pup body weight were secondary to the maternal response, should be taken into consideration. No effects on reproductive parameters were observed in animals in the 5000-ppm group. In the low concentration group (2500 ppm), no effects on reproduction were observed. For reproductive toxicity, the NOEL was established at 5000 ppm whereas the NOAEL was established at the concentration level of 10000 ppm, the highest concentration tested in the study.

 

In a key combined repeated dose, reproductive/developmental toxicity study (OECD 422), the test material (Rosin, hydrogenated; CAS# 65997-06-0) was continuously administered in feed to rats (12/sex/concentration) at concentrations of 0, 1000, 3000, and 10000 ppm. The test material was administered 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 (Harlan Laboratories Ltd., 2015b). There were no test item related microscopic findings in the reproductive organs, including the qualitative examination of the stages of spermatogenesis in the testes (no test item related abnormalities in the integrity of the various cell types present within the different stages of the sperm cycle) and the evaluation of the uterus or evaluation of follicles and corpora lutea in the ovaries. There were no test item related microscopic findings in the males or females suspected of reduced fertility. A reduction in corpora lutea count was observed in females ingroup 4 during the macroscopic evaluation at necropsy whereas histopathological evaluation of follicles and corpora lutea in the ovaries did not reveal any test item-related effect. Because no significant changes in the number of implantation sites or litter size were observed during the study, the reduction in corpora lutea count was considered not to be adverse. Further, the effect on corpora lutea count may possibly be secondary to the toxic effects in females observed in this group. Remaining reproduction parameters: mating performance, fertility, duration of gestation, post implantation and postnatal loss were not affected by the treatment with the test item at any dose level. For reproductive toxicity, the NOEL was established at the dose level of 3000 ppm whereas the NOAEL was at 10000 ppm, the highest dose level used in the study.

 

In a key reproductive/developmental toxicity study (OECD 422), the toxicological effects on rats resulting from continuous dietary oral administration of the test material (Rosin, reaction product with formaldehyde, CAS #. 91081-53-7) were evaluated (Harlan Laboratories Ltd., 2015c). The test material was administered daily in dietary mixtures at concentrations of: 0, 1000, 3000 and 10000 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. The sperm motility, morphology and sperm count, estrus cycle, mating performance, fertility, duration of gestation, corpora lutea count, implantation rate, post-implantation and postnatal loss and litter size were not affected by treatment with the test material at any concentration. Based on the result of the study, the NOAEL and NOEL for reproductive toxicity were established at a concentration of 10000 ppm, the highest concentration used in the study.

 

In another key combined repeated dose, reproductive/developmental (OECD 422) toxicity study (Harlan Laboratories Ltd., 2014a), Gum Rosin was administered to rats (12/sex/dose) in dietary mixtures at concentrations of 0, 2500, 5000, and 10000 ppm for a period of 50 days for male rats 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 (at least 36 days, up to 53 days). Mating performance, fertility index, duration of gestation, and post-implantation loss were not affected by the treatment with the test material at any dose level. In the high dose group (10000 ppm), the mean number of corpora lutea and implantations per dam as well as the mean litter size at the first litter check were decreased. The effects on reproduction were considered likely to be secondary to the effects of the treatment on food consumption and body weight development of the dams. Based on the results of this study, the NOEL and the NOAEL for reproductive toxicity were established at 5000 ppm.

 

In another key combined repeated dose, reproductive/developmental toxicity study (OECD 422), the test material (Rosin, oligomers; CAS # 65997-05-9) was administered to rats (12/sex/concentration) in dietary mixtures at concentrations of 0, 3000, 7500 and 15000 ppm (Harlan Laboratories Ltd., 2014b). The test material was continuously administered 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 (up to 55 days). No clinical signs of toxicological relevance were observed and mating performance, fertility index, and duration of gestation were not affected by the treatment at any concentration level. The mean numbers of corpora lutea and implantations per dam were decreased and the total number of post implantation losses was significantly higher in Group 4 females than in the control group. This led to a lower mean number of living pups per litter at the first litter check. These observations could be secondary to lower maternal food consumption and body weight gain in this group. The NOEL and the NOAEL for reproductive toxicity was determined to be 3000 ppm.

 

In a reproductive and developmental toxicity screening study conducted according to OECD Guideline 421 (Inveresk Research, 2003a), male and female Sprague Dawley rats were exposed to 0, 1000, 3000 or 10,000 ppm Gum Rosin (Rosin) in the diet during pre-mating, mating, gestation and lactation for a total of 30 exposure days for males and 41-45 exposure days for females. At 10,000 ppm in the diet (equivalent to 786 mg/kg bw/f for males and 869 mg/kg bw/d for females), there were no test material-related effects on mating performance, male and female fertility indices, or length of gestation and no gross or microscopic effects on reproductive organs of either sex. The mean number of implant sites per pregnancy was slightly reduced resulting in a slight reduction in litter size. Mean litter and pup weights were also slightly reduced. The effect on implantation, litter size and fetal weight may be secondary to the effects on decreased food intake and subsequent lower weight gain observed in the adult females. A NOAEL of 3000 ppm, equivalent to 248 (males) to 309 (females) mg/kg bw/d was derived from this study.

 

Additionally, in guideline repeat exposure studies (OECD 408), there were no gross or microscopic changes in reproductive organs of male or female rats exposed to Rosin; Rosin, hydrogenated; or Rosin, reaction products with formaldehyde for a period of 90 days.

 

Developmental toxicity

In a key pre-natal developmental toxicity study (Envigo Research Ltd., 2017c), the test material (Rosin, CAS# 8050-09-7) 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 of 2500, 5000, or 7500 ppm (equivalent to mean achieved dosages of 199.3, 387.2 or 561.1 mg/kg bw/day respectively). A further group of twenty-four time mated females was fed basal laboratory diet to serve as a control. In-utero survival of the developing conceptus was unaffected by maternal exposure at 7500 ppm, although reduced foetal and placental weights indicated an adverse effect on foetal growth. The absence of any structural defects indicated that development per se was unaffected at this dietary exposure level. At 5000 or 2500 ppm no adverse treatment-related changes were detected in the offspring parameters measured or on embryofoetal development. The ‘No Observed Adverse Effect Level’ (NOAEL) for foetal developmental toxicity was therefore considered to be 5000 ppm (equivalent to a mean achieved dosage of 387.2 mg/kg bw/day).

 

The potential for Rosin (Tall oil rosin, CAS# 8050-09-7) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered daily in dietary mixtures at concentrations of 0, 2500 ppm, 5000 ppm, or 10000 ppm to male rats for 42 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.For developmental toxicity, the NOEL was established at 5000 ppm, based on slightly reduced body weight and body weight gain observed in pups during lactation in the 10000 ppm concentration group. Although the reduction was only minor and predominantly not statistically significant if compared to the current control, values at the high concentration level were lower if compared to the historical control background and therefore this observation was considered to be related to the treatment with the test item. The NOAEL for developmental toxicity was established at the concentration level of 10000 ppm, the highest concentration tested in the study (Harlan Laboratories Ltd., 2015a). 

 

The potential for Rosin, hydrogenated (CAS# 65997-06-0) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was continuously administered in feed to rat (12/sex/concentration) at concentrations of 0, 1000, 3000, and 10000 ppm. The test material was administered 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. For developmental toxicity, the NOEL was established at the dose level of 3000 ppm, based on a slight retardation in pup body weights in the presence of adversely reduced food consumption and body weight in females in the high concentration group. No effects on development were observed during the study. The changes in pup body weights were only minor (not statistically significant if compared to the control group), and values in the high-dose group were close to the normal background range in this rat strain. The reduction in pup body weights represents a delayed growth rather than a developmental disturbance. This effect is commonly seen in the presence of maternal toxicity manifested as decreased food consumption associated with reduced body weights and it is considered to be secondary to the maternal toxicity. For these reasons, effects on pup body weights were considered not to be adverse and likely to be a secondary response. Therefore, the NOAEL for developmental toxicity was determined to be 10000 ppm, the highest dose level used in the study (Harlan Laboratories Ltd., 2015b).

 

The potential for Rosin, reaction products with formaldehyde has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered daily in dietary mixtures at concentrations of: 0, 1000, 3000 and 10000 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. No unscheduled deaths were recorded during the study period. No clinical signs were recorded. Slight reductions in food consumption and water consumption and low body weight and body weight gain was recorded in males and females of group 4. The effect was likely due to the reduced palatability of the diet at the higher concentration. Slightly low body weights and reduced water consumption were noted in males of groups 2 and 3. Minimal hypertrophy of the zona glomerulosa were observed in the adrenal glands in males and females of groups 3 and 4. The pathogenesis was considered to be an adaptive process following stimulation of this system. Increased liver weights were recorded at necropsy in males and females of group 4 and these findings are suggestive of an adaptive response to mixed function oxidase induction and considered not to be adverse. The sperm motility, morphology and sperm count, estrus cycle, mating performance, fertility, duration of gestation, corpora lutea count, implantation rate, post-implantation and postnatal loss and litter size were not affected by treatment with the test material at any concentration. There were no test material-related findings in pups noted during the first litter check, the first 4 days post-partum or during the necropsy. Based on the result of the study, the NOAEL (No Observed Adverse Effect Level) for general toxicity was established at a concentration of 10000 ppm and the NOEL (No Observed Effect Level) was established at a concentration of 1000 ppm.The NOAEL and NOEL for reproduction/ developmental toxicity were established at a concentration of 10000 ppm, the highest concentration used in the study (Harlan Laboratories Ltd., 2015c).

 

The potential for Rosin (Gum Rosin; CAS# 8050-09-7) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered to rats(12/sex/dose) in dietary mixtures at concentrations of 0, 2500, 5000, and 10000 ppm for a period of 50 days for male rats 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 (at least 36 days, up to 53 days). The NOEL and the NOAEL for developmental toxicity were established at 5000 ppm, based on mortality and body weight effects observed at the 10000 ppm concentration level (Harlan Laboratories Ltd., 2014a).

 

The potential for Rosin, oligomers (CAS# 65997-05-9) has been evaluated in a reproductive/developmental toxicity study conducted according to OECD Guideline 422, in which the test material was administered to rats (12/sex/concentration) in dietary mixtures at concentrations of 0, 3000, 7500 and 15000 ppm. The test material was continuously administered 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 (up to 55 days). The NOEL and the NOAEL for developmental toxicity was determined to be 3000 ppm, based on effects on pup body weight at concentrations of 7500 and 15000 ppm (Harlan Laboratories Ltd., 2014b).

 

The potential for Gum Rosin (Rosin) to cause developmental toxicity has been evaluated in a reproductive and developmental toxicity screening study conducted according to OECD Guideline 421 in which male and female Sprague Dawley rats were exposed to up to 10000 ppm test substance in the diet during premating, mating, gestation and lactation for a total of 30 exposure days for males and 41-45 exposure days for females study (Inveresk Research, 2003a). At 10000 ppm in the diet, there was a decrease in weight gain or weight loss over the first few weeks of treatment. Decreased weight gain was more severe in females, occurring during the first week on study. After this period, mean weight gain was similar to controls. Pregnant female weight gain was slightly decreased during the first half of gestation. Food consumption was significantly reduced in the 10000 ppm animals for the first 2 weeks of treatment, for both sexes. Food consumption was also slightly reduced throughout gestation and lactation. Consumption at the two lower levels was similar to that of controls. At 10000 ppm, test substance intake in the first week of treatment was lower than the second week for both sexes. There was also a decreased intake in the first week of gestation at this dietary level. For dams, no test material-related effects were noted on mean gestation length or the process of parturition at any exposure concentration. Mean litter and pup weights were slightly reduced for the 10000 ppm dams. There were no obvious external malformations noted in the pups at any of the dose levels in this study. The NOAEL was 3000 ppm, equivalent to a received dose of 288 mg/kg bw/d from GD0 to PND4.

DNEL General Population long-term dermal-systemic

Dose descriptor

A NOAEL of 213.1 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

100% absorption after ingestion and 100% after skin contact are assumed.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

General Population

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

10 (for general population)

Exposure duration

2 (subchronic to chronic)

Issues related to reliability of the dose-response

1

Issues related to completeness and consistency of the available data

1

 

Overall AF

200

 

DNEL General Population long-term dermal-systemic = 213.1 / 200 = 1.0655 mg/Kg bw/day

DNEL General Population long-term oral-systemic

Dose descriptor

A NOAEL of 213.1 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

Modification of dose descriptor not required 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Oral)

Assessment Factor

General Population

Interspecies

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

Intraspecies

10 (for general population)

Exposure duration

2 (subchronic to chronic)

Issues related to reliability of the dose-response

1

Issues related to completeness and consistency of the available data

1

 

Overall AF

200

 

DNEL General Population long-term oral-systemic = 213.1 / 200 = 1.0655 mg/Kg bw/day