Registration Dossier

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

DNEL derivation method:

other: ECHA Guidance. Generic ECHA recommendation for a long-term DNEL (inhalation, worker)

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.995 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

99.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

99.5 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 (ABS_oral-rat/ ABS_derm-rat) x (ABS_derm-rat/ ABS_derm-human)

= oral NOAEL x (ABS_oral-rat/ ABS_derm-human)

= 99.5 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: 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:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 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).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Justification for Read Across

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

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin,

calcium magnesium zinc salts are not acutely toxic following oral exposure (LD₅₀>2000 mg/Kg bw) while a low vapour pressure precludes inhalation exposure indicating a low of concern for this route of exposure. Based on available acute oral toxicity data (LD₅₀>2000 mg/Kg bw), the acute dermal toxicity of the fatty acids, tall oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts is expected to be greater than 2000 mg/Kg. Therefore, this substance is not expected to pose an acute dermal toxicity hazard and is not classified under EU CLP for the same. No DNELs for acute toxicity are therefore necessary.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. However, while read across test results indicate that Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts are irritating to eye (but not to skin), the nature of the data is such that no conclusion can be drawn with regard to any dose-response relationship present. No DNEL for irritation can therefore be derived.

Sensitisation

No key or supporting skin sensitisation data is available for Fatty acids, tall oil, oligomeric reaction products with maleaic anhydride and rosin, calcium, magnesium salts. However, data is available from tests conducted using a structural analogue Rosin, maleated. The sensitisation potential of Rosin, maleated is well understood and comprises results from one local lymph node assay, a guinea pig maximisation test and a guinea pig Buehler test. The results consistently show evidence of a potential to induce skin sensitisation.

Intrinsic sensitising potency

ECHA Guidance R.8, Appendix R.8-10, (ECHA, 2010) states that while skin sensitisation is generally regarded as a threshold effect it may be very difficult to derive a threshold and to set a DNEL. Thus, the general approach for sensitisers involves a qualitative approach where a DNEL is used to judge any remaining/residual risks after the implementation of appropriate risk management measures (RMM) and occupational controls (OC).

The extent of the RMM and OC required is dependent on the intrinsic sensitising potency of the substance.

For results obtained using the LLNA, intrinsic sensitising potency is based on the EC3 and defined (ECHA (2010), Appendix R.8-10) as follows:

Category	EC3 (%)
Extreme	<0.2%
Strong	>0.2 - <2
Moderate	>2

An EC3 value of 0.74% was obtained for Rosin, maleated. This indicates a strong potential to cause skin sensitisation.

For results obtained using the guinea pig maximisation test, intrinsic sensitising potency is based on the (intradermal) concentration employed during the induction phase of the test together with the incidence of sensitisation following challenge (ECHA, 2010):

Induction conc (%)

Incidence of sensitisation

<0.1

Strong

(30-60%)

Extreme

(>60%)

>0.1 - <1

Moderate

(30-60%)

Strong

(>60%)

>1

Moderate

(30-60%)

Moderate

(>60%)

Results obtained from a guinea pig maximisation test on Rosin, maleated using an intradermal induction concentration of 0.003% resulted in sensitisation incidences of 79% (10% challenge concentration) and 100% (30% challenge concentration) and are therefore indicative of an extreme sensitiser.

Different criteria apply to interpretation of results obtained using the Buehler test (ECHA Guidance R.8 (Appendix R.8-10)):

Induction conc (%)

Incidence of sensitisation

<0.2

Strong

(15-60%)

Extreme

(>60%)

>0.2 - <20

Moderate

(15-60%)

Strong

(>60%)

>20

Moderate

(15-60%)

Moderate

(>60%)

Results obtained from a Buehler test on Rosin, maleated using an induction concentration of 80% gave a sensitisation incidence of 80% (5% challenge concentration) indicative of a moderate sensitiser.

Given the range of outcomes obtained (1 extreme; 2 strong; 2 moderate), it will be assumed for the purposes of risk characterisation that Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts have a strong potential to cause sensitisation following skin contact.

Derivation of a DNEL for sensitisation

ECHA Guidance R.8, Appendix R.8-10 (ECHA, 2010), indicates that the EC3 concentration from a LLNA test can be taken as a LOAEL for the induction of skin sensitisation (ECHA, 2010) after conversion into an equivalent dose per unit area of skin (µg/cm²). Assuming (i) a dose volume of 25 μL (according to the standard LLNA protocol); (ii) an estimated treatment area of 1 cm²for the mouse ear; and (iii) an assumed density of is 1, the conversion is performed as follows:

EC3 [%] * 250 [µg/cm²/%] = EC3 [μg/cm²]

Based on LLNA results for Rosin, maleated, the equivalent EC3 [μg/cm²] is therefore:

0.74% * 250 = 185 µg/cm²

The EC3 of 185 µg/cm²obtained for Rosin, maleated, will be used to assess the magnitude of any remaining/residual risks after the use of RMMs and OCs recommended in the Qualitative Risk Assessment for this subtance. No Assessment Factors will be applied to this value since it is already a conservative result, with skin penetration (and hence the capacity of the substance to induce skin sensitisation) enhanced in the LLNA test by the deliberate use of a solvent system that is not present in an occupational or consumer setting. The EC3 of 185 µg/cm²will therefore be used as a human NAEL.

Repeated dose toxicity

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

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

In the 15000 ppm concentration group, slight reductions in food consumption and water consumption and low body weight and body weight gain recorded in males and females were likely due to reduced palatability of the diet at the higher concentration. In addition, differences in bilirubin, cholesterol, creatinine and triglyceride values noted in group 4 were considered not to be adverse in the absence of any histopathological or other related changes. The general lipemic trend (increased cholesterol and triglycerides) in the females of the high concentration group was not reflected in males and, although the toxicological relevance of this finding is unclear, a possible relationship with the treatment of the test item cannot be excluded.

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

The decreased adrenal weights recorded at necropsy in males and females in the high concentration group correlated histologically with hypertrophy. These findings are suggestive of an adaptive response and considered not to be adverse. Marginally low food consumption in males and females and reduced water consumption in females were noted at the 5000 ppm concentration level. No other test item-related effects were noted in males or females at any concentration.

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

In a key read across Guideline (OECD 408) sub-chronic repeated dose oral toxicity study (Envigo Research Laboratories, 2017a), the test material (Rosin, maleated; CAS# 8050-28-0) was administered by continuous dietary admixture tothree groups, each composed of ten male and ten female WistarHan™:RccHan™:WIST strain rats, for ninety consecutive days, at dietary concentrations of 500, 1500 and 3000 ppm (equivalent to mean achieved dosages of 33.7, 99.5 or 195.0 mg/Kg bw/day for males and 37.1, 120.4 or 241.7 mg/Kg bw/day for females, respectively). A control group of ten males and ten females were fed basal laboratory diet.

Clinical signs, functional observations, body weight change, diet intake and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study.Ophthalmoscopicexaminations were also performed on animals from the control and high exposure groups before the start of treatment and during Week 12 of the study. All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of tissues from high dietary level and control animals was performed. Histopathology examinations were also extended to include the urinary bladders from animals in the low and intermediate dietary levels.

No mortality or adverse signs of clinical toxicity were observed through the study period. Neurobehavioral parameters, water consumption, ophthalmoscopic parameters, hematological and clinical chemistry parametersremained unaffectedby exposure to the test material at concentrations up to 3000 ppm. Gross necropsy did not reveal any remarkable effects and absolute or relative (to body weight) organ weights were not affected by treatment.Males exposed to a dietary concentration of 3000 ppm of the test material generally showed lower mean body weight gain (Weeks 1, 3 and 11, p<0.01: Weeks 5 and 6, p<0.05) throughout the study and statistically significant lower overallmean body weight gain (p<0.01) compared to control. Statistically significant lower mean body weight (p<0.05) was apparent on Days 8, 22 and from Day 36 to termination compared with control. Females exposed to a dietary concentration of 3000 ppm of the test material, showed statistically significant lower overall mean body weight gain (p<0.05) compared to control and statistically significant lower mean body weights were apparent from Day 29 to termination (p<0.05 to p<0.01). Males exposed to a dietary concentration of 1500ppm showed statistically significant lower mean body weight gain (p<0.05) during the first week of the study compared with control. Statistically significant lower mean body weight gain (p<0.01) was also observed during week 11 (Days 71-78). Overall mean body weight gain was slightly, but not statistically significantly lower than control (91% of control). Mean body weights, weekly body weight gains and overall body weight gain for both sexes exposed to a dietary concentration of 500 ppm and females exposed to a dietary concentration of 1500 ppm showed no statistically significant differences from control throughout the study.

Males exposed to a dietary concentration of 3000 ppm showed lower food consumption throughout the study compared to control. Females exposed to a dietary concentration of 3000 ppm showed lower food consumption fromWeek 2, withdifferences from control being most pronounced during Weeks 2 to 5 and 7 to 9. Males exposed to a dietary concentration of 1500 ppm showed lower food consumption throughout the study, with differences from control being most pronounced from Week 7 onwards. For females exposed to a dietary concentration of 1500 ppm of the test material, food consumption also tended to be lower than control from Week 2, but a clear association with dietary exposure was not proven. For both sexes exposed to a dietary concentration of 500 ppm, food consumption was considered to be unaffected by treatment. Food conversion efficiency was unaffected by exposure to the test material at concentrations up to 3000 ppm.

Minimal to moderate urothelial hyperplasia was present in 3/8 males and 6/9 females exposed to a dietary concentration of 3000 ppm of the test item, with accompanying minimal to mild inflammatory changes also beingpresent in 5/9females.

Based on the results of this ninety-day study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity of Rosin, maleated was considered to be 1500 ppm (equivalent to a mean achieved dosage of 99.5 and 120.4mg/Kg bw/dayfor males and females respectively due to reduced bodyweight gains and food consumption and adverse histopathological changes in the urinary bladder of both sexes exposed to a dietary concentration of 3000 ppm of the test material.

Additionally, data from a Guideline 422 study and supporting data from a Guideline OECD 414 study (Envigo Research Laboratories, 2017b) and two dose range-finding studies (Harlan Laboratories Ltd., 2014 and Charles River Laboratories, 2017) that were conducted on Rosin, maleated is also available. This data is available in the substance dossier for Rosin, maleated.

Genetic Toxicity

Adequate information exists to characterise the mutagenicity of Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts. Results of bacterial mutation assays demonstrate that Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts was 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 cellsin vitro, in the absence and in the presence of S9 fraction, Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts was inactive in a gene mutation assay (L5178Y mouse lymphoma cells) and in a mammalian chromosome aberration test (Human lymphocytes).

Reproductive / Developmental Toxicity

Reproductive Toxicity

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

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

In the 15000 ppm concentration group, slight reductions in food consumption and water consumption and low body weight and body weight gain recorded in males and females were likely due to reduced palatability of the diet at the higher concentration. In addition, differences in bilirubin, cholesterol, creatinine and triglyceride values noted in group 4 were considered not to be adverse in the absence of any histopathological or other related changes. The general lipemic trend (increased cholesterol and triglycerides) in the females of the 15000 ppm concentration group was not reflected in males and, although the toxicological relevance of this finding is unclear, a possible relationship with the treatment of the test item cannot be excluded.

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

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

The decreased adrenal weights recorded at necropsy in males and females in the 15000 ppm concentration group correlated histologically with hypertrophy. These findings are suggestive of an adaptive response and considered not to be adverse. Marginally low food consumption in males and females and reduced water consumption in females were noted in animals exposed to the test material at 5000 ppm. No other test item-related effects were noted in males or females at any concentration.

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

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

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

Developmental Toxicity

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

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

post-partum at concentrations of 0, 1000, 5000, or 15000 ppm.

In the 15000 ppm concentration group, slight reductions in food consumption and water consumption and low body weight and body weight gain recorded in males and females were likely due to reduced palatability of the diet at the higher concentration. In addition,

differences in bilirubin, cholesterol, creatinine and triglyceride values noted in group 4 were considered not to be adverse in the absence of any histopathological or other related changes. The general lipemic trend (increased cholesterol and triglycerides) in the females of the 15000 ppm concentration group was not reflected in males and, although the toxicological relevance of this finding is unclear, a possible relationship with the treatment of the test item cannot be excluded.

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

There was also a higher incidence of red discoloured lungs in the pups at this concentration. Microscopic findings of minimal hypertrophy/vacuolation of the zona glomerulosa were observed in the adrenal glands of some males and females in the high concentration

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

The decreased adrenal weights recorded at necropsy in males and females in the 15000 ppm concentration group correlated histologically with hypertrophy. These findings are suggestive of an adaptive response and considered not to be adverse. Marginally low food

consumption in males and females and reduced water consumption in females were noted in animals exposed to the test material at 5000 ppm. No other test item-related effects were noted in males or females at any concentration.

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

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

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

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

substance dossier for Rosin, maleated.

DNEL Worker long-term dermal-systemic

Dose descriptor

A NOAEL of 99.5 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 worker)
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-systemic via dermal route = 99.5 / 100 = 0.995 mg/Kg bw/day

Endpoint for risk characterisation

Experimental results indicating a potential to cause sensitisation by skin contact, with associated classification under Regulation (EC) No. 1272/2008, indicate that Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts may present a risk to the general population during normal handling and use. Qualitative risk characterisation (ECHA, 2010) will therefore be conducted on this endpoint.

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.497 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

99.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

99.5 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 (ABS_oral-rat/ ABS_derm-rat) x (ABS_derm-rat/ ABS_derm-human)

= oral NOAEL x (ABS_oral-rat/ ABS_derm-human)

= 99.5 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: 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).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.497 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

99.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

99.5 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 (ABS_oral-rat/ ABS_derm-rat) x (ABS_derm-rat/ ABS_derm-human)

= oral NOAEL x (ABS_oral-rat/ ABS_derm-human)

= 99.5 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: 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).

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Justification for Read Across

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

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin,

calcium magnesium zinc salts are not acutely toxic following oral exposure (LD₅₀>2000 mg/Kg bw) while a low vapour pressure precludes inhalation exposure indicating a low of concern for this route of exposure. Based on available acute oral toxicity data (LD₅₀>2000 mg/Kg bw), the acute dermal toxicity of the fatty acids, tall oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts is expected to be greater than 2000 mg/Kg. Therefore, this substance is not expected to pose an acute dermal toxicity hazard and is not classified under EU CLP for the same. No DNELs for acute toxicity are therefore necessary.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. However, while read across test results indicate that Fatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc salts are irritating to eye (but not to skin), the nature of the data is such that no conclusion can be drawn with regard to any dose-response relationship present. No DNEL for irritation can therefore be derived.

Sensitisation

No key or supporting skin sensitisation data is available for Fatty acids, tall oil, oligomeric reaction products with maleaic anhydride and rosin, calcium, magnesium salts. However, data is available from tests conducted using a structural analogue Rosin, maleated.The sensitisation potential of Rosin, maleated is well understood and comprises results from one local lymph node assay, a guinea pig maximisation test and a guinea pig Buehler test. The results consistently show evidence of a potential to induce skin sensitisation.

Intrinsic sensitising potency

ECHA Guidance R.8, Appendix R.8-10, (ECHA, 2010) states that while skin sensitisation is generally regarded as a threshold effect it may be very difficult to derive a threshold and to set a DNEL. Thus, the general approach for sensitisers involves a qualitative approach where a DNEL is used to judge any remaining/residual risks after the implementation of appropriate risk management measures (RMM) and occupational controls (OC).

The extent of the RMM and OC required is dependent on the intrinsic sensitising potency of the substance.

For results obtained using the LLNA, intrinsic sensitising potency is based on the EC3 and defined (ECHA (2010), Appendix R.8-10) as follows:

Category	EC3 (%)
Extreme	<0.2%
Strong	>0.2 - <2
Moderate	>2

An EC3 value of 0.74% was obtained for Rosin, maleated. This indicates a strong potential to cause skin sensitisation.

For results obtained using the guinea pig maximisation test, intrinsic sensitising potency is based on the (intradermal) concentration employed during the induction phase of the test together with the incidence of sensitisation following challenge (ECHA, 2010):

Induction conc (%)

Incidence of sensitisation

<0.1

Strong

(30-60%)

Extreme

(>60%)

>0.1 - <1

Moderate

(30-60%)

Strong

(>60%)

>1

Moderate

(30-60%)

Moderate

(>60%)

Results obtained from a guinea pig maximisation test on Rosin, maleated using an intradermal induction concentration of 0.003% resulted in sensitisation incidences of 79% (10% challenge concentration) and 100% (30% challenge concentration) and are therefore indicative of an extreme sensitiser.

Different criteria apply to interpretation of results obtained using the Buehler test (ECHA Guidance R.8 (Appendix R.8-10)):

Induction conc (%)

Incidence of sensitisation

<0.2

Strong

(15-60%)

Extreme

(>60%)

>0.2 - <20

Moderate

(15-60%)

Strong

(>60%)

>20

Moderate

(15-60%)

Moderate

(>60%)

Results obtained from a Buehler test on Rosin, maleated using an induction concentration of 80% gave a sensitisation incidence of 80% (5% challenge concentration) indicative of a moderate sensitiser.

Given the range of outcomes obtained (1 extreme; 2 strong; 2 moderate), it will be assumed for the purposes of risk characterisation thatFatty acids, tall-oil, oligomeric reaction products with maleic anhydride and rosin, calcium magnesium zinc saltshave a strong potential to cause sensitisation following skin contact.

Derivation of a DNEL for sensitisation

ECHA Guidance R.8, Appendix R.8-10 (ECHA, 2010), indicates that the EC3 concentration from a LLNA test can be taken as a LOAEL for the induction of skin sensitisation (ECHA, 2010) after conversion into an equivalent dose per unit area of skin (µg/cm²). Assuming (i) a dose volume of 25 μL (according tothe standard LLNA protocol); (ii) an estimated treatment area of 1 cm²for the mouse ear; and (iii) an assumed density of is 1, the conversion is performed as follows:

EC3 [%] * 250 [µg/cm²/%] = EC3 [μg/cm²]

Based on LLNA results for Rosin, maleated, the equivalent EC3 [μg/cm²] is therefore:

0.74% * 250 = 185 µg/cm²

The EC3 of 185 µg/cm²obtained for Rosin, maleated, will be used to assess the magnitude of any remaining/residual risks after the use of RMMs and OCs recommended in the Qualitative Risk Assessment for this substance. No Assessment Factors will be applied to this value since it is already a conservative result, with skin penetration (and hence the capacity of the substance to induce skin sensitisation) enhanced in the LLNA test by the deliberate use of a solvent system that is not present in an occupational or consumer setting. The EC3 of 185 µg/cm²will therefore be used as a human NAEL.

Repeated dose toxicity

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

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

In the 15000 ppm concentration group, slight reductions in food consumption and water consumption and low body weight and body weight gain recorded in males and females were likely due to reduced palatability of the diet at the higher concentration. In addition, differences in bilirubin, cholesterol, creatinine and triglyceride values noted in the high concentration group were considered not to be adverse in the absence of any histopathological or other related changes. The general lipemic trend (increased cholesterol and triglycerides) in the females in the high concentration group was not reflected in males and, although the toxicological relevance of this finding is unclear, a possible relationship with the treatment of the test item cannot be excluded.

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

The decreased adrenal weights recorded at necropsy in males and females in the high concentration group correlated histologically with hypertrophy. These findings are suggestive of an adaptive response and considered not to be adverse. Marginally low food consumption in males and females and reduced water consumption in females were noted in the 5000 ppm concentration group. No other test item-related effects were noted in males or females at any concentration.