Overbased reaction products of distilled tall oil and magnesium hydroxide’

Endpoint summary

Description of key information

Data are available from one key 'read-across' dermal repeat dose toxicity study conducted in rats as well as from multiple oral repeat dose toxicity studies that tested rosin oligomers, hydrogenated rosin, and rosin. Weight of evidence suggests that Distilled tall oil, magnesium salt will have low potential to cause systemic toxicity via  oral and dermal routes. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

A number of repeat dose oral toxicity studies are available on related materials (rosin oligomers, hydrogenated rosin and rosin). Although these studies show no evidence of significant systemic toxicity, the conduct and reporting was of uncertain quality (Klimisch 4) and hence are only included for completeness.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 089.75 mg/kg bw/day

Species:

rat

Quality of whole database:

NOAEL established for systemic effects on basis that no statistically significant adverse (treatment related) effects were observed at all test doses.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

111.25

Species:

rat

Quality of whole database:

NOAEL for local effects at the test site based on observation of: minimal to moderate erosion / ulceration, epidermal hyperplasia and exudate; minimal to mild acute to subacute / chronic inflammation, and minimal edema at 345 and 1089.75 mg/kg bw/day dose groups. The 1089.75 mg/kg bw/day recovery group animals indicated partial resolution of these findings following the 14 day recovery period.

Additional information

There are no data available on the repeated dose systemic toxicity of Distilled tall oil, magnesium salt. The potential to cause systemic toxicity can however be predicted from studies available on related salts of unsaturated fatty acids, resin and rosin acids and supporting data on rosin and rosin reaction products. These data are summarized below.

In a key dermal repeat dose toxicity study (Thorsrud, B., 2011), a sample of fatty acids C18-(unsaturated) lithium salts, was tested to evaluate possible adverse effects and the reversibility, progression, or delayed appearance of any observed changes following a 2-week postdose observation period. Three treatment groups of ten P (parental) CD® [Crl: CD® (SD)] rats/sex/group were administered the test article at nominal dose levels of 100, 300, or 1000 mg/kg/day at a dose volume of 2.5 mL/kg. Actual dose levels were 111.25; 345.00, and; 1089.75 mg/kg bw/day. One additional group of ten P animals/sex served as the control and received the vehicle, distilled water. The vehicle or test article was administered to all groups via dermal application once daily for approximately 6 hours. The males were dosed for 43 days, beginning 14 days prior to pairing. Dosing of the females began 14 days prior to pairing, through the mating period, up to and including Gestation Day (GD) 19.

Additionally, two groups of five animals/sex/group at 0 (vehicle) or 1000 mg/kg/day were dosed for a total of 43 days and then began a 14-day recovery period.

All animals survived to scheduled terminal and recovery necropsies. The most significant clinical observations consisted of dose responsive localized dermal effects at the test site (dorsal surface), consisting of scabbed postdose findings and elevated dermal scores. These findings were most pronounced at 1000 mg/kg/day and were seen most frequently at this dose level. The findings at 300 mg/kg/day were at a lower incidence and with lower dermal scores. Dermal scores and findings at 100 mg/kg/day were comparable to the controls. Mean body weight showed decreasing trends during the course of the study in males at 1000 mg/kg/day. For the remaining animals there were no consistent patterns of adverse effects on body weight or food consumption at the dose levels tested. The results of the neurobehavioural and behavioural evaluations did not reveal any definitive patterns consistent with treatment-related effects.

At termination, there were no adverse test article-related effects on hematology or clinical chemistry parameters evaluated. The results at scheduled necropsy showed test article-related macroscopic findings that were limited to the dose site in the skin, consisting of minimal to moderate abrasion/scab formation at the dose site in both sexes. At the recovery necropsy, the incidence and overall severity of abrasion/scab formation was reduced at 1000 mg/kg/day, indicating partial resolution of this finding over the recovery period. Possible test article-related organ weight differences at terminal necropsy included the increased spleen and adrenal gland weights (relative to body weight) of animals at 1000 mg/kg/day. The increased spleen/body weight ratio of males may have been associated with the lower mean body weight at this dose level and, possibly, increases in extramedullary hematopoiesis noted microscopically. There was no microscopic correlate for the increased adrenal gland/body weight ratio of females at this dose level.

Test article-related microscopic findings were present in treated skin at 300 and 1000 mg/kg bw/day, and possible test article effects were also noted in the thymus and spleen at 1000 mg/kg/day.

Test article-related findings in treated skin included an increase in the incidence and/or severity of erosion/ulceration, epidermal hyperplasia and exudate, acute to subacute/chronic inflammation, and edema. At recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg/day were morphologically similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings over the recovery period.

Minimal to mild cortical lymphoid depletion was noted in the thymus in animals of both sexes at 1000 mg/kg/day at the terminal necropsy. However, there were no statistically significant differences in the mean thymus weight. Thymic lymphoid depletion in animals at 1000 mg/kg/day may have been a secondary finding due to stress associated with the test article-related lesions in treated skin. Splenic extramedullary hematopoiesis was slightly increased in both sexes at 1000 mg/kg/day. The increased severity of splenic extramedullary hematopoiesis in control and treated females may have been due to recent parturition, but the slight increase in the incidence of this finding in animals at 1000 mg/kg/day may have also reflected an adaptive response secondary to test article-related inflammation in treated skin.

In conclusion, dermal application of Fatty acids C18-(unsaturated) lithium salts to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring. In addition, results from the clinical pathology evaluations and neurobehavioral testing did not reveal any definitive effects that could be attributed to treatment at the dose levels tested.

The dermal systemic NOAEL was determined to be 1089.75 mg/kg bw/day (male/female) and the dermal local effects NOAEL was determined to be 111.25 mg/kg bw/day (male/female).

A number of repeat dose oral toxicity studies are available on related materials (rosin oligomers, hydrogenated rosin and rosin). Although these studies show no evidence of significant systemic toxicity, the conduct and reporting was of uncertain quality (Klimisch 4) and hence are only included for completeness. Further repeat dose toxicity studies planned on rosin derivatives, including a test proposal for a 90 - day oral study with Rosin, will provide additional information relevant to the repeat dose endpoint for Distilled tall oil, magnesium salt.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Based on a 'weight of evidence' evaluation on a number of repeat dose oral studies in rodent and non-rodent species with rosin and resin derivatives.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Based on a well-conducted dermal study with a lithium salt of tall oil fatty acids

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Based on a well-conducted dermal study with a lithium salt of tall oil fatty acids

Justification for classification or non-classification

Data available do not meet the criteria for classification for specific target organ toxicity – repeated exposure, according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).