Overbased reaction products of distilled tall oil and magnesium hydroxide’

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was conducted prior to the institution of GLPs, but according to acceptable scientific standards in effect at the time the study was conducted. IBT laboratories was found to have conducted fradulent work in the late 1970s, thus care must be taken in evaluating this study.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in Section 13.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: See "remarks"

Remarks:

The study was conducted prior to the institution of GLPs, but according to acceptable scientific standards in effect at the time the study was conducted. IBT laboratories was found to have conducted fradulent work in the late 1970s, thus care must be taken in evaluating this study.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in Section 13.

Reason / purpose for cross-reference:

read-across source

Guideline:

other: study pre-dated modern guidelines

Principles of method if other than guideline:

The test substance (30% w/w in corn oil) was incorporated into diet and fed to rats for up to 90 days. Two concurrent control groups received plain diet with corn oil added; oil was also added to the diet of the low and intermediate dose groups. Limited haematopoietic and urinary parameters were evaluated at intervals during the study.

GLP compliance:

no

Remarks:

Study conducted prior to GLPs

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

corn oil

Duration of treatment / exposure:

90 days

Dose / conc.:

0.01 other: %

Remarks:

Basis: nominal in diet

Dose / conc.:

0.05 other: %

Remarks:

Basis: nominal in diet

Dose / conc.:

0.2 other: %

Remarks:

Basis: nominal in diet

Dose / conc.:

1 other: %

Remarks:

Basis: nominal in diet

Dose / conc.:

5 other: %

Remarks:

Basis: nominal in diet

No. of animals per sex per dose:

10 animals/sex/group

Dose descriptor:

NOAEL

Effect level:

1 other: %

Sex:

male

Basis for effect level:

other: see "remark"

Dose descriptor:

NOAEL

Effect level:

0.2 other: %

Sex:

female

Basis for effect level:

other: Significant body weight reductions occurred in females given 5% and 1% of the test substance in the diet.

Critical effects observed:

no

Conclusions:

When Dymerex Resin (rosin, oligomers) was administered to rats via the diet at concentrations of 0, 0.010, 0.050, 0.20, 1.0, or 5.0% for 90 days, the NOAEL for systemic toxicity was determined to be 1% for males and 0.20% for females based on statistically significant decreases in body weight during the study in animals exposed to 5% (males and females) or 1% (females) Dymerex Resin. Significant decreases in body weight in turn impacted several organ-to-body weight ratios. The effects seen at the top two dose levels were attributed to palatability issues noted during the first two weeks of the study since there was a significant decrease in food consumption during this time period. There were no significant test materialrelated effects on survival, clinical signs, hematology, urinalysis parameters, or gross or microscopic exa minations.
Based on the data presented in this study, Dymerex Resin (rosin, oligomers), is not classified for Speci fic Target Organ Toxicity – Repeated Exposure according to UN Globally Harmonized System of Classif ication and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Dymerex Resin (rosin, oligomers) is not classified for target organ toxicity according to Directive 67/548/EEC.

Executive summary:

In a subchronic dietary toxicity study, Dymerex Resin (rosin, oligomers) was administered to 10 rats/ sex/group at target concentrations of 0.010, 0.050, 0.20, 1.0, or 5.0% continuously for 90 days. Two control groups, each with 10 rats/sex/group, were provided the diet without the test substance for 90 days. Effects related to the administration of Dymerex Resin were limited to reduced body weights and lower food consumption. This, in turn, also affected several organ-to-body weight ratios. The reduction in food consumption and weight gain were likely due to palatability issues which occurred during the first two weeks of the study. All other findings occurred in a non dose-dependent manner, were spurious in nature, or were biologically irrelevant and were not considered related to consumption of the test material. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1% for males and 0.20% for females. However, based on an absence of gross or microscopic findings at necropsy, no significant target organ toxicity was identified in either sex at up to 5.0% Dymerex Resin (rosin, oligomers) in the diet.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1960

Report date:

1960

Materials and methods

Test guideline

Guideline:

other: study pre-dated modern guidelines

Principles of method if other than guideline:

The test substance (30% w/w in corn oil) was incorporated into diet and fed to rats for up to 90 days. Two concurrent control groups received plain diet with corn oil added; oil was also added to the diet of the low and intermediate dose groups. Limited haematopoietic and urinary parameters were evaluated at intervals during the study.

GLP compliance:

no

Remarks:

Study conducted prior to GLPs

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Rosin, oligomers

EC Number:

500-163-2

EC Name:

Rosin, oligomers

Cas Number:

65997-05-9

Molecular formula:

not applicable as it is a UVCB substance

IUPAC Name:

OLIGOMERS OF ROSIN

Constituent 2

Reference substance name:

Rosin oligomers

IUPAC Name:

Rosin oligomers

Details on test material:

-Test substance (as cited in report): Dymerex Resin XA 10-75
-Supplier: Hercules Powder Company
-Preparation (from supplier): 30% (w/w) in Mazola corn oil

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
-Sex: male and female
-Age: weanlings
-Housing: individually housed in standard, wire-bottomed steel rat cages
-Diet: Rockland Rat Diet (Rockland Farms, New City, NY, USA), provided ad libitum
-Method of animal identification: ear-punch

Dates of Study: not provided.
Date of Final Report : August 12, 1960

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

The test substance, Dymerex Resin, was incorporated into pulverized stock diet and fed to 10 animals/sex/group for 90 days. The five dose groups corresponded to feeding levels in the daily diet of 0.010, 0.050, 0.20, 1.0, and 5.0% Dymerex Resin by weight. An additional 20 animals/sex were divided into two control groups and received only pulverized stock diet with corn oil but without the test substance. Corn oil was added to the 0.010, 0.050 and 0.20% test diets and the control diet in an amount equivalent to that in the 1% test diet.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

The diet for each test group was prepared by first adding the calculated weight of the test substance, supplied as a 30% (w/w) suspension in corn oil, to pre-weighed portions of the Rockland Rat Diet. For the 0.010, 0.050, and 0.20% diets, a pre-calculated weight of Mazola corn oil (Mazola) was added to balance total dietary corn oil to that of the 1.0% diet. Corn oil was also added to the control diet to match the level of the 1.0% group. The final corn oil content was 2.33% in all test and control diets except the 5.0% test diet, in which the level was 11.65%. Following the appropriate additions of the test substance and/or corn oil to the diet, the mixtures were thoroughly blended with a Hobart mixer and dispensed into 16-ounce glass feeding jars.

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily, ad libitum

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.010%
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.050%
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0.20%
Basis:
nominal in diet

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1.0%
Basis:
nominal in diet

Doses / concentrations 5

Remarks:

Doses / Concentrations:
5.0%
Basis:
nominal in diet

No. of animals per sex per dose:

10 animals/sex/group

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Mortality:
Mortality and morbidity assessments were performed on a daily basis.

Clinical observations:
Clinical observations were performed on a daily basis, including observations in respect to animal growth.

Body weight:
Body weights were collected at study start and weekly thereafter.

Food Consumption:
Food consumption was recorded on a weekly basis. Feed utilization was also calculated on a weekly basis. Documentation regarding food spillage was made in the study records.

Hematology:
Five rats/group were bled on study Days 0, 30, 60, and 90. Blood samples were analyzed for hemoglobin concentration, hematocrit, total leukocyte count, and differential leukocytes. It could not be ascertained from the study report if the same animals were bled at each time point.

Urinalysis:
Five rats/group were randomly selected for urine collection on study Days 0, 30, 60, and 90. Urine samples were analyzed for reducing substances, albumin, and microscopic elements. It could not be ascertained from the study report if the same animals were used for the urinalysis assessment at each time point.

Sacrifice and pathology:

Gross necropsy:
A final body weight was measured and a complete gross necropsy was performed on all surviving animals. The following organs were removed for histological examination: brain, liver, spleen, stomach, small intestine, colon, pancreas, kidneys, urinary bladder, adrenals, gonads, thyroid, parathyroid, lymph nodes, heart, lungs, bone marrow, muscle, prostate, and uterus.

Organ weights:
The following organs were weighed: brain, heart, liver, kidneys, spleen, testes, and ovaries. Organ-to-brain and organ-to-body weight ratios were determined for all animals.

Histopathology:
Histopathologic evaluation of organs was conducted on five rats/sex/group from the 0.20, 1.0, and 5.0% dietary groups and the control groups. The organs examined were: brain, liver, spleen, stomach, small intestine, colon, pancreas, kidneys, urinary bladder, adrenals, gonads, thyroid, parathyroid, lymph nodes, heart, lungs, bone marrow, muscle, prostate, and uterus.

Statistics:

Statistical analysis was performed using a standard t-test and statistical significance was ascribed at the 95 and 99% confidence levels.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

Mortality:
One rat was found dead on Day 29 of the study in the 5.0% dose group. The sex of this animal was not specified in the study report and cause of death was not determined.

Clinical observations:
No abnormal behaviors were noted in any group.

Body weights:
Statistically significant decreases in body weight occurred in both sexes exposed to 5.0% Dymerex Resin. A marked growth depression occurred in both sexes over the entire 90-day period when compared to lower dose groups or the controls. The depression was greatest during the first two weeks of the study, as the weight gains in this group compared fairly well with those for control and lower dose test groups from the third week on. The cumulative weight gain for the 5% resin group at two weeks was 30 grams compared with an average of 87 grams for the two control groups. This 57 gram difference at the two-week point was increased by only 15 grams during the rest of the study. Body weight data at the 1.0% dietary level showed a slight growth depression over the 90-day period when compared to the lower dose group or control data which reached statistical significance in females only. For the group as a whole, the depression was greatest during the first two weeks of the study.

Food consumption:
Food consumption was depressed in the 5.0% Dymerex Resin group compared to controls for the entire 90 day test period, but the greatest depression occurred during the first two weeks of the study when there was considerable food spillage. The authors believed that the palatability of Dymerex Resin was a principal factor in the depression of food consumption which also resulted in retarded growth. Food consumption was only slightly depressed in the 1.0% dietary group. Mean food utilization in the 5% dietary group was lower than controls but was similar from Week 2 onward. There was no difference in food utilization for any other group.

Hematology:
No effects. All values in test substance-exposed animals were similar to controls. Although the page containing Differential Leukocyte Counts was missing for the 1.0% dietary group, the tables containing data for the 0.2% and 5.0% dietary groups showed means similar to control values.

Urinalysis:
No effects. Differences were sporadic, did not occur in a dose-dependent manner, and were considered unrelated to test-substance exposure.

Organ weights:
When organ weights were compared to both control groups, there was a statistically significant difference in kidney and heart weights in males exposed to 5% Dymerex Resin and a statistically significant difference in liver weight in males exposed to 1% Dymerex, Resin but not at 5%. Statistical comparison of organ-body weight ratios showed statistically significant differences for liver, kidney, gonad and brain in the 5.0% male dietary group and for liver in the 1.0% dietary group. When organ-brain weights were compared with controls, there was a statistically significant difference for kidney and heart in the 5.0% male dietary group. For females, liver-to-body weight and gonad-to-body weight ratios were statistically different in the 5.0% dietary group. Body weights of both male and female rats fed the test material at the 5.0% dose level and females fed at the 1.0% dietary level were significantly depressed compared to control animals. These adverse effects on body weight would be expected to result in corresponding deviations in organ-weight ratios.

Gross pathology:
No effects.

Histopathology:
Microscopic findings in all tissues and organs examined from animals in the 0.20, 1.0, and 5.0% dose groups were comparable to controls. There were no significant histologic alterations which could be attributed to test substance exposure.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 other: %

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEL

Effect level:

0.2 other: %

Sex:

female

Basis for effect level:

other: Significant body weight reductions occurred in females given 5% and 1% of the test substance in the diet.

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

When Dymerex Resin (rosin, oligomers) was administered to rats via the diet at concentrations of 0, 0.010, 0.050, 0.20, 1.0, or 5.0% for 90 days, the NOAEL for systemic toxicity was determined to be 1% for males and 0.20% for females based on statistically significant decreases in body weight during the study in animals exposed to 5% (males and females) or 1% (females) Dymerex Resin. Significant decreases in body weight in turn impacted several organ-to-body weight ratios. The effects seen at the top two dose levels were attributed to palatability issues noted during the first two weeks of the study since there was a significant decrease in food consumption during this time period. There were no significant test material-related effects on survival, clinical signs, hematology, urinalysis parameters, or gross or microscopic examinations.

Based on the data presented in this study, Dymerex Resin (rosin, oligomers), is not classified for Specific Target Organ Toxicity – Repeated Exposure according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Dymerex Resin (rosin, oligomers) is not classified for target organ toxicity according to Directive 67/548/EEC.

Executive summary:

In a subchronic dietary toxicity study, Dymerex Resin (rosin, oligomers) was administered to 10 rats/sex/group at target concentrations of 0.010, 0.050, 0.20, 1.0, or 5.0% continuously for 90 days. Two control groups, each with 10 rats/sex/group, were provided the diet without the test substance for 90 days. Effects related to the administration of Dymerex Resin were limited to reduced body weights and lower food consumption. This, in turn, also affected several organ-to-body weight ratios. The reduction in food consumption and weight gain were likely due to palatability issues which occurred during the first two weeks of the study. All other findings occurred in a non dose-dependent manner, were spurious in nature, or were biologically irrelevant and were not considered related to consumption of the test material. Under the conditions of this study, the NOAEL for systemic toxicity was determined to be 1% for males and 0.20% for females. However, based on an absence of gross or microscopic findings at necropsy, no significant target organ toxicity was identified in either sex at up to 5.0% Dymerex Resin (rosin, oligomers) in the diet.