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EC number: 232-304-6 | CAS number: 8002-26-4 A complex combination of tall oil rosin and fatty acids derived from acidulation of crude tall oil soap and including that which is further refined. Contains at least 10% rosin.
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21st March 2002 to 26th February 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Remarks:
- It was based on the version of the test guideline available at the time (Adopted 22nd March 1996). There are some differences in the information reported compared with stipulations in the current version of OECD 422 (Adopted 29th July 2016). These are: • Functional Observations not performed • Thyroid hormones not measured • Study terminated on PND6, rather than continuing until minimally PND13 • Anogenital distance was not reported There were no deviations from the study plan that impacted upon the integrity of the study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- no certificate of analysis or details of test substance supplied, however given the nature of the distillation products this deviation was not thought to have affected the integrity of the study.
- Principles of method if other than guideline:
- N/A
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- liquid
- Details on test material:
- - Name of test material (as cited in study report): Tall Oil
- Substance type: Complex mixture
- Physical state: dark brown liquid
- Analytical purity: No data
- Composition of test material, percentage of components: Not supplied
- Purity test date: No data
- Lot/batch No.: 7252-30
- Expiration date of the lot/batch: 15.05.05
- Stability under test conditions: No data
- Storage condition of test material: Room temperature, dark, under nitrogen
Constituent 1
- Specific details on test material used for the study:
- STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
At room temperature, in the dark, under nitrogen>
STABILITY UNDER TEST CONDITIONS
Not evaluated during study.
FORM AS APPLIED IN THE TEST
Batches of diet were prepared weekly.
An appropriate quantity of the test item was dissolved in a suitable volume of acetone. This solution was added to a suitable quantity of untreated diet, then mixed for ca one hour with fan assisted venting to remove the ethanol to form a dose premix. A control premix was prepared using the same proportion of acetone and untreated diet. The diets for the Intermediate and High dose groups were prepared by dilution of the dose premix with untreated diet to give the desired concentrations. The Low dose diet was prepared by dilution of the High dose diet with untreated diet. The diet premixes were then placed on a Winkworth mixer for ca 20 min. The Control diet was prepared by dilution of the control premix with untreated diet such that the diet contained the same proportion of premix as the High dose diet.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat is a standard rodent species for the reproduction toxicity testing in animals required by regulatory authorities. The normal processes of reproduction in the rat are well documented in the test laboratory.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: Males: 180-190 g. Females: 113-161 g.
- Fasting period before study: No
- Housing: Initially two per polypropylene cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ±2
- Humidity (%): 50 ±15
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 08.04.02 To: 27.05.02
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- acetone
- Details on oral exposure:
- The test material was administered orally because this is a possible route of exposure in humans. Administration via the diet is an established experimental routine in rats.
The dose levels were selected and agreed with the Sponsor, following evaluation of existing toxicological data. This included data from a one-week dose range finding study in rats carried out under a separate contract and project number at Inveresk (Inveresk Project No. 493160). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of the formulated diets was undertaken regarding concentration and homogeneity. Diet prepared for Week 1 and Week 4 of treatment was sampled. Triplicate samples of each formulation, including control, were taken immediately after preparation. The samples were analysed by the Inveresk Product Chemistry Laboratory using a method previously validated in the Inveresk laboratory under a separate protocol and contract (Inveresk Project No. 491836).
- Duration of treatment / exposure:
- The males were treated for at least four weeks overall, starting from two weeks prior to mating until termination. The females were treated for two weeks prior to mating, then through mating, until termination after Day 4 of lactation.
- Frequency of treatment:
- Continuous in diet.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- Group 1 (control)
- Dose / conc.:
- 1 000 ppm
- Remarks:
- Group 2
- Dose / conc.:
- 5 000 ppm
- Remarks:
- Group 3
- Dose / conc.:
- 20 000 ppm
- Remarks:
- Group 4
- No. of animals per sex per dose:
- Ten
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected and agreed following evaluation of existing data and a one week dose range-finding study in rats.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: No satellite groups. - Positive control:
- No positve control
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Males: once during the week prior to the commencement of dosing and once weekly thereafter. Females: once during the week prior to commencement of treatment, and weekly thereafter until the start of the mating period, then on Day 0 of gestation (the day of detection of a positive mating sign) followed by Days 7, 14 and 20 of gestation, and then Days 1 and 4 of lactation (where Day 0 is the day of parturition).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Group mean achieved dosages of test substance calculated: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During Week 5 of dosing for males and on Day 6 of lactation for females.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: Five males and five females
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: No
- How many animals: Five males and five females
- Parameters checked in table [No.1] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2), all animals (males: after 4 weeks treatment; females: after Day 4 of lactation)
HISTOPATHOLOGY: Yes (see table 2), on control and high dose animals. - Other examinations:
- No other examinations.
- Statistics:
- Body weight and food consumption (prior to mating for females), haematology and clinical chemistry data were statistically analysed for homogeneity of variance using the 'F-max' test. If the group variances appeared homogeneous, a parametric ANOVA was used and pairwise comparisons made via Student's t-test using Fisher's F-protected LSD. If the variances were heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remained heterogeneous then Kruskal-Wallis ANOVA was used. Organ weights were also analysed likewise, and by analysis of covariance (ANCOVA) using terminal kill body weight as covariate. Histology incidence data were analysed using Fisher's Exact Probability Test. The following pairwise comparisons were performed against the Control group (Group 1): Control group vs Low dose; control group vs intermediate dose; Control group vs high dose. All statistical tests were two-sided and performed at the 5% significance level.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All clinical observations were considered to be consistent with those normally seen in rats of this age and strain.
- Mortality:
- no mortality observed
- Description (incidence):
- N/A
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Please see Table 3-Table 5 for data.
At 20000 ppm, there was a transient decrease in weight gain in both sexes. In males, decreased weight gain was most notable for over the first week, although absolute weights were significantly lower over the first 3 weeks of treatment. In females, there was a notable decrease throughout the pre-mating phase. The resulting deficit in body weight was never regained in either sex. In pregnant females, reduced weight gain was evident over Day 7- 20 of gestation, compared to the Control animals.
There were no obvious effects of treatment at 5000 or 1000 ppm. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- FOOD CONSUMPTION
Please see Table 6 to Table 8 for data.
At 20000 ppm, food consumption in males was reduced for the first 2 weeks of treatment (attaining significance during Week 1) and in Week 4 (not recorded Week 3 as paired for mating). In females, food consumption was significantly decreased during the pre-mating period. Consumption was also reduced during the first half of the gestation period, compared to the Control animals.
There were no obvious effects of treatment at 5000 or 1000 ppm.
COMPOUND INTAKE
Please see Table 9 for data. - Food efficiency:
- not examined
- Description (incidence and severity):
- N/A
- Water consumption and compound intake (if drinking water study):
- not examined
- Description (incidence and severity):
- N/A
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- N/A
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Please see Table 10 & Table 11 for data.
At 20000 ppm, there was a non-significant decrease In white blood cells in females. Any other intergroup differences were not considered to reflect an effect of treatment. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Please see Table 12 & Table 13 for data.
Alkaline phosphatase levels were significantly Increased in females at 5000 and 20000 ppm, and in males at 20000 ppm. In males, there was a non-significant increase in levels at 5000 ppm, and in females at 1000 ppm there was an equivocal increase, but, given the small group sjze, it was considered that the difference was too small to reflect an effect of treatment.
Total bilirubin was increased in both sexes at 20000 ppm.
In addition, at 20000 ppm, cholesterol levels were Increased in males; albumin (and consequently total protein) were reduced in females. - Endocrine findings:
- not examined
- Description (incidence and severity):
- N/A
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- N/A
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- N/A
- Immunological findings:
- not examined
- Description (incidence and severity):
- N/A
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Please see Table 14 & Table 15 for data.
In males, at 20000 ppm, there was a decrease in body weights, with liver weights being essentially similar to Controls. At 5000 and 1000 ppm, liver weight was slightly greater than Controls. Following covariance analysis, there was a dose related increase in liver weights, with the increases at 5000 and 20000 ppm attaining statistical significance.
In females, slight non-significant increases in liver weights following covariance analysis at 5000 and 20000 ppm were too small to attribute to treatment.
In males at 20000 ppm, spleen weight was notably increased following variance and covariance analysis. Adrenal gland and thymus weights were slightly but significantly decreased. Following covariance analysis, adrenal gland weight was still significantly decreased, but for the thymus there was no significant difference from Controls.
In females, ovary, adrenal gland and kidney weights were significantly reduced at 5000 and 20000 ppm, with pituitary gland weight reduced at 20000 ppm. Following covariance analysis, kidney and pituitary gland weights were essentially similar to Controls, but a decrease in ovary weight at 20000 ppm, and adrenal gland weight at 5000 and 20000 ppm, was still evident, but not significant. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- N/A
- Neuropathological findings:
- not examined
- Description (incidence and severity):
- N/A
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- All histology findings were typical of spontaneously arising background findings in rats of this strain and age.
- Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- N/A
- Other effects:
- not examined
- Description (incidence and severity):
- N/A
- Details on results:
- N/A
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Decreased weight gain and food consumption in both sexes at 20000 ppm. Changes in liver function in both sexes at 20000 ppm. At 5000 ppm there was increased liver weight and alkaline phosphatase in both sexes.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 3 Body Weights & Body Weight Gain (g). Male
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
BODY WEIGHT | |||||
DAY 0 | MEAN SD N | 320 17 10 | 313 9 10 | 316 11 10 | 313 10 10 |
DAY 7 | MEAN SD N | 374 26 10 | 369 16 10 | 373 16 10 | 351** 13 10 |
DAY 14 | MEAN SD N | 414 34 10 | 408 17 10 | 415 20 10 | 386* 18 10 |
DAY 21 | MEAN SD N | 447 37 10 | 437 19 10 | 444 26 10 | 413** 22 10 |
DAY 28 | MEAN SD N | 468 45 10 | 460 23 10 | 471 28 10 | 434 29 10 |
BODY WEIGHT GAIN | |||||
DAY 0 to DAY 28 | MEAN SD N | 149 30 10 | 147 16 10 | 154 20 10 | 121* 24 10 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 4 Body Weights & Body Weight Gain (g). Female – Pre-mating
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
BODY WEIGHT | |||||
DAY 0 | MEAN SD N | 194 9 10 | 199 15 10 | 197 8 10 | 188 9 10 |
DAY 7 | MEAN SD N | 217 13 10 | 221 18 10 | 219 10 10 | 200** 9 10 |
DAY 14 | MEAN SD N | 237 16 10 | 240 22 10 | 237 10 10 | 214** 15 10 |
BODY WEIGHT GAIN | |||||
DAY 0 to DAY 14 | MEAN SD N | 43 9 10 | 41 12 10 | 40 4 10 | 25** 12 10 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 5 Mean Body Weights & Mean Body Weight Gain (g). Female – Gestation and Lactation
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
BODY WEIGHT | |||||
DAY 0 Of gestation | MEAN | 245 | 247 | 240 | 218 |
DAY 7 Of gestation | MEAN | 286 | 285 | 275 | 256 |
DAY 14 Of gestation | MEAN | 329 | 320 | 317 | 288 |
DAY 20 Of gestation | MEAN
| 410 | 407 | 388 | 345 |
BODY WEIGHT GAIN | |||||
DAY 0 to DAY 20 | MEAN (% of Control) | 165 - | 160 97 | 148 90 | 127 77 |
BODY WEIGHT | |||||
DAY 1 Of lactation | MEAN | 298 | 286 | 273 | 261 |
DAY 4 Of Lactation | MEAN | 319 | 313 | 300 | 281 |
Table 6 Food Consumption (g/animal/day). Male
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
DAYS 0-7 | MEAN SD N (CAGE) | 31.5 2.2 5 | 30.9 2.0 5 | 32.6 1.6 5 | 27.2** 2.2 5 |
DAYS 7-14 | MEAN SD N (CAGE) | 35.5 3.9 5 | 34.1 1.9 5 | 34.9 1.3 5 | 32.1 2.4 5 |
DAYS 21-28 | MEAN SD N (CAGE) | 32.0 2.8 5 | 31.5 1.5 5 | 32.4 2.5 5 | 29.9 1.9 5 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 7 Food Consumption (g/animal/day). Female – pre-mating
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
DAYS 0-7 | MEAN SD N (CAGE) | 21.1 1.0 5 | 21.7 1.2 5 | 20.5 2.0 5 | 17.2*** 1.3 5 |
DAYS 7-14 | MEAN SD N (CAGE) | 22.9 1.3 5 | 22.6 1.1 5 | 21.6 1.5 5 | 20.3** 1.5 5 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 8 Mean Food Consumption (g/animal/day). Female – Gestation and Lactation
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
DAYS 0-7 Of gestation | MEAN | 26.9 | 26.5 | 26.2 | 23.9 |
DAYS 7-14 Of gestation | MEAN | 29.9 | 30.0 | 27.9 | 26.7 |
DAYS 14-20 Of gestation | MEAN | 31.8 | 32.8 | 32.6 | 30.1 |
DAYS 0-4 Of lactation | MEAN | 33.9 | 31.9 | 31.6 | 30.1 |
Table 9 Group Mean Achieved Dosage of Test Item (mg/kg/day)
| GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM |
MALES | |||
WEEK 1 | 91 | 473 | 1639 |
WEEK 2 | 88 | 443 | 1742 |
WEEK 4 | 70 | 354 | 1412 |
FEMALES | |||
WEEK 1 | 103 | 493 | 1773 |
WEEK 2 | 98 | 474 | 1961 |
DAYS 0-7 (OF GESTATION) | 100 | 509 | 2017 |
DAYS 7-14 (OF GESTATION) | 99 | 471 | 1963 |
DAYS 14-20 (OF GESTATION | 90 | 462 | 1902 |
DAYS 1-4 (OF LACTATION) | 107 | 551 | 2221 |
Table 10 Haematology, Week 5. Males
|
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM |
Hb | MEAN SD N | 16.1 0.6 5 | 16.1 0.4 5 | 15.5 0.1 5 | 15.7 0.5 5 |
RBC | MEAN SD N | 8.28 0.32 5 | 8.34 0.23 5 | 7.95 0.27 5 | 8.10 0.25 5 |
Hct | MEAN SD N | 0.453 0.019 5 | 0.452 0.014 5 | 0.442 0.004 5 | 0.440 0.015 5 |
MCH | MEAN SD N | 19.5 0.4 5 | 19.3 0.5 5 | 19.5 0.7 5 | 19.4 0.3 5 |
MCV | MEAN SD N | 54.7 1.5 5 | 54.2 1.4 5 | 55.5 1.7 5 | 54.3 0.9 5 |
MCHC | MEAN SD N | 35.6 0.3 5 | 35.7 0.4 5 | 35.1* 0.2 5 | 35.7 0.4 5 |
WBC | MEAN SD N | 14.50 2.21 5 | 14.33 2.85 5 | 15.82 4.05 5 | 12.97 3.93 5 |
Neut | MEAN SD N | 1.54 0.37 5 | 2.30 1.46 5 | 1.57 0.49 5 | 1.49 0.74 5 |
Lymp | MEAN SD N | 12.39 1.96 5 | 11.41 3.59 5 | 13.71 4.23 5 | 10.91 3.02 5 |
Mono | MEAN SD N | 0.25 0.07 5 | 0.28 0.10 5 | 0.20 0.02 5 | 0.22 0.11 5 |
Eos | MEAN SD N | 0.19 0.05 5 | 0.17 0.07 5 | 0.16 0.07 5 | 0.15 0.10 5 |
Baso | MEAN SD N | 0.04 0.02 5 | 0.04 0.02 5 | 0.06 0.03 5 | 0.04 0.02 5 |
LUC | MEAN SD N | 0.09 0.03 5 | 0.12 0.03 5 | 0.12 0.05 5 | 0.16 0.10 5 |
Plat | MEAN SD N | 1023 102 5 | 975 122 5 | 967 119 5 | 994 195 5 |
PT | MEAN SD N | 13 1 5 | 13 1 5 | 13 1 5 | 12* 1 5 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 11 Haematology, Week 7. Females
|
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM |
Hb | MEAN SD N | 14.0 1.0 5 | 13.9 0.6 5 | 13.2 0.4 5 | 13.0 1.7 5 |
RBC | MEAN SD N | 7.30 0.46 5 | 7.13 0.31 5 | 6.88 0.29 5 | 6.87 0.85 5 |
Hct | MEAN SD N | 0.394 0.029 5 | 0.390 0.021 5 | 0.370 0.014 5 | 0.365 0.048 5 |
MCH | MEAN SD N | 19.1 0.6 5 | 19.5 0.2 5 | 19.2 0.4 5 | 19.0 0.4 5 |
MCV | MEAN SD N | 54.0 1.4 5 | 54.7 1.3 5 | 53.8 1.3 5 | 53.2 1.6 5 |
MCHC | MEAN SD N | 35.4 0.6 5 | 35.7 0.7 5 | 35.7 0.4 5 | 35.7 0.3 5 |
WBC | MEAN SD N | 12.99 3.46 5 | 12.79 3.85 5 | 12.15 2.84 5
| 8.89 2.28 5 |
Neut | MEAN SD N | 3.84 1.68 5 | 3.30 1.19 5 | 3.62 1.09 5 | 2.44 0.98 5 |
Lymp | MEAN SD N | 8.55 2.89 5 | 8.78 2.85 5 | 7.99 2.05 5 | 6.04 1.83 5 |
Mono | MEAN SD N | 0.28 0.13 5 | 0.34 0.22 5 | 0.26 0.04 5 | 0.15* 0.04 5 |
Eos | MEAN SD N | 0.18 0.07 5 | 0.15 0.07 5 | 0.14 0.03 5 | 0.17 0.17 5 |
Baso | MEAN SD N | 0.03 0.03 5 | 0.04 0.03 5 | 0.03 0.01 5 | 0.02 0.01 5 |
LUC | MEAN SD N | 0.11 0.06 5 | 0.17 0.10 5 | 0.12 0.07 5 | 0.08 0.02 5 |
Plat | MEAN SD N | 1073 133 5 | 1061 145 5 | 1110 170 5 | 906 478 5 |
PT | MEAN SD N | 14 1 5 | 14 1 4 | 14 1 4 | 13 2 3 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 12 Clinical Chemistry, Week 5. Male
|
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM |
Urea | MEAN SD N | 7.3 0.5 5 | 7.4 1.1 5 | 6.5 0.5 5 | 6.4 0.6 5 |
Glu | MEAN SD N | 7.92 0.42 5 | 7.95 0.76 5 | 8.12 0.88 5 | 7.90 0.29 5 |
AST | MEAN SD N | 86 8 5 | 92 15 5 | 92 6 5 | 83 5 5 |
ALT | MEAN SD N | 59 2 5 | 71 8 5 | 70 11 5 | 65 9 5 |
AP | MEAN SD N | 683 39 5 | 699 137 5 | 842 183 5 | 1891** 905 5 |
Na | MEAN SD N | 144 1 5 | 144 2 5 | 143 2 5 | 142 3 5 |
k | MEAN SD N | 4.9 0.2 5 | 5.0 0.1 5 | 4.9 0.3 5 | 5.0 0.2 5 |
Cl | MEAN SD N | 101 1 5 | 102 2 5 | 101 2 5 | 101 4 5 |
TP | MEAN SD N | 68 2 5 | 70 2 5 | 66 2 5 | 66 2 5 |
Alb | MEAN SD N | 41 1 5 | 43 1 5 | 41 1 5 | 41 2 5 |
AG-R | MEAN SD N | 1.6 0.2 5 | 1.6 0.1 5 | 1.6 0.3 5 | 1.7 0.1 5 |
Chol | MEAN SD N | 2.0 0.4 5 | 1.9 0.3 5 | 2.0 0.3 5 | 2.4* 0.1 5 |
Crea | MEAN SD N | 51 2 5 | 53 2 5 | 52 3 5 | 56 4 5 |
Ca | MEAN SD N | 2.91 0.06 5 | 2.95 0.07 5 | 2.94 0.07 5 | 2.94 0.07 5 |
Phos | MEAN SD N | 2.01 1.13 5 | 2.58 0.09 5 | 2.60 0.14 5 | 2.08 1.17 5 |
T. Bi | MEAN SD N | 0.6 0.2 5 | 1.0 0.6 5 | 0.9 0.2 5 | 1.7*** 0.4 5 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 13 Clinical Chemistry, Week 7. Female
|
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM |
Urea | MEAN SD N | 10.7 1.2 5 | 11.1 2.7 5 | 11.8 1.2 5 | 10.5 0.7 5 |
Glu | MEAN SD N | 6.68 0.90 5 | 6.65 0.70 5 | 6.00 0.35 5 | 6.44 0.77 5 |
AST | MEAN SD N | 96 17 5 | 88 17 5 | 98 8 5 | 84 14 5 |
ALT | MEAN SD N | 105 23 5 | 114 31 5 | 128 28 5 | 113 21 5 |
AP | MEAN SD N | 509 203 5 | 638 152 5 | 980* 378 5 | 1649*** 929 5 |
Na | MEAN SD N | 145 3 5 | 141 3 5 | 144 1 5 | 142 3 5 |
k | MEAN SD N | 5.3 0.7 5 | 5.6 0.3 5 | 5.9 0.4 5 | 5.9 0.5 5 |
Cl | MEAN SD N | 106 4 5 | 103 4 5 | 105 2 5 | 104 1 5 |
TP | MEAN SD N | 64 1 5 | 65 4 5 | 62 2 5 | 59* 4 5 |
Alb | MEAN SD N | 40 1 5 | 39 2 5 | 39 2 5 | 35*** 1 5 |
AG-R | MEAN SD N | 1.6 0.1 5 | 1.5 0.1 5 | 1.7 0.2 5 | 1.4* 0.1 5 |
Chol | MEAN SD N | 2.4 0.5 5 | 2.2 0.5 5 | 1.9* 0.1 5 | 2.7 0.3 5 |
Crea | MEAN SD N | 59 4 5 | 58 2 5 | 62 4 5 | 63 3 5 |
Ca | MEAN SD N | 2.84 0.12 5 | 2.90 0.06 5 | 2.79 0.08 5 | 2.77 0.09 5 |
Phos | MEAN SD N | 1.89 0.27 5 | 1.93 0.31 5 | 1.58 0.21 5 | 1.86 0.24 5 |
T. Bi | MEAN SD N | 0.9 0.2 5 | 0.9 0.6 5 | 1.4 0.6 5 | 1.9** 0.5 5 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 14 Absolute Organ Weights (Following Covariance Analysis). Males
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
BODY WEIGHT | MEAN SE N | 458 11 10 | 458 11 10 | 458 11 10 | 458 11 10 |
ADRENAL GLANDS | MEAN SE N | 0.0757 0.0036 10 | 0.0803 0.0036 10 | 0.0674 0.0036 10 | 0.0634* 0.0038 10 |
BRAIN | MEAN SE N | 2.10 0.03 10 | 2.12 0.03 10 | 2.12 0.03 10 | 2.08 0.03 10 |
EPIDIDYMIDES | MEAN SE N | 1.2041 0.0292 10 | 1.2032 0.0287 10 | 1.2048 0.0291 10 | 1.2047 0.0311 10 |
HEART | MEAN SE N | 1.72 0.06 10 | 1.82 0.06 10 | 1.73 0.06 10 | 1.72 0.06 10 |
KIDNEYS | MEAN SE N | 3.77 0.10 10 | 3.85 0.10 10 | 4.01 0.10 10 | 4.07 0.11 10 |
LIVER | MEAN SE N | 17.88 0.53 10 | 18.88 0.52 10 | 19.46* 0.53 10 | 20.12** 0.56 10 |
LUNG | MEAN SE N | 1.82 0.06 9 | 1.86 0.05 10 | 1.76 0.05 10 | 1.75 0.06 10 |
PITUITARY GLAND | MEAN SE N | 0.0013 0.0001 10 | 0.012 0.001 10 | 0.013 0.001 10 | 0.011 0.001 10 |
PROSTATE | MEAN SE N | 0.771 0.046 10 | 0.777 0.045 10 | 0.704 0.046 10 | 0.761 0.049 10 |
SPLEEN | MEAN SE N | 0.85 0.03 10 | 0.83 0.03 10 | 0.85 0.03 10 | 1.04*** 0.03 10 |
SALIVARY GLANDS | MEAN SE N | 0.7770 0.0240 10 | 0.7572 0.0236 10 | 0.7501 0.0239 10 | 0.7978 0.0255 10 |
TESTES | MEAN SE N | 3.55 0.08 10 | 3.51 0.07 10 | 3.69 0.08 10 | 3.74 0.08 10 |
THYMUS | MEAN SE N | 0.491 0.032 10 | 0.415 0.031 10 | 0.435 0.032 10 | 0.385 0.034 10 |
THYROID GLANDS | MEAN SE N | 0.0219 0.0010 10 | 0.0233 0.0009 10 | 0.0225 0.0010 9 | 0.0230 0.0010 10 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Table 15 Absolute Organ Weights (Following Covariance Analysis). Females
| GROUP 1 CONTROL | GROUP 2 1000 PPM | GROUP 3 5000 PPM | GROUP 4 20000 PPM | |
BODY WEIGHT | MEAN SE N | 310 7 10 | 310 7 10 | 310 7 10 | 310 8 8 |
ADRENAL GLANDS | MEAN SE N | 0.0911 0.0037 10 | 0.0843 0.0032 10 | 0.0791 0.0032 10 | 0.0774 0.0042 8 |
BRAIN | MEAN SE N | 1.87 0.02 10 | 1.87 0.02 10 | 1.90 0.02 10 | 1.96 0.03 8 |
HEART | MEAN SE N | 1.12 0.04 10 | 1.16 0.04 10 | 1.25 0.04 10 | 1.18 0.05 8 |
KIDNEYS | MEAN SE N | 2.59 0.05 10 | 2.53 0.05 10 | 2.47 0.05 10 | 2.53 0.06 8 |
LIVER | MEAN SE N | 16.69 0.48 10 | 16.16 0.43 10 | 17.77 0.43 10 | 17.87 0.55 8 |
LUNG | MEAN SE N | 1.32 0.04 9 | 1.38 0.03 10 | 1.29 0.03 10 | 1.37 0.04 8 |
OVARIES | MEAN SE N | 0.114 0.005 10 | 0.106 0.004 10 | 0.104 0.004 10 | 0.097 0.006 8 |
PITUITARY GLAND | MEAN SE N | 0.014 0.001 10 | 0.016 0.001 10 | 0.015 0.001 10 | 0.013 0.001 8 |
SPLEEN | MEAN SE N | 0.59 0.03 10 | 0.63 0.03 10 | 0.68 0.03 10 | 0.72 0.03 8 |
SALIVARY GLANDS | MEAN SE N | 0.6038 0.0208 10 | 0.6027 0.0184 10 | 0.6121 0.0185 10 | 0.5755 0.0238 8 |
THYMUS | MEAN SE N | 0.198 0.024 10 | 0.233 0.021 10 | 0.201 0.021 10 | 0.242 0.028 8 |
THYROID GLANDS | MEAN SE N | 0.0166 0.0010 9 | 0.0165 0.0009 10 | 0.0152 0.0009 10 | 0.0171 0.0011 8 |
UTERUS | MEAN SE N | 0.53 0.02 10 | 0.53 0.02 10 | 0.51 0.02 10 | 0.50 0.03 8 |
Significantly different from the Control: * P<0.05, ** P<0.01, *** P<0.001
Applicant's summary and conclusion
- Conclusions:
- In a good quality Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted to OECD test guideline 422, and GLP, the parental NOAEL ,for Tall Oil administered continuously in the diet to rats (Sprague-Dawley), was 1000ppm.
- Executive summary:
Four groups of 10 male and 10 female Sprague-Dawley rats received Tall Oil in diets at concentrations of 0, 1000, 5000 and 20000 ppm. The males were dosed for at least four weeks, starting from two weeks prior to mating. The females were dosed from two weeks prior to mating until at least Day 6 of lactation. The animals were monitored for clinical signs, body weight, food consumption,
mating and litter performance. Blood samples were taken from five males (during week five) and five females (lactation Day 6) per group for laboratory investigations. All parental animals were subjected to necropsy, which included weighing of major organs. Histopathology was conducted on tissues from five males from Control and High dose, and seven females from the Control and eight females from the High dose.
At 20000 ppm in-life observations included decreased weight gain and food consumption in both sexes. Increased male liver weight, and increases in bilirubin and alkaline phosphatase were noted in both sexes. In addition, small decreases were noted in adrenal gland weight in both sexes, and in albumin, white blood cell count and ovary weight in females; spleen weight and cholesterol were slightly increased in males.
At 5000 ppm liver weight in males and alkaline phosphatase in both sexes were increased. Female adrenal gland weight was reduced.
In conclusion, under the conditions of this study, toxicity was exhibited at levels of 5000 and 20000 ppm, but there were no clear effects of toxicity at 1000 ppm. Therefore the parental NOAEC was considered to be 1000 ppm.
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