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EC number: 263-009-0 | CAS number: 61788-81-6
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002-03-02 to 2002-07-02
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- 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)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Tall oil
- EC Number:
- 232-304-6
- EC Name:
- Tall oil
- Cas Number:
- 8002-26-4
- Molecular formula:
- Not applicable - UVCB substance
- Test material form:
- liquid: viscous
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- acetone
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: An appropriate quantity of the test substance was dissolved in a suitable volume of acetone.
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Rat and Mouse Breeder diet No. 3 (expanded) SQC
- Storage temperature of food: No data
This solution was added to a suitable quantity of untreated diet, then mixed for about 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 approximately 20 minutes. 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.
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: No data
- Purity: No data - Details on mating procedure:
- Pairing was on a one male to one female basis, within the same treatment group. Each female was transferred to the cage of an appropriate co-group
male near the end of the working day, and remained there until mating was detected. Vaginal lavages were taken early each morning commencing on the day of pairing, until mating was detected, and the day of observation of a copulatory plug in situ and/or sperm in the lavage was designated Day 0 of gestation. Each female remained with its first designated male for a maximum of 7 consecutive nights. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of the formulated diets was undertaken with regard to 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.
- 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
- Details on study schedule:
- - Age at mating of the mated animals in the study: approximately 10 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 ppm
- Dose / conc.:
- 5 000 ppm
- Dose / conc.:
- 20 000 ppm
- No. of animals per sex per dose:
- 10
- Control animals:
- other: Acetone
- 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 positive control
Examinations
- Parental animals: Observations and examinations:
- 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: During Week 5 of dosing for males and on Day 6 of lactation for females.
- Animals fasted: No
- How many animals: Five males and five females
- Parameters checked in table No.1 were examined. - Oestrous cyclicity (parental animals):
- Not examined
- Sperm parameters (parental animals):
- Parameters examined in male parental generations: testis weight, epididymis weight
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, physical abnormalities.
GROSS EXAMINATION OF DEAD PUPS: yes, for external abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals following four weeks of treatment.
- Maternal animals: All surviving animals after four days of lactation.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 2 were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- All of the F1 offspring.
- These animals were subjected to postmortem examinations: externally visible abnormalities only.
GROSS NECROPSY: None
HISTOPATHOLOGY / ORGAN WEIGTHS: None - 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.
- Reproductive indices:
- Fertility Index (female) = Number Pregnant/Number Paired
Fertility Index (male) = Number Siring a Litter/Number paired
Gestation Index = Number bearing live pups/Number pregnant
Birth Index = Total number of pups born (live and dead)/number of implantation scars
Live Birth Index = Number of pups live on Day 0 of lactation/Total number born (live and dead) - Offspring viability indices:
- Viability Index = Number of pups live on Day 4 of lactation/number live on Day 0
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
BODY WEIGHT AND WEIGHT GAIN: 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 effects on body weight at 5000 and 1000 ppm.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): 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 premating period. Consumption was also reduced during the first half of the gestation period, compared to the Control
animals. There were no effects on food consumption at 5000 and 1000 ppm.
HAEMATOLOGY (See Table 4): At 20000 ppm there was a non-significant decrease in white blood cells in females.
CLINICAL CHEMISTRY (See Table 4): 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 size 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.
ORGAN WEIGHTS (see Table 3): 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 PATHOLOGY: No findings attributable to treatment.
HISTOPATHOLOGY: No findings attributable to treatment. All histology findings were typical of spontaneously arising background findings in rats of this strain and age.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): The achieved intake in the first week of treatment for males and females at 20000 ppm was lower than the second week. For males and females at the low and intermediate dose levels, intake was higher than in the following weeks (as expected). At other times, the achieved intake was essentially proportional to the diet concentrations.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Not examined
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Not examined
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): At 20000 ppm mean number of implant sites per pregnancy was marginally decreased and hence mean total number of pups born was lower than that of all other dose groups. However, due to the very slight differences compared to the Control group, there is some doubt as to the reproducibility of this finding.
Effect levels (P0)
- Dose descriptor:
- NOAEC
- Effect level:
- 1 000 ppm (nominal)
- 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 (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
CLINICAL SIGNS (OFFSPRING): No data
BODY WEIGHT (OFFSPRING): At 20000 p.p.m. mean litter weights were slightly reduced compared to the Controls, reflecting the decrease in litter size.
SEXUAL MATURATION (OFFSPRING): Not examined
ORGAN WEIGHTS (OFFSPRING): Not examined
GROSS PATHOLOGY (OFFSPRING): No abnormal findings.
HISTOPATHOLOGY (OFFSPRING): Not conducted
Effect levels (F1)
- Dose descriptor:
- NOEC
- Generation:
- F1
- Effect level:
- ca. 5 000 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Marginal decrease in implant sites at 20000 ppm with a corresponding decrease in the mean total number of pups born compared to all other dose groups.
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
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 NOAEC , for Tall Oil administered continuously in the diet to rats (Sprague-Dawley), was 1000ppm. The NOAEC for reproductive toxicity was 5000 ppm.
- 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.
The only indication of reproductive toxicity was a marginal decrease in implant sites at 20000 ppm with a corresponding decrease in the mean total number of pups born compared to all other dose groups. However, due to the very slight differences compared to the Control group, there is some doubt as to the reproducibility of this finding. 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. For reproductive parameters the NOEC was considered to be 5000 ppm.
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