Fatty acids, tall-oil, magnesium salts

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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

Justification for type of information:

Justification for read-across, see attached file.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

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)

Version / remarks:

There was no certificate of analysis or detailes of the test item supplied by the sponsor. Given the nature of the test item (distillation products) it was considered that this deviation from the protocol did not affect the intergrity od the study. As the test item was a complex mixture of distillation products the study was conducted on the tst item as recieved by the sponsor (Pine Chemicals Association)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

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

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

acetone

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Diet prepared for Week 1 and Week 4 of treatment was sampled.

Duration of treatment / exposure:

The males were treated for at least 4 weeks overall, starting from 2 weeks prior to mating until termination.
The females were treated for 2 weeks prior to mating, then through mating until termination after Day 4 of lactation

Frequency of treatment:

The animals were dosed continuously via the diet.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm

Doses / concentrations 2

Dose / conc.:

1 000 ppm

Doses / concentrations 3

Dose / conc.:

5 000 ppm

Doses / concentrations 4

Dose / conc.:

20 000 ppm

No. of animals per sex per dose:

Four groups of 10 male and 10 female

Control animals:

yes, concurrent no treatment

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

At 20000 p.p.m: Increased male liver weight, small decreases were noted in adrenal gland weight in both sexes, small decreases in ovary weight in, females; slightly increased spleen weight in males.

At 5000 p.p.m. liver weight in male was increased. Female adrenal gland weight was reduced.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At 20000 p.p.m. in-life observations included decreased weight gain.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

At 20000 p.p.m. in-life observations included decreased food consumption in both sexes.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

At 20000 p.p.m. increases in bilirubin and alkaline phosphatase were noted in both sexes, small decreases in albumin and white blood cell count in females, cholesterol were slightly increased in males.

At 5000 p.p.m alkaline phosphatase in both sexes were increased.

Urinalysis findings:

not examined

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:

no effects observed

Other effects:

effects observed, treatment-related

Description (incidence and severity):

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.

Details on results:

LINICAL SIGNS AND MORTALITY: There were no clinical signs of toxicity or deaths.


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.

Effect levels

1

Key result

Dose descriptor:

NOEL

Effect level:

1 000 ppm

Based on:

test mat.

Basis for effect level:

other: Decreased weight gain and food consumption in both sexes at 20000ppm. Changes in liver function in both sexes at 20000ppm. At 5000 ppm there was increased liver weight and alkaline phosphatase in both sexes.

2

Key result

Dose descriptor:

NOEL

Effect level:

5 000 ppm

Based on:

test mat.

Basis for effect level:

other: Reproductive toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In conclusion, under the conditions of this study, toxicity was exhibited at levels of 5000 and 20000 p.p.m., but there were no clear effects of toxicity at 1000 p.p.m.  Therefore the parental NOEL was considered to be 1000 p.p.m. For reproductive parameters the NOEL was considered to be 5000 p.p.m.

Executive summary:

Aim:

The test item, Tall Oil (CAS No. 8002-26-4), is a chemical undergoing testing by the Sponsor. The objective of this study was to provide initial information on possible effects on reproduction and development in rats.

Method:

Four groups of 10 male and 10 female Sprague-Dawley rats received the test item via the diet at concentrations of 0, 1000, 5000 and 20000 p.p.m. Tall Oil. The males were dosed for at least 4 weeks, starting from 2 weeks prior to mating. The females were dosed from 2 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 5 males and 5 females per group for laboratory investigations. Males were sampled during Week 5: females were sampled on Day 6 of lactation. All animals were subjected to necropsy, which included weighing of major organs.  Histopathology was conducted on tissues from 5 males from Control and High dose, and 7 females from the Control and 8 females from the High dose.

Results

At 20000 p.p.m. in-life observations included decreased weight gain and food consumption in both sexes. Increased male liver weight following covariance analysis, 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 p.p.m. 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.

Conclusion

In conclusion, under the conditions of this study, toxicity was exhibited at levels of 5000 and 20000 p.p.m., but there were no clear effects of toxicity at 1000 p.p.m.  Therefore the parental NOEL was considered to be 1000 p.p.m. For reproductive parameters the NOEL was considered to be 5000 p.p.m.