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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1974 - 1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable, well documented study report which meets basic scientific principles. Read-Across justification for CAS No. 61790-12-3: On the basis of Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby human health effects may be predicted from data for a reference substance, provided that the physicochemical, toxicological and ecotoxicological properties of the reference and target substances are likely to be similar as a result of structural similarity, read-across from the surrogate substance fatty acids, tall-oil (CAS No. 61790-12-3) is conducted and the aforementioned study is selected as a key study for assessment of potential reproduction toxicity effects of the members of the category Dimerised Fatty Acids and its Derivates. The similarities between fatty acids, tall-oil and the category members are based on the following considerations: The Dimerised Fatty Acids and its Derivates category includes the following members: 61788-89-4 Fatty acids, C18-unsaturated, dimers, “Dimer” 68937-90-6 Fatty acids, C18-unsaturated, trimers, “Trimer” 68783-41-5 Fatty acids, C18-unsaturated, dimers, hydrogenated, “Hydrogenated dimer” 71808-39-4 Fatty acids, C16-18 and C18 unsaturated, dimerized, “Crude dimer” 68955-98-6 Fatty acids, C16-18 and C18-unsaturated, branched and linear, “Monomer acid” 68201-37-6 Octadecanoic acid, branched and linear, “Hydrogenated monomer acid” 30399-84-9 Isooctadecanoic acid All the members of this category of substances are derived from unsaturated fatty acids, for example from fatty acids, tall-oil, which contains predominantly C18 unsaturated and saturated fatty acids. Natural fatty acids, tall-oil has the following properties: Chemical name: Fatty acids, tall-oil Chemical formula: not available - UVCB substance EC No.: 263-107-3 CAS Name: Fatty acids, tall-oil CAS number: 61790-12-3 logKow: determined range 4.9 – 7.6 (Lightbody et al., 2002) Solubility in water (mg/L, at 20 °C): 12.6 (The quoted value represents the sum solubility of all the components of the test material) (Dinwoodie, 2004) Biodegradation at 28 days: 56-84% (Madsen, 1993; Aniol, 1999; Sewell, 1994) The HPV report final submission for fatty acids, tall-oil and related substances; CAS No. 61790-12-3 CAS No. 65997-03-7 CAS No. 68955-98-6 CAS No. 68201-37-6 CAS No. 61790-44-1 CAS No. 61790-45-2 Submitted to the US EPA August 2004 was screened by the US EPA and a screening level hazard characterisation report was published in 2007 (U. S. Environmental Protection Agency, 2007). This report prepared by the High Production Volume Chemicals Branch indicated that fatty acids, tall-oil are non-toxic following acute oral exposure (LD50 (rat) > 10000 mg/kg bw) and following a 90-day test in rats the No Observed Effect Level (NOEL) was 5% (approximately 2500 mg/kg bw/day). Fatty acids, tall-oil were negative in an Ames test with 5 S. typhimurium strains and in an in vitro chromosomal aberration assay with Chinese Hamster Ovary cells. In a Two-Generation Reproduction Toxicity study in rats, the NOEL for reproduction and systemic toxicity was 10% in diet (ca. 5000 mg/kg bw/day). Furthermore, fatty acids, tall-oil were not acute toxic in fish (96 h NOELr 1000 mg/L), daphnia (48 h NOELr 1000 mg/L) and algae (72 h NOELr 845 mg/L). Given their chemical nature, fatty acids, tall-oil are expected to be absorbed, metabolised and excreted following the same well-known pathways of dietary fatty acids. In conclusion, the physicochemical, toxicological and ecotoxicological properties of fatty acids, tall-oil and the members of the category Dimerised Fatty Acids and its Derivates are considered to be similar, and similarity is based on common functional groups (long-chain fatty acids, saturated and unsaturated) and the likelihood of common breakdown products via the metabolism of fatty acids. It is therefore considered appropriate that the data of fatty acids, tall-oil on toxicity to reproduction is used for read-across purposes to this category. The selected study fulfils the requirements laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 for read-across, i.e. the results are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method referred to in Article 13(3); cover an exposure duration comparable to or longer than the corresponding test method referred to in Article 13(3); and adequate and reliable documentation of the applied method is provided.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1977
Report Date:
1977

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
initial treatment period was 3 instead of 10 weeks prior to mating
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tall Oil Fatty Acid
- Physical state: clear ambered-coloured liquid
- Analytical purity: no data
- Odour: heavy vegetable oil-like odor
- Source: Arizona Chemical Company, Panama City, Florida, USA

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Worcester, Massachusetts, USA
- Age at study initiation: (P) 80 days
- Housing: 5 per sex per cage before mating
- Diet (e.g. ad libitum): CHARLES RIVER 19RF, RAT, MOUSE, HAMSTER MEAL (with and without test material) ad libitum
- Water (e.g. ad libitum): tap water ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Charles River 19RF
Details on mating procedure:
- M/F ratio per cage: (P) 1/2; (F1) 1/2
- Length of cohabitation: 20 days
- After successful mating each pregnant female was caged (how): single
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
(P) Males: 23 days before mating, 20 days during mating
(P) Females: 23 days before mating, 20 days during mating, 41 days through gestation and weaning of their F1 offspring.
(F1) Males: ca. 5 months at weaning, during growth into adulthood, mating and production of an F2 generation
(F1) Females: ca. 5 months at weaning, during growth into adulthood, mating and production of an F2 generation, until weaning of the F2 generation.
Frequency of treatment:
continuous
Details on study schedule:
- F1 parental animals not mated until 12 weeks after selected from the F1 litters.
- Age at mating of the mated animals in the study: 12 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
5 and 10% (w/w), corresponding to ca. 2000 and 4000 mg/kg bw/day (males) and ca. 2500 and 5000 mg/kg bw/day (females)
Basis:
nominal in diet
Dose calculation was based on standard conversion factors as described in ECHA (2008) Guidance on information requirements and chemical safety assessment Chapter R.8
No. of animals per sex per dose:
15 (P) males caged with 30 (P) females; 20 (F1) males, 20 (F1) females.
Control animals:
yes, plain diet
other: 5 and 10% (w/w) oleic acid in diet

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily by animal caretaker, weekly by supervising technician
Litter observations:
STANDARDISATION OF LITTERS
- Performed on Day 4 postpartum: yes
- If yes, maximum of 20 pups/sex/litter ; excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
Total number of pups (liveborn, stillborn, number discarded on day 4, number alive on day 21), average number of pups per sex per litter (born, day 4, weaned), average weaning weight of pups per sex


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (offspring):
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGTHS
The following tissues were prepared for microscopic examination: brain, pituitary gland, spinal cord, eye, sub-maxillary gland, thyroids, lungs, heart, liver, kidneys, spleen, adrenals, pancreas, stomach, intestines, lymph nodes, bladder, gonads, skin, bone and marrow, nerve and muscle, any unusual lesions.

The following tissues were weighed: thyroids, heart, liver, adrenals, kidneys, gonads.
Statistics:
Data on clinical chemistry hematology and organ weights was treated statistically by Student's t-test.
Reproductive indices:
Fertility index: (No. of pregnancies / No. of matings)*100
Offspring viability indices:
Viability index: (No. of live pups at 4 days / No. of live pups born)*100
Lactation index: (No. of weaned pups / [No. of live pups - No. of pups discarded at day 4])*100
Gestation index: (No. of litters born alive / No. of pregnancies)*100

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
One male in the control group of the P generation died. No further effects on clinical signs and mortality were reported.

BODY WEIGHT (PARENTAL ANIMALS)
No effects on terminal body weights.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Data only reported for F1 generation:

- Liveborn litters and pups: there was neither statistical nor biological significance between the teated and control groups.
- Litters with and numbers of stillborn: based on the laboratory experience, the data obtained was considered neither statistically nor biologically significant the teated and control groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Data only reported for the F1 generation:

The adrenal weight of the males of the 5% group was statistically increased comapred to the male control group. The liver and the kidneys of the females of the 10% group weighed statistically more than the control group. The statistical significance was reported to be lost when compared to the historical control data of the laboratory.

GROSS PATHOLOGY (PARENTAL ANIMALS)
The dead male in the control group of the P generation showed pulmonary hemorrhage and acute retroperitoneal abscesses in pancreas and liver. One male in the control group of the F1 generation showed chronic sialadenitis. No gross pathological effects were reported for the treated groups.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Data only reported for F1 generation:

There were several animals in the control and treated groups with pathological findings such as respiratory disease and renal disease which were regarded as endemically found in the strain of rat tested. It was concluded that there was no compound-related pathology in any of the rats examined.

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING)
Control and treated groups had a viability index of 97.0. There was neither statistical nor biological significance between the teated and control groups.

CLINICAL SIGNS (OFFSPRING)
No effects were reported.

BODY WEIGHT (OFFSPRING)
The average weaning weight of pups was increased in the treated groups. There was neither statistical nor biological significance between the teated and control groups.

HISTOPATHOLOGY (OFFSPRING)
No effects were reported for the F2 generation.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 4 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 5 000 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
10 other: % oleic acid in diet (control)
Sex:
male/female
Basis for effect level:
other: overall effects

Results: F2 generation

Effect levels (F2)

open allclose all
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
4 000 - 5 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: gross pathology and histopathology
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
10 other: % oleic acid in diet (control)
Sex:
male/female
Basis for effect level:
other: gross pathology and histopathology

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Indices

Fertility index was 100.0 for the control and 5%-treated groups and 95.0 for the 10%-treated group.

Lactation index was 98.0 for the control group and 97.0 for both treated groups.

Gestation index was 100 for all groups.

Clinical chemistry

Blood Glucose: All animals examined had normal results according to the experience of the laboratory.

Blood Urea Nitrogen: All animals examined had normal values according to the experience of the laboratory.

Serum Glutamic Oxaloacetic Transaminase: All animals examined had normal values according to the experience of the laboratory.

Serum Glutamic Pyruvic Transaminase: All animals exemined had normal values according to the experience of the laboratory.

Hematology

Hematocrit: All animals had normal concentrations according to the experience of the laboratory.

Hemoglobin: All animals had normal concentrations according to the experience of the laboratory.

White Blood Cell Count: Several animals in all groups had high counts. Their bone marrows, however, were histologically normal.

Red Blood Cell Morphology: All smears revealed normochromic normocytic red blood cells.

Urinalysis

Several males in all groups exhibited various degrees of protein in their urine. This was not considered to be dose-related.

Oleic acid control

Control groups of animals concurrently treated with 5 and 10% (w/w) oleic acid in diet showed no statistically or toxicologically significant effects in any of the parameters assessed.

Applicant's summary and conclusion

Conclusions:
It was concluded that fatty acids, tall-oil, under the conditions of this experiment, does not alter the reproduction physiology of the rat. No statistically significant adverse effects were observed at dose levels up to 10% (w/w) fatty acids, tall-oil in diet. This is therefore considered the NOAEL, corresponding to ca. 5000 mg/kg bw/day for female rats and 4000 mg/kg bw/day for male rats.