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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 450 mg/kg bw/day
Additional information

Justification for read-across from fatty acids, tall-oil (CAS No. 61790-12-3)

In accordance with the specifications listed in Regulation (EC) No. 1907/2006 Annex XI, 1.5 Grouping of substances and read across, the similarity of category members has been shown to be justified based on the scope of variability and overlapping of composition, representative molecular structure, physico-chemical properties, tox-, ecotoxicological profiles and supporting Information by various validated QSAR methods. This information is given in further detail within the category justification for the grouping of chemicals and read-across (see IUCLID Section 13) for the dimerised fatty acids and its derivatives, and once more within the endpoint summary and discussion for Toxicokinetics.

For assessment of human health hazards of the category members, trends and similarities in toxicokinetic behaviour are most relevant. In particular, the molecular weight-dependent decrease in oral and dermal absorption and common metabolic and pathways, which are explained by trends in molecular structure and common functional groups (monomers, dimers and trimers of similar long-chain fatty acids). This justifies the assumption that the toxicological profile of all category members is similar and effects or the lack of effects observed in toxicological studies of one ore more substances can also be expected and explained for the other substances in the category.

For the endpoint toxicity to reproduction, within the chemical categoryDimerised Fatty Acids and its Derivatives, a reproduction / developmental toxicity screening test (OECD Guideline 416) is available for fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4).

Furthermore, aTwo-Generation Reproduction Toxicity Study (similar to OECD Guideline 416)with fatty acids, tall-oil(CAS No. 61790-12-3)is available.

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.

 

Discussion

Effects on fertility

The toxicity to reproduction of fatty acids, C18-unsaturated, dimers was assessed in a reproduction / developmental toxicity screening test according to OECD Guideline 421 and compliant with GLP (Clubb and Sutherland, 2004).

Sprague-Dawley rats (10/sex/dose) were administered the test material via the diet at 0, 200, 2000 and 20000 ppm (14.5, 147 and 1450 mg/kg bw/day and 16.5, 166, 1692 mg/kg bw/day for males and females, respectively). Males were treated for at least 4 weeks, starting from 2 weeks prior to mating; females were treated for 2 weeks prior to mating, during mating and gestation until at least day 4 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance. All animals were submitted to necropsy, which included weighing of testes and epididymides. Histopathology was conducted on male and female reproductive organs of the control and high dose group. The observed effects were limited to the 20000 ppm males and included slightly decreased body weight gain during the first week of treatment and an increased incidence of piloerection. However, weight gain for males at 20000 ppm was essentially similar to control animals for the rest of the study on weeks 2-4 and the incidence of piloerection lacked any dose-relationship. There were no effects on testes, epididymides and ovaries and on reproductive performance between control and test animals. The fertility index was 100% for males and females in all dose groups. A NOAEL (reproductive toxicity/fertility) of ≥ 1450 mg/kg bw/day and ≥ 1692 mg/kg bw/day for males and females, respectively, was determined based on no toxicologically significant effects at the highest dose tested.

There are no further data available on the reproductive/developmental toxicity of fatty acids, C18-unsaturated, dimers or another member of the chemical category the substance belongs to.

A two-generation study with the surrogate substance fatty acids, tall-oil, (CAS No. 61790-12-3)is available andread-across from this surrogate was conducted for assessment of potential toxic effects to reproduction.

The reproductive toxicity of fatty acids, tall-oil (CAS No. 61790-12-3) was evaluated by oral administration in a Two-Generation Reproduction Toxicity Study similar to OECD Guideline 416 performed at a time before implementation of GLP (Tegeris, 1977). 30 male and 15 female Sprague-Dawley rats per dose group were administered the test material at concentrations of 0, 5 or 10% (w/w) in the diet (corresponding to 0, 2000 and 4000 mg/kg bw/day for males and 0, 2500 and 5000 mg/kg bw/day for females, respectively). Additionally, groups of rats were concurrently treated with oleic acid at 5 and 10% (w/w) in diet as controls.

The parental animals were fed the test substance starting at 20 days pre-mating.Treatment continued through weaning of the first generation (F1). After weaning, 20 F1 males and 20 F1 females per group were maintained on the parental diet and mated at 100 days of age (with the members of each sex coming from a different dam). The delivered F2 generation survived through weaning.Parameters evaluated included F1 reproductive parameters, F1 fertility, viability, lactation, and gestation indices. Haematology, serum chemistry, urinalysis, and organ weights for F1 animals, gross pathology of F1 and F2 animals and microscopic pathology of various organs of the F2 pups were performed.

There were no treatment effects on reproductive performance, the number of liveborn or stillborn F1 litters and pups, or weaning weight of the F1 pups.No treatment-related changes in fertility, viability, lactation, or gestation indices were measured. Clinical chemistry, haematology and urinalysis parameters were similarly unchanged, organ weights were unchanged, and gross and microscopic pathology revealed no treatment-related effects.

Fatty acid, tall-oil had no effect on the reproductive physiology of rats at doses as high as 10% (w/w) in diet. The no-observed-adverse-effect-level (NOAEL) for reproduction toxicity was therefore considered to be ≥ 4000 and ≥ 5000 mg/kg bw/day for males and females, respectively.

As previously discussed (see Toxicokinetics), physicochemical data and the weight of evidence on toxicokinetic behaviour of fatty acids, C18-unsaturated, dimers and/or structurally related substances indicate a low level of systemic absorption and bioavailability both via the oral and the dermal routes. Furthermore, the whole body of available data on the toxicity of fatty acids, C18-unsaturated, dimers and/or structurally related substances indicates as well a low level of toxicological activity. Thus, fatty acids, C18-unsaturated, dimers are considered non-toxic after acute oral exposure, not irritating to skin and eyes, not skin sensitising and not genotoxic (in vitro). In a 90-day feeding study with fatty acids, C18-unsaturated, dimers no changes were found after histopathological examination of male and female reproductive organs up to the highest dose tested (ca. 3590 and 4085 mg/kg bw/day for males and females, respectively) (see Repeated dose toxicity).

Taken together, the available data on physicochemical properties, toxicokinetics and toxicological activity of fatty acids, C16-18 and C18-unsaturated, branched and linear and/or supporting substances do not suggest or indicate any potential for adverse effects on fertility.


Short description of key information:
Read-across based on grouping of substances (category approach):
NOAEL (fertility) ≥ 1450 (male) and ≥ 1692 (female) mg/kg bw/day (OECD 421)

Read-across from supporting substance (surrogate fatty acids, tall-oil):
NOAEL (fertility) ≥ 4000 (male) and ≥ 5000 (female) mg/kg bw/day (similar to OECD 416)

Effects on developmental toxicity

Description of key information
Read-across based on grouping of substances (category approach):
NOAEL (developmental toxicity) ≥ 1692 mg/kg bw/day (OECD 421)
No developmental toxicity was observed in a study similar to OECD 416 performed with the surrogate substance fatty acids, tall-oil.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 692 mg/kg bw/day
Additional information

There are no data available on potential developmental/teratogenic effects of fatty acids, C16-18 and C18-unsaturated, branched and linear. There are data on developmental toxicity / teratogenicity after oral exposure of the category member fatty acids, C18-unsaturated, dimers, which was analysed in a reproduction/developmental toxicity screening test performed according to OECD Guideline 421 (Clubb and Sutherland, 2004). Thus, read-across based on a category approach was conducted.

Sprague-Dawley rats (10/sex/dose) were administered fatty acids, C18-unsaturatred, dimers via the diet at 0, 200, 2000 and 20000 ppm (14.5, 147 and 1450 mg/kg bw/day and 16.5, 166, 1692 mg/kg bw/day for males and females, respectively). Males were treated for at least 4 weeks, starting from 2 weeks prior to mating; females were treated for 2 weeks prior to mating, during mating and gestation until at least day 4 of lactation. The females were allowed to litter normally. No effects on litter size and litter survival and on litter and pup weights were noted. No externally visible abnormalities were noted among all pups. Thus, a NOAEL (developmental toxicity) of ≥ 1692 mg/kg bw/day was determined based on no toxicologically significant effects at the highest dose tested.

There are no further data available on potential developmental/teratogenic effects of any other member of the chemical category they belong to.

Taking into account the toxicokinetic behaviour of fatty acids in general and the available toxicity studies on fatty acids, C18-unsaturated, dimers and/or structurally related substances, the weight of evidence does not indicate any potential for the induction of developmental/teratogenic effects by any route of exposure.

Based on the toxicokinetic information available, absorption and systemic bioavailability of fatty acids is strongly dependent on their molecular weight, which in turn is related to chain length and degree of saturation. Thus, C16-18 fatty acids are generally less well absorbed than fatty acids of shorter chain length via the oral route. For dimerised and trimerised fatty acids, a much lower level of absorption by the gastrointestinal tract is expected.

Furthermore, and also considering their low water solubility and lipophilic nature, a low level of absorption is expected for C16-C18 fatty acids via the dermal route, while for dimerised and trimerised fatty acids dermal absorption is virtually ruled out.

The fraction of systemically absorbed C16-C18 fatty acids is expected to undergo rapid metabolisation and excretion mainly in the expired CO2, as it occurs in the case of dietary fatty acids. By contrast, ingested dimerised and trimerised fatty acids are expected to be mainly excreted in the faeces without being metabolised.

The whole body of available toxicological information on fatty acids, C18-unsaturated, dimers (and/or other members of the chemical category they belong to, as well as further structurally related substances) does not suggest or indicate potential toxic effects after exposure by any route, and in particular does not give rise to concern with regard to potential developmental/teratogenic effects. Thus, in a 90-day feeding study conducted with fatty acids, C18-unsaturated, dimers no changes were found after histopathological examination of male and female reproductive organs up to the highest dose tested (ca. 3590 and 4085 mg/kg bw/day for males and females, respectively) (Spurgeon and Hepburn, 1993). In a Two-Generation Reproduction Toxicity Study performed with fatty acids, tall-oil (CAS No. 61790-12-3), no treatment-related effects were observed in pups of the F1 and F2 generations of rats orally given up to 5000 mg fatty acids, tall-oil/kg bw/day via the diet. In the same study, no treatment-related effects were observed a control group treated with oleic acid, a mono-unsaturated omega-9 C18 fatty acid, at the same dose levels (Tegeris, 1977).

Additionally, publicly available information on the potential toxic effects of naturally occurring fatty acids was taken into account. Placental transfer of some fatty acids has been reported for several species including humans (CIR, 1987). In a combined repeated dose and reproductive/developmental toxicity test according to OECD 422 with docosanoic acid (CAS No. 112-85-6) no adverse effects on viability, sex ratio or body weight of pups were noted and no morphological abnormalities in external and visceral observations in pups were observed in concentrations up to and including 1000 mg/kg bw/day (OECD SIDS, 2001).

In conclusion, considering the available information on the physicochemical properties, the toxicokinetic behaviour and toxicity of fatty acids, C18-unsaturated, dimers (and/or other members of the chemical category they belong to, as well as further supporting substances) no developmental/teratogenic effects are expected. Therefore, based on the weight of evidence a developmental toxicity study by any route of exposure is considered scientifically unjustified and not necessary in terms of animal welfare.

 

 

References (not in IUCLID)

OECD SIDS (2001) DOCOSANOIC ACID; CAS N°: 112-85-6, SIDS Initial Assessment Report for 13th SIAM, November 6-9, 2001

Justification for classification or non-classification

Based on read-across within the category approach and on read-across from a surrogate substance, the available information on the reproductive potential of fatty acids, C16-18 and C18-unsaturated, branched and linear is conclusive but not sufficient for classification.