Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Justification for grouping of substances and read-across

There are no data available on the toxicity to reproduction of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7). In order to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of toxicity to reproduction:

CAS

173832-46-7 (a)

104-76-7 (b)

Chemical Name

Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters

2-Ethylhexanol

Molecular weight

973.62

1085.84

1184.02

130.23

Toxicity to reproduction – screening studies

Waiving

--

Toxicity to reproduction – (pre-natal) development

RA: CAS 104-76-7

Experimental result:
NOAEL (mouse) ≥ 191 mg/kg bw/day

(a) Category members subjected to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font.

Lack of data for a given endpoint is indicated by “--“.

(b) Surrogate substances are indicated in normal font and are precursors/breakdown products of the target substance (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described for the present analogue approach.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Toxicity to reproduction - fertility

This information is not available.

Conclusions for toxicity to reproduction (fertility)

There are no data available on the toxicity to reproduction (fertility) of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters.

However, data on the oral repeated dose toxicity of the hydrolysis product 2-Ethylhexanol (CAS 104-76-7) and Fatty acids, C18-unsatd., dimers (61788-89-4), which shows a strong structural relationship to the hydrolysis product Fatty acids, C18 unsatd., trimers, demonstrate no adverse effects on reproduction organs and tissues after subchronic exposure up to and including the highest dose tested. Therefore, based on the weight of evidence, a reproduction toxicity study by any route of exposure is considered scientifically unjustified and not necessary in terms of animal welfare.

In summary, the available data provide sufficient evidence to conclude that the substance of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is not toxic to reproduction.


Short description of key information:
Toxicity to reproduction - Fertility: no study available

Effects on developmental toxicity

Description of key information
Based on read-across from 2-ethylhexanol (CAS 104-76-7), which is a hydrolysis product of the target substance, no hazard was identified.
NOAEL developmental toxicity (mouse, m/f) = 1428.0-1736.5 mg/kg bw/day (based on read-across from 2-ethylhexanol and after correction for differences in molecular weight)
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-05-18 to 1990-08-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Weight at study initiation: 23.52-31.59 g
- Housing: Plug-positive females were individually housed in solid-bottom polycarbonate cages with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ) and Ab-Sorb-Dri® cage litter (Laboratory Products, Garfield, NJ
- Diet (e.g. ad libitum): Ground Purina Certified Rodent ChoW® (#5002) available ad libitum throughout gestation
- Water (e.g. ad libitum): deionized/filtered water were available ad libitum throughout gestation
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2
- Humidity (%): 48
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: feed
Vehicle:
other: food grade modified corn starch microcapsules
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh supplies of dosed feed were obtained from refrigerated stock on the mornings of gd 0, 3, 6, 9, 12 and 15

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis by gas chromatography (GC) prior to use verified the formulations to be within 99-108% of the theoretical concentrations. 2EH/feed mixes were determined to be stable throughout the period of use for each study replicate.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage:1/1
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- Verification of same strain and source of both sexes: yes

Duration of treatment / exposure:
continuously exposure to 2-EH (0, 0.009, 0.03, or 0.09%) microencapsulated in the feed from gestational day 0-17
Frequency of treatment:
continuously ad libitum feed
Duration of test:
sacrifice at gestational day 17
Remarks:
Doses / Concentrations:
0.009, 0.03 or 0.09%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 17, 59 and 191 mg/kg bw/d
Basis:
other: calculated consumption, based on gestational food consumption
No. of animals per sex per dose:
28
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: DEHP was previously evaluated for potential developmental toxicity in timed-pregnant Swiss (CD-I) mice exposed via the diet throughout gestation (gd 0 to 17) (Tyl et oZ., 1988). An average dose of 44 mg/kg/day (0.025% DEHP in feed) was the maternal and embryo/fetal NOAEL. An increased incidence of malformations was observed at 91 mg/kg/day (0.05% DEHP in feed) in the absence of other indications of maternal and embryo/fetal toxicity. At 191 and 292 mg/kg/day (0.10% and 0.15% DEHP in feed), maternal toxicity (reduced weight gain during treatment and increased relative liver weight) was observed, as well as decreased fetal weight and an increased incidence of prenatal mortality and fetal malformations. Based upon these findings, additional studies were designed to characterize the developmental toxicity of DEHP's principal metabolites (MEHP and 2-18 ethylhexanol) at approximately equimolar doses and under comparable experimental conditions as those from the study of DEHP in mice (Tyl et aZ., 1988). Accordingly, the concentrations of MEHP in feed included 0% (control), 0.017%, 0.035%, 0.070%, and 0.140%, with the average daily intake of 0, 35, 73, 134, and 269 MEHP mg/kg/day, respectively (NTP, 1990), approximately equivalent on a molar basis to the dose levels of DEHP used by Tyl et aZ. (1988). The target concentrations of 2-EH in feed employed for this study included 0.00% (control), 0.009%, 0.030%, and 0.090%. The expected average daily intake of 2-EH at the proposed dietary concentrations were 0, 15, 52.5, and 157.5 mg/kg/day, respectively. (The actual intake was 0, 17, 59 and 191 mg/kg/day; see results.) Therefore, the target dietary dose levels of 2-EH employed for this study were intended to encompass the range of intakes obtained with DEHP.

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily from gestation day 0-17

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation days 0, 3, 6, 9, 12, 15, and 17

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: on gestation days 0, 3, 6, 9, 12, 15, and 17

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: The maternal body, liver, and intact uterus were weighed

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
analyses of variance (ANOVA), when ANOVA revealed a significant (p<0.05) dose effect, Dunnett's Multiple Comparison Test (Dunnett, 1955; 1964) compared each 2-EH-exposed group to the control group. One-tailed tests were used for all pairwise comparisons except maternal body and organ weights and fetal body weight, General Linear Models (GLM), chi square test, when a chi square test showed significant group differences, a one-tailed Fisher's exact probability test was used for pairwise comparisons of each 2-EH group with the control group.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No females died, delivered early or were removed from the study. Pregnancy rates were high and equivalent across all groups (93-96%); maternal
weight change for the gestational (and treatment) period, gd 0-17, was unaffected, as was weight change corrected for gravid uterine weight; maternal organ weights and food consumption were also unaffected; Treatment related clinical signs of toxicity were limited to hyperactivity observed in
one dam on gd 6, 9 and 12 at 0.090% and in one dam on gd 6 at 0.030%
Dose descriptor:
NOAEL
Effect level:
191 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
191 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of exposure on the number of ovarian corpora lutea, or of uterine implantation sites (resorptions, dead fetuses or live fetuses) per litter. Live litter size and fetal body weight per litter (all fetuses, males or females) were equivalent across all groups.
There were also no effects of treatment on the incidence of malformations (external, visceral, skeletal or total) or variations, whether expressed as number or percentage of fetuses per litter or of litters with one or more affected fetuses. Examination of individual fetal findings also indicated no specific malformations or variations with a dose-related incidence.
Abnormalities:
not specified
Developmental effects observed:
not specified

In conclusion, 2-EH administered in the diet during gestation (gd 0-17) in CD1 mice at concentrations comparable to or exceeding those employed for DEHP and MEHP in the same study design, resulted in no maternal or developmental toxicity. It is therefore clear that 2-EH plays essentially no role in the expression of DEHP-induced maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable study (Klimisch score 2) from a reference substances with similar structure and intrinsic properties. Read-across is justified based on the structural similarity between the source and target substance, as the source substance comprises a hydrolysis product (CAS 104-76-7) of the target substance. Refer to endpoint discussion for further details. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available on the repeated dose toxicity of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7). In order to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of toxicity to reproduction:

CAS

173832-46-7 (a)

104-76-7 (b)

Chemical Name

Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters

2-Ethylhexanol

Molecular weight

973.62

1085.84

1184.02

130.23

Toxicity to reproduction – screening studies

Waiving

--

Toxicity to reproduction – (pre-natal) development

RA: CAS 104-76-7

Experimental result:
NOAEL (mouse) ≥ 191 mg/kg bw/day

(a) Category members subjected to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font

Lack of data for a given endpoint is indicated by “--“.

(b) Surrogate substances are indicated in normal font and are precursors/breakdown products of the target substance (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described for the present analogue approach.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Toxicity to reproduction – (pre-natal) development

CAS 104-76-7

A developmental toxicity study was performed with 2-ethylhexanol, which was administered microencapsulated in the diet to pre-mated CD-1 mice (Tyl, 1991). Twenty-eight animals per group were treated continuously from Day 0 to Day 17 of gestation with dietary concentrations of 0.009, 0.03 or 0.09% in feed equivalent to 17, 59 and 191 mg/kg/day of the test substance. No females died, delivered early or were removed from the study. Pregnancy rates were high and equivalent across all groups (93-96%), maternal weight change for the gestational (and treatment) period (GD 0-17) was unaffected, as was weight change corrected for gravid uterine weight and maternal organ weights and food consumption were also unaffected. There were no effects of exposure on the number of ovarian corpora lutea, or of uterine implantation sites (resorptions, dead foetuses or live foetuses) per litter. Live litter size and foetal body weight per litter (all foetuses, males or females) were equivalent across all groups. There were also no treatment-related effects on the incidence of malformations (external, visceral, skeletal or total) or variations, whether expressed as number or percentage of foetuses per litter or of litters with one or more affected foetuses. Examination of individual foetal findings also indicated no specific malformations or variations with a dose-related incidence. In conclusion, the administered in the diet during gestation (GD 0-17) in CD1 mice at concentrations of 17, 59 and 191 mg/kg bw/day resulted in no maternal or developmental toxicity.

Based on the results, the developmental NOAEL for 2-ethylhexanol in mice was found to be 191 mg/kg bw/day.

Conclusions for toxicity to reproduction (development)

No study is available investigating the developmental toxicity of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (173832-46-7). However, a study with the surrogate substance 2-Ethylhexanol (CAS 104-76-7), which is the toxicologically most critical metabolite of the substance to be registered, did not show any treatment-related effects up to the highest dose level tested (191 mg/kg bw/day). .

The NOAEL of 191 mg/kg bw/day for 2-ethylhexanol (molecular weight = 130.23 g/mol) is selected for hazard assessment of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (molecular weight = 973.62-1184.02 g/mol). In order to account for differences in molecular weight, full enzymatic hydrolysis of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters into Fatty acids, C18 unsatd., trimers and 2-ethylhexanol is assumed. A resulting estimated NOAEL for developmental toxicity ranging from 1428.0-1736.5 mg/kg bw/day was established for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters.

Thus, no hazard for developmental toxicity is expected for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the surrogate substance, the available data on the toxicity to reproduction do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.