Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7 of Regulation (EC) No 1907/2006.
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

The long-chain aliphatic ester (LCAE) category covers mono-esters of a fatty acid and a fatty alcohol. The category contains both mono-constituent and UVCB substances. The fatty acid carbon chain lengths range is C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) in varying proportions to mono-esters.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group, by interpolation to the target substances in the group (read-across approach), applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements for adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Overview of toxicity to reproduction

CAS

Toxicity to reproduction

Developmental toxicity/ teratogenicity

91031-48-0 (b)

--

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

868839-23-0

Experimental result:
NOAEL fertility ≥ 1000 mg/kg bw/day

--

3687-46-5

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

59231-34-4 (a)

Experimental result:

NOAEL fertility = 300 mg/kg bw/day

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

36078-10-1

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-86-0

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-87-1

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

91031-91-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

85116-88-7

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-88-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

3234-85-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

22393-85-7

Experimental result: 

NOAEL ≥ 1000 mg/kg bw/day

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

101227-09-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

97404-33-6

RA: CAS 59231-34-4
RA: CAS 17671-27-1
RA: CAS 22393-85-7

RA: CAS 91031-48-0
RA: CAS 111937-03-2
 

RA: CAS 90411-68-0

Former CAS 97404-33-6

RA: CAS 59231-34-4
RA: CAS 17671-27-1
RA: CAS 22393-85-7

RA: CAS 91031-48-0
RA: CAS 111937-03-2
 

RA: CAS 90411-68-0

72576-80-8

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

3687-45-4

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

17673-56-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

96690-38-9

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

93803-87-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

17671-27-1

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

RA: CAS 59231-34-4

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

111937-03-2 (c)

--

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

 90411 -68 -0 (c) --    

Experimental result:

NOAEL ≥ 1500 mg/kg bw/day

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

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font.

(c)Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by "--".

Toxicity to reproduction

CAS 868839-23-0

A 90-day repeated dose toxicity study was performed in rats according to OECD 408, using propylheptyl octanoate (CAS 868839-23-0) (Leuschner, 2006). 10 Wistar rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day of the test substance in soybean oil by gavage, for 90 consecutive days. There were no statistically significant differences in the mean length of the oestrus cycles and the number of complete cycles between the females in the control group and the treatment groups. In males, there were no statistically significant differences between the control group and the treatment groups in the mean number and percentage of ultrasound-resistant spermatids, number of motile spermatozoa in the cauda epididymis, and in the percentage of spermatids with malformations. No treatment-related gross pathological or histopathological effects were observed in organs or tissues, including those of the reproductive system in males and females, respectively.

 

CAS 59231-34-4

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed with isodecyl oleate (Hansen, 2013). 10 rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day isodecyl oleate once daily for 36 days (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test Day 1 and ended on the day or one day before sacrifice. Day of sacrifice was on test Day 36 for the male rats and on lactation Day 4 or shortly thereafter for the female rats. The dose levels in the main study are based on the results of the dose range-finding study, in which 5 rats/sex/dose were administered 100, 300 and 1000 mg /kg bw/day isodecyl oleate for a period of 14 days. No mortality occurred in the parental generation and no clinical signs were observed during the study period. The body weight and food consumption was comparable between the control group and treatment groups in the low- and medium dose groups. In the high dose group, however, a reduction in body weight and food consumption was seen in female only, indicating maternal toxicity at a dose level of 1000 mg/kg bw/day. No substance-related findings were noted at necropsy, which also included the macroscopic examination of the appearance and size of the gonads, adrenal glands, uterus, and accessory reproductive organs. However, changes in reproduction parameters of the dam and in the development of pups were seen in the high dose females and their offspring, respectively. A statistically significant increase in post-implantation loss was noted as well as a non-statistically significant decrease in the birth index. The observed elevated number of stillbirths led to a statistically significant reduction in the live birth index. No test item related influence was noted for the fertility index, the gestation index and the pre-implantation loss. The qualitative sperm staging revealed no test item related spermatogenic changes. Furthermore, a statistically significant decrease in the viability index of the pups of high dose dams was seen and a non-statistically significant decrease in mean litter weight of the pups and in total litter weight per dam. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. The NOAEL for systemic toxicity of the males was ≥ 1000 mg/kg bw/day. For the females the NOAEL for systemic toxicity was 300 mg/kg bw/day because of maternal toxicity observed in the high dose group (1000 mg/kg bw/day). For isodecyl oleate the NOAEL for toxicity to reproduction was 300 mg/kg bw/day for females, due to the observed effects at the highest dose level. For males, the NOAEL for toxicity to reproduction was 1000 mg/kg bw/day.  

 

CAS 22393-85-7

A combined repeated dose toxicity study and reproduction/developmental toxicity screening test, performed according to OECD 422 and GLP, is available (Rossiello, 2014). 10 rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day of tetradecyl oleate, formulated in carboxymethylcellulose (0.5% in purified water), once daily for at least 28 to 29 days (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test Day 1 and ended on the day of, or one day before sacrifice. Day of sacrifice was on test Day 28 to 29 for the male rats and on Day 4 post-partum for the female rats, except for one single female, which was killed the day after the occurrence of total litter loss. The dose levels in the main study are based on the results of the dose range-finding study, in which 3 rats/sex/dose were administered 0, 100, 300 and 1000 mg /kg bw/day tetradecyl oleate for 14 days.

In the parental animals, no test item-related signs of toxicity were observed during the observational and neurological screenings. No differences of toxicological significance were seen in terminal body weight, body weight gain and in food consumption. No relevant changes were recorded in parental animals on clinical pathology investigations (haematology and clinical chemistry). Macroscopic inspection at autopsy and histopathological examination revealed no test item-related changes. The mating performance including the pre-coital interval and the copulatory evidence did not show any differences between groups. The resulting copulatory and fertility indices were 100% in all groups. All females were pregnant and had a comparable length of gestation. No variations were found in the number of corpora lutea and implantations between groups. All pregnant females gave birth to live pups with the exception of one high dose female which had a total litter loss on Day 3 post-partum. This female and two control females had unilateral implantation. This finding was considered incidental since it was observed also in two control females. The litter size at birth and on Day 4 post-partum, as well as the mean litter and pup weights, were also similar between groups. Statistically significant increased mean group sex ratio for males was seen in high dose group on Day 4. No relevant findings were found in the pups at daily clinical observation or at post-partum examination. On the basis of the results obtained in the study, the NOAEL for systemic toxicity was considered to be ≥1000 mg/kg bw/day for males and females. The NOAEL for toxicity to reproduction was considered to be ≥1000 mg/kg bw/day for males and females.

 

CAS 17671-27-1

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) was performed using docosyl docosanoate (Reig, 2014). The test item was administered orally (gavage) once daily at the doses of 100, 300 and 1000 mg/kg bw/day to male and female rats from two weeks before pairing to day 4 postpartum for females and to 5 weeks post-coitum for males.

Treatment with the test item did not cause signs of paternal toxicity. No mortality was recorded in either sex and there were no noteworthy differences in food consumption, water consumption or body weight. Lower locomotor activity was recorded in males at 100 mg/kg bw/day and in females at 300 and 1000 mg/kg bw/day. No changes of toxicological relevance were recorded in the clinical pathology analysis. Bilirubin values tended to increase at 300 and 1000 mg/kg bw/day in both sexes. Concerning the differences in organ weights observed in males and females, it cannot be concluded that there is a relationship with the test item given that the differences are not related with any histopathological finding. All macroscopic and microscopic findings recorded were considered to be within the range of normal background lesions that may be seen in rats of this strain and age and under the experimental conditions used in this study. From the type, location, distribution and severity of all findings recorded, there were no differences between the control and the test substance-treated animals.

Regarding fertility, no treatment-related effects on the percentage of mating, gestation index, fertility index or conception rate were recorded. The mean and median precoital time was slightly higher at 300 mg/kg bw/day. It cannot be concluded that there is a relationship with the test item as the differences are not dose-related. One female from this dose group did not mate with the male after 14 days of pairing. Those animals were mated again with a different male of the same group and with female from a reserve group and mating led to pregnancy. No differences in pre- or postimplantation losses or dead or live pups at first check were recorded compared to the control group. One female from the control group had 100% postimplantation losses.

Regarding breeding, pregnancy length was similar in all groups. Lower milk production was observed in one female at 1000 mg/kg bw/day, which did not nurse its pups and therefore all pups died or were devoured between days 0-4 postpartum. In consequence, the postnatal losses increased.

No differences from the control group were recorded in mean body weight in the F1-generation. Regarding physical development, no differences from the control group were recorded. Regarding motor development, a lower percentage of pups with positive response to the surface righting reflex was recorded at 1000 mg/kg bw/day. The macroscopic findings recorded at necropsy could be considered of no toxicological relevance and within the range of normal background lesions that may be seen in animals of this strain.

In conclusion, for docosyl docosanoate, the NOAEL for systemic toxicity was considered to be ≥1000 mg/kg bw/day for males and females. The NOAEL for toxicity to reproduction was considered to be ≥1000 mg/kg bw/day in males and females.

 

Overall conclusion for toxicity to reproduction

In the available 90-day repeated dose toxicity study performed with propylheptyl octanoate (CAS 868839-23-0) and according to OECD 408, no treatment-related gross pathological or histopathological effects were observed in organs or tissues, including those of the reproductive system in males and females, respectively (Leuschner, 2006). Furthermore, combined repeated dose toxicity and reproduction/developmental toxicity screening studies are available for the following category members: tetradecyl oleate (CAS 22393-85-7), isodecyl oleate (CAS 59231-34-4) and docosyl docosanoate (CAS 17671-27-1). The OECD 422 studies with tetradecyl oleate and docosyl docosanoate showed no adverse effects up to and including the highest dose level of 1000 mg/kg bw/day for systemic and reproduction parameters (Rossiello, 2014 and Reig, 2014). However, the OECD 422 study conducted with the test material isodecyl oleate (CAS 59231-34-4) revealed adverse effects in parental females and F1-offspring at the highest dose level of 1000 mg/kg bw/day (Hansen, 2013).

The NOAEL for reproduction toxicity in this study was 300 mg/kg bw/day, the NOAEL for systemic toxicity of the males was ≥ 1000 mg/kg bw/day, for the females however the NOAEL for systemic toxicity was 300 mg/kg bw/day because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/day). Thus, the effects observed in the pups at 1000 mg/kg bw/day were not considered to be relevant due to the maternal toxicity at the highest dose level. Overall, the NOAEL for reproduction toxicity is therefore considered to be 300 mg/kg bw/day, based on the adverse effects observed in the OECD 422 screening study with isodecyl oleate, at a dose level of 1000 mg/kg bw/day (Hansen, 2013).

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.


Short description of key information:
NOAEL (fertility) = 300 mg/kg bw/day
NOAEL (systemic) = 300 mg/kg bw/day

Effects on developmental toxicity

Description of key information
NOAEL (development) = 300 mg/kg bw/day
NOAEL (systemic) = 300 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7 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

The long-chain aliphatic ester (LCAE) category covers mono-esters of a fatty acid and a fatty alcohol. The category contains both mono-constituent and UVCB substances. The fatty acid carbon chain lengths range is C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) in varying proportions to mono-esters.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group, by interpolation to the target substances in the group (read-across approach), applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements for adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Overview of toxicity to reproduction

CAS

Toxicity to reproduction

Developmental toxicity/ teratogenicity

91031-48-0 (b)

--

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

868839-23-0

Experimental result:
NOAEL fertility ≥ 1000 mg/kg bw/day

--

3687-46-5

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

59231-34-4 (a)

Experimental result:

NOAEL fertility = 300 mg/kg bw/day

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

36078-10-1

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-86-0

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-87-1

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

91031-91-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

85116-88-7

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

95912-88-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

3234-85-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

22393-85-7

Experimental result: 

NOAEL ≥ 1000 mg/kg bw/day

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

101227-09-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

97404-33-6

RA: CAS 59231-34-4
RA: CAS 17671-27-1
RA: CAS 22393-85-7

RA: CAS 91031-48-0
RA: CAS 111937-03-2
 

RA: CAS 90411-68-0

Former CAS 97404-33-6

RA: CAS 59231-34-4
RA: CAS 17671-27-1
RA: CAS 22393-85-7

RA: CAS 91031-48-0
RA: CAS 111937-03-2
 

RA: CAS 90411-68-0

72576-80-8

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: 90411-68-0

3687-45-4

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: 90411-68-0

17673-56-2

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2

RA: CAS 90411 -68 -0

96690-38-9

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: 90411-68-0

93803-87-3

RA: CAS 59231-34-4

RA: CAS 17671-27-1

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

17671-27-1

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

RA: CAS 59231-34-4

RA: CAS 22393-85-7

RA: CAS 91031-48-0

RA: CAS 111937-03-2 

RA: CAS 90411-68-0

111937-03-2 (c)

--

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

 

90411-68-0 (c)

 
 --  

Experimental result:

NOAEL ≥ 1500 mg/kg bw/day

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

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font.

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by "--".

Developmental toxicity/teratogenicity

CAS 91031-48-0

A prenatal developmental toxicity study was performed according to OECD guideline 414, using Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) (Pittermann, 1994). Groups of 24 female Sprague-Dawley rats were administered the test substance in peanut oil at dose levels of 100, 300 and 1000 mg/kg bw/day by gavage during gestation days 6 to 15. On Day 20 of gestation the animals were euthanized and examined for maternal and foetal effects. No systemic effects were noted. No treatment-related effects were seen on the number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions, foetal resorptions, and live foetuses. The examination of foetus litter size and weights, sex ratio and abnormalities (external, head, soft tissue and skeletal abnormalities) showed no differences between the control group and treatment groups and no indications of teratogenic effects. The NOAEL for developmental toxicity and teratogenicity in rats for Fatty acids C16-18, 2-ethylhexyl esters was considered to be ≥ 1000 mg/kg bw/day.

 

CAS 111937-03-2

The potential of isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) to cause developmental toxicity was assessed in a prenatal developmental toxicity study (similar to OECD guideline 414) (Pitterman, 1997). 23-24 pregnant female Sprague-Dawley rats/dose level were administered 100, 300 and 1000 mg/kg bw/day of the test substance by gavage on gestation Days 6 to 15. On Day 20 the females were euthanized and examined.

No treatment-related systemic effects were observed in the P-females. One female in the high-dose group had blood in the uterine horn, but this is not considered to be treatment-related as no related effects were observed. One female in each of the control group and the low-dose group did not become pregnant, while all the pregnant females had viable foetuses. No treatment-related effects on the reproductive parameters (number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions, foetal resorptions, live foetuses, dead foetuses) were observed. The external examination of the F1-foetuses did not reveal any treatment-related macroscopic findings. The skeletal examination showed a statistically significant increase in the number of foetuses with 6 ossified sternebrae in the high-dose group. As there were no increases in ossification anywhere else and no overall increase in abnormal findings for this group, the result is considered to be incidental. The results for the remaining offspring parameters (body weight, placental weight, sex ratio) were comparable between the control and treatment groups. The NOAEL for developmental toxicity and teratogenicity was set at ≥ 1000 mg/kg bw/day.

CAS 90411-68-0

The potential of hexanoic acid, 2-ethyl-, C16-18 alkyl esters (CAS 90411-68-0) to cause developmental toxicity was assessed in a study performed according to OECD guideline 414 and in compliance with GLP (Hellwig, J., 1997). 22 to 25 pregnant Wistar rats were treated by oral gavage with the test substance from gestation day 6 until day 20 at doses of 600, 1000 and 1500 mg/kg bw/day. A concurrent negative control group (vehicle only) and a positive control group (2-ethylhexanoic acid) were included in this study. No mortality and no compound-related symptoms were observed in dams of all test groups. In addition, body weight and body weight gains were within the expected ranges. No compound-related differences were noted in conception rate, mean number of corpora lutea, implantation sites, pre- and post- implantation losses, the number of resorptions and viable fetuses after administration of the test substance.

At scheduled necropsy no macroscopic changes were noted in the dams of the treatment groups. Furthermore, the mean number of total fetuses was not affected by treatment with the test substance. In addition, mean fetal placental and uterus weights were not affected. The fetal sex ratio was comparable in all groups and no treatment-related fetal abnormalities were found at necropsy. The examined fetuses showed no treatment-related malformations in the test groups compared to the negative control group. The various external, skeletal and soft tissue malformations observed in the study were observed incidentally and lay within the range of historical controls. Therefore, these effects were not considered as substance-related. As described in the available reproductive and postnatal development study (Pennanen et al. 1993), oral administration of 600 mg 2-ethylhexanoic acid/ kg bw/day as a ‘positive control’ revealed some signs of maternal toxicity (reduction in food consumption, impairment in body weight gains and increased liver weights) and clear indications for selective developmental toxicity (external malformations, skeletal variations and skeletal retardations), including indications for teratogenicity (impairment in body weight gains and lower mean placental weights). In the positive control group, the overall rate of malformed fetuses/litter, fetal and litter incidences for skeletal and overall variations (especially accessory vertebra; rudimentary cervical, accessory 14th and wavy rib(s)) and skeletal and overall retardation and the mean percentage of fetuses/litters with these findings were distinctly increased and were above the historical control range. Based on the lack of adverse effects in this study, the NOAEL for maternal and developmental toxicity for rats was considered to be above 1500 mg/kg bw/day.

 

CAS 59231-34-4

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed (Hansen, 2013). 10 rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day isodecyl oleate once daily for 28 day (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test Day 1 and ended on the day of, or one day before sacrifice. Day of sacrifice was on test Day 36 for the male rats and on lactation Day 4 or shortly thereafter for the female rats. The dose levels in the main study were based on the results of the dose range-finding study, in which 5 rats/sex/dose were administered 100, 300 and 1000 mg /kg bw/day isodecyl oleate for a period of 14 days.

No mortality occurred in the parental generation and no clinical signs were observed during the study period. The body weight and food consumption was comparable between the control group and treatment groups in the low and medium dose groups, in the high dose group however, a reduction in body weight and food consumption was seen in females only, indicating maternal toxicity at a dose level of 1000 mg/kg bw/day. No substance-related findings were noted at necropsy, which also included the macroscopic examination of the appearance and size of the gonads, adrenal glands, uterus, and accessory reproductive organs. However, changes in reproduction parameters of the dam and in the development of pups were seen in the high dose females and their offspring, respectively. A statistically significant increase in post implantation loss was noted as well as a non-statistically significant decrease in the birth index. The observed elevated number of stillbirths led to a statistically significant reduction in the live birth index. Five (5) pups of the control group died during the lactation period, 2 of the low dose group, none of the intermediate dose group and 30 of the high dose group, leading to a viability index of 71.3% (control group: 98.3%) The high number of dead pups in the high dose group was limited to 2 dams with no surviving pups on lactation day 4 (3 pups of one dam died early after birth, 10 pups were cannibalized on lactation day 4 and 11 pups of the other dam were found dead without milk on lactation day 2) Severe signs of maternal toxicity were seen in those two dams during the administration period of the test material. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. No test item related influence was noted for the fertility index, the gestation index and the preimplantation loss. Furthermore, a statistically significant decrease in the viability index of the pups of high dose dams was seen and a non-statistically significant decrease in mean litter weight of the pups and in total litter weight per dam. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. The NOAEL for systemic toxicity for males was ≥ 1000 mg/kg bw/day. The NOAEL for systemic toxicity of the females was 300 mg/kg bw/day, because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/day). The NOAEL for development was 300 mg/kg bw/day. However, the effects observed in the pups were not considered to be adverse due to the maternal toxicity observed at the highest dose level.

CAS 22393-85-7

A combined repeated dose toxicity and reproduction/developmental toxicity screening study, performed according to OECD 422 and under GLP conditions is available (Rossiello, 2014). 10 rats/dose/day were administered 100, 300 and 1000 mg/kg bw/day of tetradecyl oleate, formulated in carboxymethylcellulose (0.5% in purified water), once daily for at least 28 to 29 days (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test Day 1 and ended on the day of, or one day before sacrifice. Day of sacrifice was on test Day 28 to 29 for the male rats and on Day 4 post-partum for the female rats, except for one single female, which was killed the day after the occurrence of total litter loss. The dose levels in the main study are based on the results of the dose range-finding study, in which 3 rats/sex/dose were administered 100, 300 and 1000 mg /kg bw/day tetradecyl oleate for 14 days.

In the parental animals no test item-related signs of toxicity were observed during the observational and neurological screenings. No differences of toxicological significance were seen in terminal body weight, body weight gain and in food consumption. No relevant changes were recorded in parental animals on clinical pathology investigations (haematology and clinical chemistry). Macroscopic inspection at autopsy and histopathological examination revealed no test item related changes. The mating performance including the pre-coital interval and the copulatory evidence did not show any differences between groups. The resulting copulatory and fertility indices were 100% in all groups. All females were pregnant and had comparable length of gestation. No variations were found in the number of corpora lutea and implantations between groups. All pregnant females gave birth to live pups with the exception of one high dose female which had a total litter loss on day 3 post-partum. This female and two control females had unilateral implantation. This finding was considered incidental since it was observed also in two control females. The litter size at birth and on day 4 post-partum was also similar between groups as well as the mean litter and pup weights. Statistically significant increased mean group sex ratio for males was seen in high dose group on day 4. No relevant findings in pup were found at daily clinical observation not at post-partum examination. On the basis of the results obtained in the study, the NOAEL for systemic toxicity was considered to be ≥1000 mg/kg bw/day for males and females. The NOAEL for developmental toxicity is considered to be ≥1000 mg/kg bw/day.

 

CAS 17671-27-1

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) with docosyl docosanoate is available (Reig, 2014). The test item was administered orally (gavage) once daily at the doses of 100, 300 and 1000 mg/kg bw/day to male and female rats from two weeks before pairing to day 4 postpartum for females and to 5 weeks postcoitum for males.

Treatment with the test item did not cause signs of parental toxicity. No mortality was recorded in either sex and there were no noteworthy differences in food consumption, water consumption or body weight. No changes of toxicological relevance were recorded in the clinical pathology analysis. All macroscopic and microscopic findings recorded were considered to be within the range of normal background lesions that may be seen in rats of this strain and age and under the experimental conditions used in this study. No reproductive toxicity was observed. No differences from the control group were recorded in mean body weight in the F1-generation. Regarding physical development, no differences from the control group were recorded. Regarding motor development, a lower percentage of pups with positive response to the surface righting reflex was recorded at 1000 mg/kg bw/day. The macroscopic findings recorded at necropsy could be considered of no toxicological relevance and within the range of normal background lesions that may be seen in animals of this strain. In conclusion, a NOAEL of 1000 mg/kg bw/day was considered for developmental toxicity. The NOAEL for systemic toxicity was considered to be ≥ 1000 mg/kg bw/day in parental animals.

 

Overall conclusion for developmental toxicity/teratogenicity

Three studies investigating developmental toxicity are available within the LCAE category. The studies with the surrogate substances isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2), fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) and hexanoic acid, 2-ethyl-, C16-18 alkyl esters (CAS 90411-68-0) did not show treatment-related effects on development or teratogenicity up to and including the highest dose level (Pittermann, 1994; Pitterman, 1997; Hellwig, 1997). No hazard for developmental toxicity and teratogenicity was identified.

The most recent version of OECD guideline 414, adopted in January 2001, stipulates that the dams should be dosed from implantation (gestation day 0) to the day prior to scheduled caesarean section (around gestation day 19 for rats). The available studies were performed according to the previous version of OECD guideline 414, adopted in May 1981, which recommended exposure during organogenesis; gestation day 6-15 for rats. The available data on developmental toxicity is of high quality and does not show any treatment-related adverse effects at dose levels up to and including the highest dose of 1500 mg/kg bw/day.

Furthermore, combined repeated dose toxicity and reproduction/developmental toxicity screening studies are available for the following category members: tetradecyl oleate (CAS 22393-85-7), isodecyl oleate (CAS 59231-34-4) and docosyl docosanoate (CAS 17671-27-1). The OECD 422 studies with tetradecyl oleate and docosyl docosanoate showed no adverse effects up to and including the highest dose level of 1000 mg/kg bw/day (Rossiello, 2014 and Reig, 2014). However, the OECD 422 study conducted with the test material isodecyl oleate (CAS 59231-34-4) revealed adverse effects at the highest dose level of 1000 mg/kg bw/day in parental females (Hansen, 2013). The NOAEL for systemic toxicity of the males was ≥ 1000 mg/kg bw/day, while for the females the NOAEL for systemic toxicity was 300 mg/kg bw/day because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/day). The NOAEL for developmental toxicity was 300 mg/kg bw/day. However, the effects observed in the pups at 1000 mg/kg bw/day were not considered to be relevant due to the maternal toxicity at the highest dose level. Overall, the NOAEL for developmental toxicity is therefore considered to be 300 mg/kg bw/day, based on the adverse effects observed in the OECD 422 screening study with isodecyl oleate, at a dose level of 1000 mg/kg bw/day (Hansen, 2013).

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the LCAE category, data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, the available data on toxicity to reproduction and development 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.