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) 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

--

59231-34-4 (a)

Experimental result:

NOAEL fertility = 300 mg/kg bw/day

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

Experimental result:

NOAEL developmental = 300 mg/kg bw/day

36078-10-1

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

95912-86-0

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

95912-87-1

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

91031-91-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

85116-88-7

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

3234-85-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

22393-85-7

Experimental result:

OECD 422 study ongoing

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

101227-09-2

RA: CAS 59231-34-4, 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

72576-80-8

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

3687-45-4

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

17673-56-2

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

96690-38-9

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

93803-87-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

17671-27-1

Experimental result:

OECD 422 study ongoing

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

111937-03-2 (c)

--

Experimental result:

NOAEL ≥ 1000 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. Lack of data for a given endpoint is indicated by “--“.

(c) Surrogate substances are chemicals of structurally similar fatty acid esters. 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.

Discussion

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 0, 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 (Hansen, 2013). 10 rats/dose/day were administered 0, 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 one 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 0, 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/d. 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 preimplantation 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 reproduction and development was 300 mg/kg bw/day in this screening study, 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/d). Thus, the effects observed in the pups were not considered to be adverse due to the maternal toxicity at the highest dose level.

 

CAS 22393-85-7

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) is currently being performed using tetradecyl oleate. 10 rats/dose/day will be administered 0, 100, 300 and 1000 mg /kg bw/day of the test substance for 28 day (males) and up to 54 days (females). The following parameters will be evaluated: mortality, clinical signs, body weight, haematology, clinical chemistry, macroscopic and microscopic histopathology, fertility, reproduction, and development (up to lactation day 4). 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.

The results of the main study will be included and evaluated when available.

 

CAS 17671-27-1

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) is currently being performed using docosyl docosanoate. 10 rats/dose/day will be administered 0, 100, 300 and 1000 mg /kg bw/day of the test substance for 28 day (males) and up to 54 days (females). The following parameters will be evaluated: mortality, clinical signs, body weight, haematology, clinical chemistry, macroscopic and microscopic histopathology, fertility, reproduction, and development (up to lactation day 4). 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, 500 and 1000 mg /kg bw/day docosyl docosanoate for a period of 14 days. During the study, no mortalities and no relevant clinical signs of toxicity were observed. Food consumption was comparable between treated and control animals. A dose-dependent, but non-adverse, lower water consumption was recorded in males from all treatment groups and in females treated with 1000 mg/kg bw/day. Body weight gain in all treatment groups was similar or slightly higher compared to control group. No toxicologically relevant alterations in clinical chemistry and haematological parameters were observed. Alterations in absolute and/or relative organ weights of thymus, testes and thyroid were recorded at the end of the treatment period. At all dose levels, decreases in thyroid weight in females and increases in testes weight in males were observed. Furthermore, a decrease in thymus weight was observed in both genders of all treatment groups. However, in the absence of abnormal findings at gross pathology, these effects were not considered to be toxicologically relevant. Macroscopic examination did not reveal any treatment-related findings in any other organs or tissues. All lesions (reddish mandibular lymph nodes, reddish foci in thymus and dilation of uterine horns) noted in individual females treated with 500 and 1000 mg/kg bw/day were within the normal range of background alterations observed in rats of this strain and age and under the experimental conditions used in this study, and thus not related to treatment with the test substance.

The results of the main study will be included and evaluated when available.

 

Overall conclusion for toxicity to reproduction

In a 90-day repeated dose toxicity study performed in rats according to OECD 408, and using propylheptyl octanoate (CAS 868839-23-0) 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). A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed (Hansen, 2013). The NOAEL for reproduction and development was 300 mg/kg bw/day in this screening study, 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/d). Thus, the effects observed in the pups at 1000 mg/kg bw/d were not considered to be relevant due to the maternal toxicity at the highest dose level. Two combined repeated dose toxicity and reproduction/developmental toxicity screening studies are being performed with tetradecyl oleate and docosyl docosanoate, respectively. In the 14-day dose range-finding studies with isodecyl oleate and docosyl docosanoate, no effects were observed on clinical signs, body weight or food consumption. Furthermore, no substance-related findings were noted during the necropsy. The results of the main studies will be included and evaluate when available.

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


Short description of key information:
NOAEL (fertility) = 300 mg/kg bw/day
NOAEL (systemic) = 300 mg/kg bw/d
The OECD 422 screening studies for the two category members CAS 22393-85-7 and CAS 17671-27-1 are not yet available, the studies are ongoing.

Effects on developmental toxicity

Description of key information
NOAEL (development) = 300 mg/kg bw/day
NOAEL (systemic) = 300 mg/kg bw/d
The OECD 422 screening studies for the two category members CAS 22393-85-7 and CAS 17671-27-1 are not yet available, the studies are ongoing.
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) 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

--

59231-34-4 (a)

Experimental result:

NOAEL fertility = 300 mg/kg bw/day

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

Experimental result:

NOAEL developmental = 300 mg/kg bw/day

36078-10-1

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

95912-86-0

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

95912-87-1

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

91031-91-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

85116-88-7

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

3234-85-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

22393-85-7

Experimental result:

OECD 422 study ongoing

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

101227-09-2

RA: CAS 59231-34-4, 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

72576-80-8

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

3687-45-4

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

17673-56-2

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

96690-38-9

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

93803-87-3

RA: CAS 59231-34-4

RA: CAS 22393-85-7,

17671-27-1 (OECD 422 study ongoing)

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

17671-27-1

Experimental result:

OECD 422 study ongoing

RA: CAS 91031-48-0, 111937-03-2, 59231-34-4

111937-03-2 (c)

--

Experimental result:

NOAEL ≥ 1000 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 chemicals of structurally similar fatty acid esters. 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.

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

Discussion

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 0, 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 0, 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 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/dose/day were administered 0, 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 one 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 0, 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/d.

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. In detail, 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 reproduction and development was 300 mg/kg bw/day in this screening study, the NOAEL for systemic toxicity of the females was 300 mg/kg bw/day as well, because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/day). Thus, the effects observed in the pups were not considered to be adverse due to the maternal toxicity at the highest dose level.

 

Overall conclusion for developmental toxicity/teratogenicity

Two studies investigating the developmental toxicity are available within the LCAE category. The studies with the surrogate substances isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) and Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) did not show treatment-related effects on development or teratogenicity up to and including the highest dose level (Pittermann, 1994; Pitterman, 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 study was 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 repeated dose toxicity and developmental toxicity is of high quality and does not show treatment-related adverse effects at dose levels up to and including the highest dose of 1000 mg/kg bw/day.

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed with isodecyl oleate (CAS 59231-34-4) (Hansen, 2013). The NOAEL for reproduction and development was 300 mg/kg bw/day in this screening study, 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/d). Thus, the effects observed in the pups at 1000 mg/kg bw/d were not considered to be relevant due to the maternal toxicity at the highest dose level.

Two further combined repeated dose toxicity and reproduction/developmental toxicity screening studies (according to OECD 422) using category members are currently being performed. The results of these studies will be included and evaluated when available.

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