Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral: OECD 422, rat, NOAEL fertility ≥ 1000 mg/kg bw/day
Oral: OECD 422, rat, NOAEL systemic ≥ 1000 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 Dec 2012 - 29 Jan 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Wistar Hannover RccHan
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Models, S.L., Barcelona, Spain
- Age at study initiation: 11-12 weeks
- Mean weight at study initiation: males: 312 to 364 g; females: 198 to 219 g
- Fasting period before study: no
- Housing: cages with standard, granulated, softwood Lignocel S8/15 bedding
Pretreatment period: 5 per cage
Mating period: 1 male and 1 female per cage
Postmating: single housing
- Diet: pelleted standard Harlan Teklad 2014C rat/mouse maintenance diet; ad libitum
- Water: tap water; ad libitum
(Analyses of diet and water was performed.)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 30-60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 1% methylcellulose+1% Tween 80 in aqueous solution
Details on exposure:
VEHICLE
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 18 h
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as day 0 postcoitum
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged individually
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of dose formulation was determined in samples taken from the formulation to be administered to Groups 1 to 4 at the start and end of treatment by GC-FID analysis.
Duration of treatment / exposure:
Males: two weeks prior to mating and at least up to and including the day before sacrifice (day 49 of treatment).
Females: two weeks prior to mating and at least up to and including the day before sacrifice (day 4 postpartum).
Frequency of treatment:
Once daily; 7 days/week
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a dose-range finding toxicity study in rats (Harlan Laboratories Study S40412 14-day Oral (gavage) DRF using dose levels of 100, 500 and 1000 mg/kg bw/day.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 2 hours after dosing
- Detailed clinical observations were performed on all test and control group animals before the first exposure to the test item and once weekly thereafter, at least two hours after dosing. Observations were also performed on females with litters on Day 4 postpartum. These observations were performed outside the home cage, in a standard arena, at least two hours after dosing (where applicable) to ensure that any transient effects of treatment are identified.

BODY WEIGHT: Yes
- Time schedule for examinations:
F0 males: twice weekly during the pre-pairing and pairing period and daily during postpairing period.
F0 females: twice weekly during the pre-pairing and pairing period and daily until day 4-5 postpartum.

FOOD CONSUMPTION: Yes
F0 males: once weekly during the pre-pairing period and two weeks of postpairing period.
F0 females: once weekly during the pre-pairing period and days 0-7, 7-14, 14-21 postcoitum and days 1-4 postpartum.
No food consumption was recorded during the mating period.

WATER CONSUMPTION: Yes
F0 males: one week during the pre-pairing and postpairing period.
F0 females: one week during the pre-pairing, postcoitum period and days 1-4 postpartum.
No water consumption was recorded during the remaining periods.:
Oestrous cyclicity (parental animals):
Smearing of individual females was evaluated during pairing period and was discontinued when sperm are found.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight, qualitative staging of spermatogenesis and histopathology evaluation of interstitial cells of all males from the control
and high-dose groups
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes (males on day 50, females on day 5 postpartum)
- Organ weights: epididymes and testicles, adrenal gland, brain, heart, kidney, liver, ovaries, pituitary, spleen, thymus, thyroid and parathyroids, uterus and oviducts
- Fixation: Adrenals, Aorta (thoracic), Bone with bone marrow- (Sternum), Peyer’s patches, Pharynx, Pituitary, Bone marrow smear (femur) (air-dried smear), Brain (cerebrum, cerebellum, medulla/pons), Epididymides (Bouin's solution), Esophagus, Eyes with optic nerve (Davidson’s fixative), Femur (with articular surface), Heart (with papillary muscle), Intestine, large (cecum, colon and rectum), Intestine, small (duodenum, jejunum and
ileum), Kidneys, Larynx, Liver, Lungs, with main bronchi and bronchioles, Lymph nodes (mandibular and mesenteric), Nose (the entire head will be collected), Mammary gland area, Ovaries, Pancreas, Prostate, coagulating gland and seminal vesicles, Salivary glands (mandibular, sublingual and parotid), Sciatic nerve, Skeletal muscle, Skin (abdominal), Spinal cord (cervical, thoracic and lumbar), Spleen, Stomach (glandular and nonglandular), Testes (Bouin's solution), Thymus, Thyroid (incl. parathyroid gland, if possible), Tongue, Trachea, Urinary bladder, Uterus (cervix, corpus and oviducts), Vagina, All gross lesions
Postmortem examinations (offspring):
On day 4 postpartum, all live pups were sacrificed by an intraperitoneal injection of sodium pentobarbital and examined macroscopically.
Any F1 offspring that died during the study was examined externally and necropsied, except those excessively cannibalized. Samples of the organs and tissues with macroscopic alterations were taken and preserved in neutral phosphate buffered 4% formaldehyde solution for possible microscopic examination.
Statistics:
The following statistical methods were used to analyse food consumption during postpairing period, body weight, clinical laboratory data, organ weights, postnatal development and reproduction data, as well as macroscopic findings:
The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables can be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data cannot be assumed to follow a normal distribution.
Fisher's exact-test was applied to the macroscopic findings.
Armitage/Cochran Trend Test [5] for non-neoplastic lesions, if appropriate.
Bonferroni-test was applied to some reproduction parameters.
Reproductive indices:
- Percentage Mating [%] = Number of females mated/Number of females paired x 100
- Fertility Index female [%] = Females achieving pregnancy/Number of females paired x 100
- Gestation Index [%] = Number of litters with live pups/Number of pregnant rats x 100
- Concenption rate [%] = Females achieving pregnancy/Number of females mated x 100
- Pre-implantation loss [%] = Number of corpora lutea - Number of implantation sites/Number of corpora lutea x 100
- Post-implantation loss [%] = Number of implantation sites - Total number of offspring born/Number of implantation sites x 100
Offspring viability indices:
- Post-natal loss [%] = Number of offspring/Number of offspring alive on day 4 x 100
- Viability Index [%] = Number of offspring alive on day 4/Number of offspring alive on day 1 x 100

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
females: lower left ovary weight at 1000 mg/kg bw/day (non adverse)
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality and no relevant clinical signs were observed. One female from the control group, one female and three males at 100 mg/kg bw showed occasionally up of the product. In addition, one male at 300 mg/kg bw had missing upper incisors in week 4 of treatment. No clinical sings were observed at 1000 mg/kg bw in either males or females.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No test-item-related differences from the control group were recorded for body weight. Some significant differences were observed in group 3 but these were not considered of toxicological relevance.
Food consumption was similar in all groups.

REPRODUCTIVE FUNCTION:

SPERM MEASURES (PARENTAL ANIMALS)
All findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age. There were only single cases with isolated tubules that showed minor changes. They consisted of single sperm resorption in stage VII. In epididymides, there was only one animal in group 1 with unilateral monounclear cell foci of a minimal serverity.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Mating Performance: Median precoital time and mean precoital time (approx. 3 days) were similar in animals treated with the test item at 100 and 1000 mg/kg bw with respect to the control group. However, mean and median precoital time was longer at 300 mg/kg bw (5.7 and 4 days, respectively). In addition, female no. 68 from this group did not mate with the first male (no. 28) after a pairing period of 14 days and was mated a second time with male no. 23. This female showed an anestrus cycle of 11 days. Moreover, some animals from all groups took more than 2-4 days to mate. Females nos. 43 (control group), 53 (100 mg/kg), 61 and 70 (300 mg/kg) and 73 (1000 mg/kg) took 12, 12, 13, 14 and 13 days, respectively, to mate and showed an anestrus cycle.

Fertility: No treatment-related differences were recorded in the percentage of mating or the gestation index in females at the three doses with respect to the control group. Although fertility index and conception rate was lower in test-item-treated groups (100% vs. 90%), it was considered to be within the range of normal background findings which may be seen in rats.
Females no. 53 at 100 mg/kg bw, no. 70 at 300 mg/kg bw and no. 77 at 1000 mg/kg bw, which mated with males nos. 13, 30 and 37, respectively, were not pregnant despite the presence of sperm in the vaginal smear and vaginal plug in the last two females. Duration of the mating period of those couples was 12, 14 and 4 days, respectively. Females no. 69 at 300 mg/kg bw and no. 74 at 1000 mg/kg bw, which mated with males nos. 29 and 34, did not show signs of pregnancy and were mated again to ensure eight pregnant females per group. These animals were identified as 81 and 82 to record the data and their second mating led to pregnancy. To check the fertility of the male whose first pairing did not result in mating, male no. 28 from the 300-mg/kg bw group was mated a second time with one female from a reserve group and mating led to pregnancy.

Reproduction data:
No treatment-related differences from the control group were recorded in the mean of implantation sites per litter or corpora lutea.
No treatment-related differences from the control group were recorded in the percentage of pre- or postimplantation losses. Female no. 45 from control group showed 100% implantation site loss. No differences in sex ratio were recorded.

Breeding data:
The length of pregnancy was similar in all groups with a mean of 21-22 days.
Female no. 78 at 1000 mg/kg bw had not enough milk and did not nurse correctly its pups; consequently, the pups died or were devoured between days 2 and 3 of lactation. Despite the fact that the pups had milk in the stomach when alive, they did not have any at necropsy and showed hypothermia and pallor. Female no. 78 showed slightly enlarged mammary glands. Even the percentage of pups showing milk in the stomach was similar in all groups. One pup in the litter of females no. 43 from control group, no. 63 at 300 mg/kg bw, no. 78 and two pups from no. 73 at 1000 mg/kg bw showed no milk in stomach on day 1 postpartum and died.

ORGAN WEIGHTS (PARENTAL ANIMALS)
At 1000 mg/kg bw, kidney weights tended to be slightly higher in males. These differences were not statistically significant. Moreover, lower pituitary and adrenal weights were recorded; the differences were statistically significant for pituitary in males. A trend to higher liver weight was recorded in females at 1000 mg/kg bw, but the differences were not statistically significant.
Concerning reproductive organs, lower left ovary weights were recorded at 1000 mg/kg bw. This difference was statistically significant in relation to body weight ratio.

GROSS PATHOLOGY (PARENTAL ANIMALS)
At 1000 mg/kg bw, large right kidney was observed in one male and reddish thymus in another one. A reddish area on cecum wall was observed in one male and reddish foci in lungs in another one. Likewise, thickened gastric mucosa was observed in one female and small spleen in another one.
At 300 mg/kg bw, reddish foci were observed in the thymus of one male. No findings were observed in females.
At 100 mg/kg bw, pale kidneys were observed in one male and reddish foci in lungs in another one. Likewise, left seminal vesicle reduced in size was observed in one male and reddish thymus in three males. Thickened gastric mucosa was observed in one female.
In the control group, one male had left seminal vesicle reduced in size. One male and one female had pale kidneys. In addition, one male had pancreas reduced in size and thymus with reddish foci.
Yellowish-whitish gastric mucosa was recorded in few females from all groups (including control group).

HISTOPATHOLOGY (PARENTAL ANIMALS)
All 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.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in the study
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in the study
Key result
Critical effects observed:
no
Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
No treatment-related differences from the control group were recorded in the mean of dead pups at the first litter check and living pups. During the first 4 days postpartum, the percentage and mean of postnatal losses was slightly higher at 1000 mg/kg bw; however the number of litters affected was similar to that of the control group (2 vs 1 litters) due to the fact that female no. 78 (1000 mg/kg bw) lost all its litter. The resulting viability index was lower than in the control group (84.7% versus 99.1%, respectively).
No differences were recorded at 100 and 300 mg/kg bw.


BODY WEIGHT (OFFSPRING)
No differences were recorded between groups and sexes. At 1000 mg/kg bw, one runt pup *no.7 from litter no.54) was observed.

GROSS PATHOLOGY (OFFSPRING)
No noteworthy findings were recorded in the control, 100, 300 or 1000 mg/kg bw pups.

MORPHOLOGICAL EXAMINATION
No treatment-related alterations were recorded in the morphological examination of the pups.
One pup from control group had a hematoma on toes and one pup from 300 and 1000 mg/kg bw group had a wound on scapula or limbs.

OTHER FINDINGS (OFFSPRING)
Motor development: Regarding postural reflexes in the pups, a significantly lower percentage of fetuses with positive response in the surface-righting reflex (righting reflex) at 1000 mg/kg bw was recorded compared to the control group. There were no treatment-related differences compared to the control animals at 100 or 300 mg/kg bw.
Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in the study
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate,reliable (Klimisch score 2 due to read-across) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the 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 fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across

There are no data on the reproduction toxicity of Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate (CAS 97338-28-8). The assessment was therefore based on studies conducted with analogue substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. 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 of 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 analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 17671-27-1

A combined repeated dose toxicity and reproduction/developmental toxicity screening study was performed according to OECD guideline 422 under GLP conditions (key, 2014). 10 rats/ sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day Docosyl docosanoate once daily, via gavage. Males were exposed for 28-29 days, from two weeks before mating on test day one until after mating. Females were exposed for 54 days (during 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation).

No treatment-related parental effects were seen on viability, clinical signs, body weight (gain), food consumption, clinical chemistry parameters, during observational screening, and during macroscopic and microscopic examinations. In females, an increase in bilirubin, cholesterol and triglyceride levels was recorded at 300 and 1000 mg/kg. As this was only observed in one sex and no other hepatic changes were observed, this is not considered to be toxicologically relevant. Lower locomotor activity was recorded in males at 100 mg/kg and in females at 300 and 1000 mg/kg. As no effects were noted on other neurological parameters, this is not considered to be toxicologically relevant. Therefore the NOAEL for parental systemic toxicity was ≥ 1000 mg/kg bw/day.

In parental animals, no effects on reproductive function (qualitative sperm staging, oestrus cycle) or performance (male and female mating and fertility indices, conception index, precoital interval, and number of corpora lutea and implantation sites, gestation length) were observed, compared with the control animals. One female from the control group had a 100% postimplantation loss, which is considered to be incidental. The testis weight, epididymis weight, and histological examination of the testes in males as well as the weight and histological examination of the uterus and ovaries in females did not reveal any substance-related effects in the parental animals. Therefore, a NOAEL for parental fertility of ≥ 1000 mg/kg bw/day was derived for male and female rats.

 

CAS 22393-85-7

A combined repeated dose toxicity and reproduction/developmental toxicity screening study was performed according to OECD guideline 422 under GLP conditions (supporting, 2014). 10 rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day Tetradecyl oleate (CAS 22393-85-7) once daily, via gavage. Males were exposed for 28-29 days, from two weeks before mating on test day one until after mating. Females were exposed for 54 days (during 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation). No treatment-related parental effects were seen on viability, clinical signs, body weight (gain), food consumption, haematological parameters, clinical chemistry parameters, during observational and neurological screening, and during macroscopic and microscopic examinations. Therefore the NOAEL for parental systemic toxicity was ≥ 1000 mg/kg bw/day.

In parental animals, no effects on reproductive function (qualitative sperm staging, oestrus cycle) or performance (male and female mating and fertility indices, conception index, precoital interval, and number of corpora lutea and implantation sites, gestation length) were observed, compared with the control animals. The testis weight, epididymis weight, and histological examination of the testes in males as well as the weight and histological examination of the uterus and ovaries in females did not reveal any substance-related effects in the parental animals. All the 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 females in the control group had unilateral implantation, which is not considered to be treatment-related. Therefore, a NOAEL for parental fertility of ≥ 1000 mg/kg bw/day was derived for male and female rats.

Overall conclusion for effects on fertility

There are no available studies on the toxicity to reproduction and fertility of Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate. Therefore analogue read-across from 2 source substances was applied. The potential for reproductive toxicity of the source substances was assessed in reproductive/developmental screening studies (OECD 422). The NOAEL value for fertility was equal to or higher than the currently applied limit dose value of 1000 mg/kg bw/day. Therefore, no hazard to reproduction was identified. Based on the available data and following the analogue approach, the target substance Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate is not expected to affect fertility.


Effects on developmental toxicity

Description of key information
Oral: OECD 422, rat, NOAEL development ≥ 1000 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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 read-across

There are no available data on the developmental toxicity of Isohexadecyl 12 -[(1 -oxooctadecyl)oxy]octadecanoate (CAS 97338-28-8). The assessment was therefore based on studies conducted with analogue substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. 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 of 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 analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Developmental toxicity/teratogenicity

CAS 17671-27-1

A combined repeated dose toxicity and reproduction/developmental toxicity screening study was performed according to OECD guideline 422 under GLP conditions (key, 2014). 10 rats/ sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day Docosyl docosanoate once daily, via gavage. Males were exposed for 28-29 days, from two weeks before mating on test day one until after mating. Females were exposed for 54 days (during 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation). No reproductive toxicity was observed. The results of the offspring (viability) parameters pre-implantation loss, pre-birth loss, stillbirths, live births, litter size and pup weight were comparable between control and treatment groups. Lower milk production was observed in one female administered 1000 mg/kg bw/day. The female did not nurse her pups; leading to the pups dying or being cannibalised between day 0 and 4 postpartum. As a consequence, the cumulative pup loss on day 4 post-partum increased significantly. This occurrence is considered to be incidental as only 1/10 dams exhibited this behaviour and no other treatment-related developmental effects were noted. In the motor development assessment, the percentage of high-dose pups with negative response to the surface righting reflex was significantly increased, compared with the control group. As no effects were noted on other parameters, this is not considered to be toxicologically relevant. The gross pathological examinations did not reveal any treatment-related effects. In conclusion, the NOAEL for developmental toxicity/teratogenicity is considered to be ≥ 1000 mg/kg bw/day.

 

CAS 22393-85-7

A combined repeated dose toxicity and reproduction/developmental toxicity screening study was performed according to OECD guideline 422 under GLP conditions (supporting, 2014). 10 rats/ sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day Tetradecyl oleate (CAS 22393-85-7) once daily, via gavage. Males were exposed for 28-29 days, from two weeks before mating on test day one until after mating. Females were exposed for 54 days (during 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation).

The results of the offspring (viability) parameters pre-implantation loss, pre-birth loss, stillbirths, live births, cumulative pup loss on day 4 post-partum, litter size and pup weight were comparable between control and treatment group. Clinical signs of pups such as pallor, cold to touch, small and/or bruised muzzle, were observed in control and treatment groups and were therefore not considered to be of toxicological relevance. The number of male pups was significantly increased compared with the control group on Day 4 only. As the sex ratio (absolute percentage of males to females) was not significantly different from control , this is not considered to be a toxicologically relevant effect. The gross pathological examinations did not reveal any treatment-related effects. Based on the lack of effects, the NOAEL for developmental toxicity/teratogenicity is considered to be ≥ 1000 mg/kg bw/day.

Overall conclusion fordevelopmental toxicity/teratogenicity

There are no available studies on the developmental toxicity and teratogenicity of Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate. Therefore analogue read-across from 2 source substances was applied. The potential for developmental toxicity and teratogenicity of the source substances was assessed inreproductive/developmental screening studies (OECD 422). NOAEL values for developmental toxicity/teratogenicity were all at the currently applied limit dose value of 1000 mg/kg bw/day. Therefore, no hazard to in utero development was identified. Based on the available data and following the analogue approach, the target substance Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate is considered to be not toxic to uterine development.

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 analogue concept is applied to Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate (CAS 97338-28-8), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Based on the analogue read-across approach, the available data on toxicity to reproduction/development does not meet the classification criteria according to Regulation (EC) 1272/2008, and is therefore conclusive but not sufficient for classification.