Dodecyl laurate

Endpoint summary

Description of key information

Oral (equivalent to OECD 407, read across): NOAEL rat = 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 Mar - 12 May 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No neurological examinations were performed, no clinical observations outside the home cage, the test substance was administered 5 days/week, the analytical purity of the test substance was not specified.

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

yes

Remarks:

no neurological examinations performed, no clinical observations outside the home cage

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no neurological examinations performed, no clinical observations outside the home cage

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Wistar Bor:WISW (SPF) Cpb

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: approximately 4 weeks
- Weight at study initiation: 44-61 g (males), 46-60 g (females)
- Housing: 2-3 animals of the same sex in macrolon cages, type III with wood shavings (ARWI-Center, Essen, Germany)
- Diet: nitrosamine-poor pellets, Altromin 1324 DK (Fa. Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): 41-55
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 25 Feb 1992 To: 9-10 Mar 1992 (main groups), 12 May 1992 (satellite groups)

Route of administration:

oral: gavage

Vehicle:

other: 0.5% carboxymethylcellulose and 0.25% cremophor in aqua dest. (CMCC)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: dosing solutions were prepared daily prior to administration. The application volumes were adopted weekly to the current body weights.

VEHICLE
- Concentration in vehicle: 1, 2 and 10% for the 100, 300 and 1000 mg/kg bw/day groups, respectively.
- Amount of vehicle (if gavage): 10 mL/kg bw

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 days (control and treatment group)
28 days and 33 days post-exposure observation period (satellite control and treatment group)

Frequency of treatment:

once daily, 5 days/week (23-24 doses in total)

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 (main groups)
5 (satellite groups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: the dose levels were selected in order to find the highest possible safety margin for the determination of the non-cumulative toxic dose level and the determination of toxic dose ranges.
- Rationale for selecting satellite groups: satellite control and high-dose groups were selected to determine the reversibility of potentially cumulative toxic effects
- Post-exposure recovery period in satellite groups: 33 days

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: the animals were observed for mortality and clinical signs twice daily (once daily during weekends and public holidays)

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, the intake per cage per week was recorded and calculated as g/rat/week
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes
- Time schedule for examinations: once weekly, per cage

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one day prior to the sacrifice of the animals. Mydriaticum Roche R (Hoffmann-La Roche, Grenzach-Wyhlen) was instilled into the right eye, which was then examined using a Topcon-SL-5D slit lamp (Bon, D-Wahlstedt).
- Dose groups that were examined: control and 1000 mg/kg bw/day group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: all animals in the main groups
- Parameters examined: haematocrit, haemoglobin content, red blood cell count, white blood cell count, mean cell volume, thrombocyte cell count, differential blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Animals fasted: No
- How many animals: all animals in the main groups
- Parameters examined: gamma-glutamyl transferase, aspartate-aminotransferase, alanine-aminotransferase, alkaline phosphatase, sodium, potassium, glucose, urea, total protein, calcium, creatinine, cholesterol, chloride, bilirubin

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. The animals in the main groups and satellite groups were sacrificed using an overdose of ether and gross pathology was conducted with all animals. The eyeballs and the inner organs were removed and fixed in 10% neutral formalin solution (Formol-Fixx-Concentrate, Shandon). The weight of the brain, testes, heart, liver, spleen, adrenals, kidneys and thymus of all main and satellite groups was recorded.

HISTOPATHOLOGY: Yes. For the control and 1000 mg/kg bw/day groups, the following organs were histologically examined: aorta thoracica, eyes, colon, stomach, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis, cerebellum, liver, trachea, lung, axilliary lymph nodes, mesenteric lymph nodes, spleen, epididymides, adrenals, periphery nerve, kidneys, ovaries, pancreas, prostate, seminal vesicle, thyroid, salivary gland, oesophagus, sceletal muscle, thymus, uterus, forestomach, tongue.
In the satellite groups and the 500 mg/kg bw/day main group, the forestomach was examined as a target organ.

Statistics:

The inter-groups variations for body weight, clinical chemistry and hematology were determined using a t-test. The differences in organ weight were evaulated using a Steel-test.

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs were observed during the study period.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

100 mg/kg bw/day: 1/10 females died at the end of the study during the collection of blood (not test substance-related). There was no substance-related mortality.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There was no difference in body weight gain between the control and treatment groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There was no statistically significant difference in food consumption between the control and treatment groups.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

There was no statistically significant difference in water consumption between the control and treatment groups. The females in the 1000 mg/kg bw/day group showed an increase in water consumption in week 2, however, as this was due to a mechanical failure this is not considered to be a relevant finding (see Table 1).

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no substance-related changes to the eyes of the examined animals.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The males administered 1000 mg/kg bw/day had a significant increase in the level of leucocytes with segmented nuclei (see Table 2). As this effect was non-adverse and only observed in one sex and there were no other hematologic or histopathologic effects, this is not considered to be a treatment-related effect.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

In males administered 1000 mg/kg bw/day, the ALT-level was statistically significantly increased (see Table 3). This increase in a liver enzyme may be caused by an increase in the liver metabolism due to the test substance. However, no other effects were seen on clinical chemistry parameters or in the histopathological results and the effects are considered not to be of toxicological relevance (non-adverse). An increase in the protein- and calcium levels of males in the 100 mg/kg bw/day group is not considered to be substance-related as these increases were not observed at any other dose level and in one sex only.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

300 mg/kg bw/d: increased relative heart weight, males; 100 mg/kg bw/day: increased relative/absolute heart weight, males (non-adverse)
A slight decrease was observed in the relative and absolute heart weight of males in the 100 mg/kg bw/day group and in the relative heart weight in males in the 300 mg/kg bw/day group (see Table 4). As no effect was observed in the highest dose group, this is not deemed to be a treatment-related effect.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

1/10 females administered 1000 mg/kg bw/day had severe oedema in the forestomach and 1/10 had thickening of the forestomach mucosa. These findings were probably compound-related, however, humans do not have a forestomach and this effect is therefore not relevant to human exposure. No other effects were noted during necropsy.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day: effects on the mucosa of the forestomach
4/10 males and 2/10 females in the 1000 mg/kg bw/day group had oedema in the mucosa of the forestomach, and the 2 females also had ulcerations (see Table 5). These findings were probably compound-related, however, as humans do not have a forestomach this effect is not relevant to human exposure. As none of the animals in the satellite group had effects on the forestomach, this is considered to be a reversible effect.

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects were observed up to and including the highest dose level

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

System:

gastrointestinal tract

Organ:

other: forestomach

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

no

Table 1: Water consumption as group mean value (mL/animal/day)

	Group (mg/kg bw/day)
	Males				Females
Week	Control	100	300	1000	Control	100	300	1000
1	209	196	205	197	156	154	159	155
2	209	215	217	192	145	152	158	195
3	229	215	209	207	138	141	147	149
4	217	208	203	211	141	143	145	149

 

 

Table 2: Haematological results

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
leucocytes with segmented nuclei (%)	0.3	0.1	0.4	1.1*	0.7	0.7	0.7	0.7

*Statistically significant (p < 0.01)

 

Table 3: Clinical chemistry

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
ALT (U/L)	30	30	30	40*	23	23	21	27
Protein (g/L)	60	62**	61	60	63	63	63	63
Calcium (mmol/L)	2.3	2.4**	2.4	2.4	2.4	2.4	2.4	2.4

*Statistically significant (p < 0.01)

**Statistically significant (p < 0.05)

 

Table 4: Organ weights

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
Heart, absolute (g)	0.84	0.75**	0.77	0.82	0.58	0.61	0.59	0.60
Heart, relative (%)	0.34	0.32**	0.31*	0.33	0.36	0.36	0.36	0.37

*Statistically significant (p < 0.01)

**Statistically significant (p < 0.05)

 

 

 

Table 5: Histopathological effects

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
Edema in forestomach	0/10	-	-	4/10	0/10	-	-	2/10
Ulcer(s) in forestomach	0/10	-	-	0/10	0/10	-	-	2/10

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

06 Jun 2013 - 20 Oct 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

adopted in 22 Mar 1996

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco (Lecco), Italy
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: 191 to 204 g (males) and 172 to 179 g (females)
- Housing: From arrival to pairing: animals were housed 5 of one sex to a cage, in polysulphone solid bottomed cages measuring 59.5x38x20 cm (Techniplast Gazzada S.a.r.l., Buguggiate, Varese, Italy). Nesting material was provided inside suitable bedding bags and changed at least twice a week.
During mating: animals were housed one male to one female in clear polysulphone cages measuring approximately 43x27x18 cm with a stainless steel mesh lid and floor (Techniplast Gazzada S.a.r.l., Buguggiate, Varese, Italy). Each cage tray held absorbent material which was inspected and changed daily. After mating, the males were re-caged as they were before mating; the females were transferred to individual solid bottomed cages (Techniplast Gazzada S.a.r.l., Buguggiate, Varese, Italy) for the gestation period and parturition.
- Diet: laboratory rodent diet, 4 RF 21 (Mucedola S.r.l., Settimo Milanese (MI), Italy), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous carboxymethylcellulose (0.5% CMC)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test substance was suspended in the vehicle. Formulations were prepared daily.

VEHICLE
- Concentration in vehicle: 10, 30 and 100 mg/mL for dose levels of 100, 300 and 1000 mg/kg bw/day, respectively
- Amount of vehicle: 10 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration, homogeneity and stability of the test substance in the vehicle were verified by gas chromatopgraphy with a flame ionisation detection (FID). Concentration verification was conducted on a weekly basis.

Duration of treatment / exposure:

Males: The daily administration of the test item was started two weeks before mating and lasted until test day 28 to 29, which was one day before sacrifice.
Females: The daily administration of the test item was started two weeks before mating and continued until day 3 post-partum.
Maximum: 54 days of treatment.

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: based on a 14-day range-finding study (Rossiello, 2013. RTC Study No.: 93730EXT)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily during the study, each animal was observed and any clinical signs recorded.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before commencement of treatment and at least once a week thereafter, each animal was given a detailed clinical examination. Each animal was removed from the home cage and observed in an open arena. The tests included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypes or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern).

BODY WEIGHT: Yes
- Time schedule for examinations: females: weekly from allocation to positive identification of mating and on gestation Days 0, 7, 14 and 20. Dams were also weighed on Days 1 and 4 post partum.

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: the weight of food consumed by each cage of males and females was recorded weekly during the pre-mating period starting from allocation. Individual food consumption for the females was measured on gestation Days 7, 14 and 20 starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE : Yes
- Time schedule for examinations: daily by visual appraisal

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of treatment
- Anaesthetic used for blood collection: Yes with isofluorane
- Animals fasted: Yes
- How many animals: 5/sex/dose
- Parameters examined: haematocrit, haemoglobin, red blood cell count, reticulocyte count, mean red blood cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white blood cell count and differential leucocyte count

Coagulation tests: Prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of treatment
- Animals fasted: Yes
- How many animals :5/sex/dose
- Parameters examined: albumin, globulin, albumin/globulin ratio, bile acids, total bilirubin, total cholesterol, creatinine, glucose, urea, total protein, calcium, chloride, potassium, sodium, alanine aminotransferase (ALAT), alkaline phosphatase (AP), aspartate aminotransferase (ASAT), gamma-glutamyltransferase, triglycerides, inorganic phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once during the study, towards the end of treatment, 5 males and 5 females were randomly
selected from each group for evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli), for assessment of grip strength and for the motor activity was measured (for approximately 5 min).
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory reactivity to stimuli of different types (e.g. auditory, visual and proprioceptive stimuli) (based on Gad), as well as the assessment of grip strength (Meyer) and motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
-Organ weights: adrenal glands, brain (cerebrum, cerebellum, medulla/pons), epididymides, heart, kidneys, liver, ovaries with oviducts, parathyroid glands, prostate gland, seminal vesicles with coagulating glands, spleen, testes, thymus (where present), thyroid and uterus-cervix,
-Fixation: adrenal glands, bone marrow (from sternum), brain (cerebrum, cerebellum, medulla/pons), caecum, clitoral gland, colon, duodenum, epididymides, heart, ileum (including Peyer’s patches), jejunum, kidneys, liver, lungs (including mainstem bronchi), lymph nodes (mesenteric and cervical), ovaries with oviducts, parathyroid glands, pituitary gland, penis, preputial gland, prostate gland, rectum, sciatic nerve, seminal vesicles with coagulating glands, spinal column, spinal cord (cervical, thoracic, lumber), spleen, stomach, testes, thymus (where present), thyroid, trachea, urinary bladder, uterus-cervix and vagina.

HISTOPATHOLOGY: Yes, all organs that were included for fixation (5/sex of control and high dose group)

In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS). The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed. A detailed qualitative evaluation of testes was performed on 5 randomly selected control and high dose males. The evaluation took into account the tubular stages of the spermatogenic cycle, in order to identify treatment-related effects such as: missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen.

Other examinations:

Vaginal smears were taken daily in the morning starting two weeks before pairing until a positive identification of copulation was made.

Statistics:

Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the nonparametric version of the Williams test.
The criterion for statistical significance was p<0.05.

Clinical signs:

no effects observed

Description (incidence and severity):

No relevant clinical signs or mortality were observed in males and females throughout the study.

Mortality:

no mortality observed

Description (incidence):

No relevant clinical signs or mortality were observed in males and females throughout the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences of toxicological significance were seen in terminal body weight or body weight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No intergroup differences were seen in food consumption.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No changes of toxicological significance were observed. The statistically significant differences between control and treated animals (erythrocytes, mean corpuscular haemoglobin and leucocytes in males, haemoglobin, haematocrit and platelets in females) were of low magnitude and/or not dose-related, therefore considered incidental.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No changes of toxicological significance were observed. Statistically significant fluctuations of some biochemical parameters (mean group values) were recorded such as: increase of glucose in males dosed with 100 and 1000 mg/kg bw/day (48% for both dosages), increase in urea in those receiving 100 mg/kg bw/day (19%), increase of aspartate aminotransferases in females dosed with 300 mg/kg bw/day (35%), decrease of bilirubin (81%) and increase of potassium (10%) in those treated with 1000 mg/kg/day when compared to controls.
Due to the lack of dose- and sex-consistency and to the absence of other relevant findings, the above alterations were considered unrelated to treatment.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No significant differences were observed between groups, in motor activity, grip strength and sensory reactivity to stimuli, evaluated at the end of treatment.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No relevant differences in organ weights were seen between the controls and treated animals of both sexes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No remarkable changes were noted at post mortem examination in treated animals when compared with controls.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related changes were observed. The lesions reported in control and treated animals were considered to be an expression of spontaneous and/or incidental pathology, commonly seen in this species and age under the experimental conditions.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Spermatogenic cycle
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted. No relevant difference in estrous cycle was observed in treated females when compared to controls.

Key result

Dose descriptor:

NOAEL

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

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 1-2) studies from reference substances 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 studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Read across justification

There are no data on the repeated dose toxicity with Lauryl laurate (CAS 13945-76-1). 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).

Repeated dose toxicity, oral, subacute

CAS 95912-86-0

A 28-day oral repeated dose toxicity study equivalent to OECD guideline 407 (key study, 1993) was performed with Fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0). Ten Wistar rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day by gavage, for 28 days (treatment 5 days/week). There was no treatment-related mortality and no clinical signs were observed during the study period. No significant differences in body weight, body weight gain, food consumption, ophthalmology, haematology results and clinical chemistry results were noted between the control group and treatment groups. At 1000 mg/kg bw/day macroscopic and microscopic changes in the forestomach were seen, however, as humans do not have a forestomach this effect is not relevant to human exposure. As none of the animals in the satellite group had effects on the forestomach, this was considered to be a reversible effect. Based on the lack of other toxicologically relevant effects up to and including the highest dose level, the NOAEL was considered to bw 1000 mg/kg bw/day.

 

CAS 22393-85-7

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD guideline 422 and in compliance with GLP) was performed (supporting study, 2014) with Tetradecyl oleate (CAS 22393-85-7). Ten Sprague-Dawley rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day once daily for 28-29 days (males) and up to 54 days (females) via oral gavage. The application started two weeks before mating on test day one and ended on the day of or one day before sacrifice. Day of sacrifice was on test day 29 or 30 for the male rats and on lactation day 3 or shortly thereafter for female rats. There was no mortality during the study period. No toxicologically relevant clinical signs were observed. The body weight, body weight gain and food consumption was comparable between the control and treatment groups. There were no toxicologically relevant effects on organ weights. The statistically significant differences in haematological parameters between control and treated animals (erythrocytes, mean corpuscular haemoglobin and leucocytes in males, haemoglobin, haematocrit and platelets in females) were of low magnitude and/or not dose-related, and therefore considered incidental. Statistically significant fluctuations of some biochemical parameters, compared with the control groups, were recorded in both sexes. An increase in glucose levels in males administered 100 and 1000 mg/kg bw/day (48% for both doses), and an increase in urea in males receiving 100 mg/kg bw/day (19%) was observed. In females in the 300 mg/kg bw/day group, an increase in aspartate aminotransferase level (35%) was noted, while for females administered 1000 mg/kg bw/day, a decrease in bilirubin levels (81%) and an increase in potassium levels (10%) were observed. Due to the lack of dose- and/or sex-consistency, and due to the absence of other relevant findings, these changes are not considered to be toxicologically relevant. There was no significant difference between control and treatment groups during the observational and neurological screenings. The macroscopic inspection at autopsy and subsequent histopathological examination did not reveal any treatment-related changes. The NOAEL for systemic toxicity was considered to be ≥ 1000 mg/kg bw/day.

 

Overall conclusion for repeated dose toxicity

The data for the read-across analogue substances showed that no effects were observed up to and including the recommended limit values. Therefore, as the available data did not identify any hazard for repeated dose toxicity, Lauryl laurate (CAS 13945-76-1) is also not considered to be hazardous following repeated exposure.

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 Lauryl laurate (CAS 13945-76-1), 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.

Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.