Registration Dossier

Administrative data

Description of key information

Read-across from supporting substance (structural analogue).

The experimental data obtained by testing 8-methylnonyl octadec-9-enoate can be reliably extrapolated (by read-across) to 11-methyldodecyl laurate and support the absence of repeated dose toxicity effect.

Overall, 11-methyldodecyl laurate should not be classified for repeated dose toxicity in accordance with Regulation (EC) n. 1272/2008.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The justification for type of information is provided in attachment.
Reason / purpose:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
statistically significant decrease (-9.4%) in body weight in females during lactation at 1000 mg/kg bw/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high dose group (females: gestation/lactation period) a statistically significant reduction in food consumption by 21.7% was noted.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Piloerection was seen in 1 female of the high dose group at on day 2-4 of lactation.

BODY WEIGHT AND WEIGHT GAIN
A reduction in body weight (-9.7%) in high dose females during lactation period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduction in food intake (-21.7%) in high dose females during gestation/lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No effects on water consumption in any treatment group were observed.

OPHTHALMOSCOPIC EXAMINATION
No effects were observend in any treatment group.

HAEMATOLOGY
No effects on water consumption in any treatment group were observed.

CLINICAL CHEMISTRY
An decrease of ASAT activity was seen in high dose females on day 15. This effects was considered to be due to the relative low or high value observed for the control group and not to be test item related.

NEUROBEHAVIOUR
No effects observed.

ORGAN WEIGHTS
All effects observed (slight increase in absolute and relative liver weight in males) were still within the historical control data of the laboratory and thus not of toxicological relevance.

GROSS PATHOLOGY
No effects observed.

HISTOPATHOLOGY:
No effects observed.

OTHER FINDINGS
The qualitative sperm staging revealed no test item-related specific spermatogenic changes in the male animals from the high dose group (1000 mg/kg b.w./day).
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: adverse effects on body weight and body weight gain and food consumption
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: no adverse affects observed
Key result
Critical effects observed:
not specified

Individual body weights of females during the pre-mating and lactation period.

Control group

Day(s) relative to start

 

1

8

15

11

196

209

212

12

217

228

243

13

210

220

213

14

217

234

244

15

3211

215

232

16

195

208

197

17

205

224

239

18

212

238

233

19

224

236

259

20

200

218

214

Mean

209

223

229

SD

9

10

19

1000 mg/kg bw

Day(s) relative to start

 

1

8

15

71

200

210

225

72

210

231

234

73

206

234

247

74

210

222

235

75

194

219

218

76

218

243

223

77

214

230

227

78

222

225

210

79

198

200

201

80

203

223

231

Mean

207

224

225

SD

9

12

13

Control group

Day(s) relative to littering

 

 

1

4

11

286

309

12

323

330

13

325

311

14

331

327

15

311

322

16

282

302

17

309

327

18

312

328

19

315

331

20

300

329

Mean

309

322

SD

16

10

1000 mg/kg bw

Day(s) relative to littering

 

 

1

4

71

270

281

72

339

301

73

289

309

75

289

317

77

253

247

78

280

271

79

290

296

80

293

308

Mean

288

291

SD

24

23

Relative food consumption of females between day 1 and 4 of lactation

Control group

1000 mg/kg bw

 

 

11

122

71

115

12

91

72

96

13

105

73

63

14

107

75

110

15

106

77

30

16

121

78

63

17

114

79

98

18

100

80

110

19

101

 

 

20

126

 

 

Mean

109

Mean

86

SD

11

SD

30

Conclusions:
The experimental data obtained by testing 8-methylnonyl octadec-9-enoate can be reliably extrapolated (by read-across) to 11-methyldodecyl laurate and support the low toxicity of the substance.
Overall, 11-methyldodecyl laurate should not be classified for the STOT RE in accordance with Regulation (EC) n. 1272/2008.
Furthermore, the study allows to suitably identify a NOAEL which can be used in the risk assessment.
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01 Nov - 13 Dec 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP - Guideline study.
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
22 Mar 1996
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Behoerde fuer Soziales, Familie, Gesundheit und Verbraucherschutz; Hamburg, Germany
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Research Models and Services Germany GmbH, Sulzfeld, Germany
- Age at study initiation: males: 50 days; females: 60 days
- Mean weight at study initiation: males: 248.8 to 298.7 g; females: 195.2 to 228.1 g
- Fasting period before study: no
- Housing: single housing in MAKROLON cages (type III plus)
- Diet: commercial ssniff R-Z V1324 (ssniff Spezialdiäten GmbH, Soest, Germany); ad libitum
- Water: tap water; ad libitum
(Analyses of diet and water was performed.)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50, 150 and 500 mg/mL
- Amount of vehicle (if gavage): 2 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the analysis of the test item-vehicle mixtures samples were taken at the following time points and stored at ≤ -20°C until analysis:
Start of treatment period; immediately after preparation of the test item-vehicle mixtures; 8 and 24 hours after storage of the test item preparations at room temperature; end of treatment period; during treatment with the test item always before administration to the last animal of the dose level group
The following parameters were determined: linearity, accuracy, precision, sensitivity, specificity, stability at +2°C to +8°C or -20°C (0, 24, 72 and 168 hours)
Duration of treatment / exposure:
Males: The daily administration of the test item was started two weeks before mating and lasted until test day 35, which was one day before sacrifice.
Females: The daily administration of the test item was started two weeks before mating and continued to at least day 3 of lactation.
Maximum: 56 days of treatment
Frequency of treatment:
once daily; 7 days/week
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw
Basis:
actual ingested
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 (Leuschner, 2012)
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing
- Cage side observations checked: skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns

MORTALITY AND CLINICAL SIGNS
- Time schedule: at least once daily (the frequency was increased when signs of toxicity were observed); deaths were recorded twice daily (animals which died or were sacrificed during the study were necropsied as soon as possible after exitus)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first exposure (to allow within-subject comparisons) and once a week thereafter
- Paramters: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, pilo-erection, pupil size, and unusual respiratory pattern); changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- 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 (if drinking water study): Yes
- Time schedule for examinations: daily by visual appraisal

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the pre-mating period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, overnight
- How many animals: 5/sex/dose
- Parameters: haemoglobin, erythrocytes, leucocytes, differential blood count (absolute/relative), reticulocytes, platelets, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, thromboplastin time, activated partial thromboplastin time

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

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: two hours after dosing shortly before scheduled sacrifice in 5 males per group (day 35); two hours after dosing during lactation, shortly before scheduled sacrifice in 5 females per group (day 39-56)
Screening of assessment were conducted as described on the following pages in five males and five females randomly selected from each group.
- 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

OTHER: Qualitative sperm analysis was performed.
(for further reproduction parameters see respective study entry (chapter 7.8.1))
Males were sacrificed on day 36, females were sacrifices on day 4 post-partum or shorty thereafter.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organ weights: epididymes and testicles (all males); adrenal gland, brain, heart, kidney, liver, spleen, thymus (5/sex/dose)
- Fixation: epididymis, gross lesions, mammary gland, ovary, prostate, seminal vesicle, testicle, uterus (incl. cervix and oviducts), vagina (all animals); adrenal gland, bone marrow (os femoris), brain (cerebrum, cerebellum, brain stem), heart (left and right ventricle, septum), intestine, small (duodenum, jejunum, ileum, incl. Peyer's patches, Swiss roll method), intestine, large (colon, rectum), kidney and ureter, liver, lungs (with mainstem bronchi and bronchioles), preserved by inflation with fixative and then immersion, lymph node (1 cervical, 1 mesenteric), nerve (sciatic), oesophagus, spinal cord (3 sections), spleen, stomach, thyroid (incl. parathyroids), thymus, tissue masses or tumours (incl. regional lymph nodes), tongue (incl. base), trachea (incl. larynx), urinary bladder (5/sex/dose)
HISTOPATHOLOGY: Yes, all organs that were included for fixation (5/sex of control and high dose group)
Statistics:
STUDENT's t-test (p ≤ 0.01): all numerical functional tests
Multiple t-test based on DUNNETT (p≤0.05 and p ≤ 0.01): body weight, food consumption, haematology, clinical chemistry, absolute and relative organ weights
For all numerical values homogeneity of variances was tested by using the BARTLETT chi-square test. If the variances were homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group. In case of heterogeneity of variances, the STUDENT's t-test was carried out; limit of significance was p ≤ 0.01.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
statistically significant decrease (-9.4%) in body weight in females during lactation at 1000 mg/kg bw/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high dose group (females: gestation/lactation period) a statistically significant reduction in food consumption by 21.7% was noted.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Piloerection was seen in 1 female of the high dose group at on day 2-4 of lactation.

BODY WEIGHT AND WEIGHT GAIN
A reduction in body weight (-9.7%) in high dose females during lactation period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduction in food intake (-21.7%) in high dose females during gestation/lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No effects on water consumption in any treatment group were observed.

OPHTHALMOSCOPIC EXAMINATION
No effects were observend in any treatment group.

HAEMATOLOGY
No effects on water consumption in any treatment group were observed.

CLINICAL CHEMISTRY
An decrease of ASAT activity was seen in high dose females on day 15. This effects was considered to be due to the relative low or high value observed for the control group and not to be test item related.

NEUROBEHAVIOUR
No effects observed.

ORGAN WEIGHTS
All effects observed (slight increase in absolute and relative liver weight in males) were still within the historical control data of the laboratory and thus not of toxicological relevance.

GROSS PATHOLOGY
No effects observed.

HISTOPATHOLOGY:
No effects observed.

OTHER FINDINGS
The qualitative sperm staging revealed no test item-related specific spermatogenic changes in the male animals from the high dose group (1000 mg/kg b.w./day).
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: adverse effects on body weight and body weight gain and food consumption
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: no adverse affects observed
Critical effects observed:
not specified

Individual body weights of females during the pre-mating and lactation period.

Control group

Day(s) relative to start

 

1

8

15

11

196

209

212

12

217

228

243

13

210

220

213

14

217

234

244

15

3211

215

232

16

195

208

197

17

205

224

239

18

212

238

233

19

224

236

259

20

200

218

214

Mean

209

223

229

SD

9

10

19

1000 mg/kg bw

Day(s) relative to start

 

1

8

15

71

200

210

225

72

210

231

234

73

206

234

247

74

210

222

235

75

194

219

218

76

218

243

223

77

214

230

227

78

222

225

210

79

198

200

201

80

203

223

231

Mean

207

224

225

SD

9

12

13

Control group

Day(s) relative to littering

 

 

1

4

11

286

309

12

323

330

13

325

311

14

331

327

15

311

322

16

282

302

17

309

327

18

312

328

19

315

331

20

300

329

Mean

309

322

SD

16

10

1000 mg/kg bw

Day(s) relative to littering

 

 

1

4

71

270

281

72

339

301

73

289

309

75

289

317

77

253

247

78

280

271

79

290

296

80

293

308

Mean

288

291

SD

24

23

Relative food consumption of females between day 1 and 4 of lactation

Control group

1000 mg/kg bw

 

 

11

122

71

115

12

91

72

96

13

105

73

63

14

107

75

110

15

106

77

30

16

121

78

63

17

114

79

98

18

100

80

110

19

101

 

 

20

126

 

 

Mean

109

Mean

86

SD

11

SD

30

Conclusions:
8-methylnonyl octadec-9-enoate should not be classified for the STOT RE in accordance with Regulation (EC) n. 1272/2008.
Furthermore, the study allows to suitably identify a NOAEL which can be used in the risk assessment.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
other: general toxicity
Organ:
not specified
other: no specific target organs were identified.

Additional information

Justification for classification or non-classification