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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data waiving - Toxicity to reproduction screening
Data waiving - Toxicity to reproduction extended one-generation reproductive toxicity study

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
other justification
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reproductive effects observed:
not specified
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction - fertility (screening)

According to Regulation (EC) No 1907/2006, Annex VIII, 8.7.1, column 2, testing for effects on fertility by a screening test is not required. A test for prenatal developmental toxicity (Annex IX, 8.7.2) is available for a structurally related substance, which is used for read-across according to Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Toxicity to reproduction - fertility (extended one-generation reproductive toxicity study)

In accordance with REACH Annex X, Section 8.7.3, Column 1 the extended one-generation reproductive toxicity study is a standard data requirement for registrations of≥1000 t/a. REACH Annex X, Section 8.7, Column 2 sets certain rules on specific conditions for adaptation of the required standard information.

In the available 28-day and 90-day repeated dose toxicity studies on the registration substance or on read-across substances with similar structure and similar intrinsic properties no adverse effects on reproductive organs and tissues were observed up to the highest dose tested (1000 mg/kg bw/day). A subchronic repeated dose toxicity study (BSL, 2015) according to OECD guideline 408 was conducted with the structurally related substance erucamide (CAS 112-84-5), which is used for read-across in accordance with Regulation (EC) No 1907/2006, Annex XI, paragraph 1.5. The study included the additional assessment of fertility parameters and effects on reproductive organs and tissues. No test item related effects on epididymal sperm motility or testicular sperm count was noted at the end of the treatment of this study. The test substance had no biologically significant effect on the oestrous cycle analyzed 4, 8, and 12 weeks after the first administration. In addition, histopathology demonstrated no effects on reproductive organs.

Mangelsdorf et al. (2003) investigated “the suitability of different study designs and endpoints for detecting adverse effects of chemicals on male reproduction in animal species. Of the endpoints investigated, the most sensitive proved to be histopathology of the testes. […] Sperm motility was found to be in some cases more sensitive than histopathology. The above parameters showed a higher sensitivity than fertility parameters. […] Continuous breeding studies and 90-day studies with additional measurements of sperm parameters were similarly effective in detecting compounds which affect male fertility.” Therefore, the information gained from an extended one-generation reproductive toxicity study can be regarded as minimal if a 90 day study with an additional focus on fertility parameters including sperm motility and histopathology of reproductive organs is available, as it is the case here.

Based on the general toxicological profile derived from the available data (no adverse effects seen in all available toxicological studies), stearamide is considered to have no potential to cause reproductive toxicity. Therefore, performing an extended one-generation reproductive toxicity study, is considered not to add new and relevant information for the hazard assessment and therefore and with regard to animal welfare considerations, is deemed scientifically unjustified.

References:

Mangelsdorf I, Buschmann J, Orthen B (2003). Some aspects relating to the evaluation of the effects of chemicals on male fertility. Reg Toxicol Pharmacol 37: 356-369


Effects on developmental toxicity

Description of key information

RA-S CAS 112-84-5, Oral (OECD 414), rat: NOAEL (maternal toxicity) >= 1000 mg/kg bw/day

RA-S CAS 112-84-5, Oral (OECD 414), rat: NOAEL (developmental) >= 1000 mg/kg bw/day

Data waiving - Pre-natal developmental toxicity study, second species

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
25 Sep 2014 - 11 May 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to the appropriate OECD test guideline and in compliance with GLP. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(2001)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit
Species:
rat
Strain:
other: Wistar rats, Crl:WI(Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 11 - 12 weeks (females), 19 – 20 weeks (males)
- Weight at study initiation: 200 – 243 g (females), 390 – 522 g (males)
- Housing: The animals were kept individually in IVC cages (except during the pre-mating period when females were kept in groups of two animals and mating period when two females were paired with one male), type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 02102140509)
- Diet: Altromin 1324 maintenance diet for rats and mice (lot no. 1526), ad libitum
- Water: Sulphur acidified tap water, ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was ground to a fine powder with the help of a mortar and pestle. The powdered test item was weighed into a tarred plastic vial on a precision balance and the vehicle corn oil was added to give the appropriate final concentration of the test item. Homogeneity of the test item in the vehicle was maintained by vortexing the prepared suspension thoroughly before every dose administration. The test item formulation was prepared freshly on each administration day before the administration procedure.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline.
- Concentration in vehicle: 14.29 mg/mL (low dose, LD), 42.86 mg/mL (medium dose, MD), 142.86 mg/mL (high dose, HD)
- Amount of vehicle (if gavage): 7 mL/kg bw/day
- Lot/batch no. (if required): MHBP7039V
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of 13-Docosenamide, (Z)- was performed using GC with FID detection. Formulation analysis was performed on samples of all dose groups collected at various intervals during the study. Concentration analysis of formulation samples was performed in the first and the last study week for all dose groups. The mean recoveries observed in the low dose (LD), medium dose (MD) and high dose (HD) groups were 98.2%, 96.3% and 110.8% of the nominal concentration, respectively. Nominal concentrations were confirmed for all dose groups, as measured concentrations did not differ from nominal concentrations by more than 20%. Stability of formulation samples was investigated in study week 1 based on concentration in the samples taken from the LD, MD and HD dose groups. After 3 hours storage at room temperature the recovery compared to the starting value was between 90.1% and 96.3%. All samples were stable, as concentration after storage did not differ from the start value by more than 20%. Homogeneity of formulation samples was determined in the first and the last study week for the LD, MD and HD dose groups. The mean recovery observed for the LD dose group was 113.5% and 109.2% of the nominal value, for the MD dose group 99.8% and 113.8% of the nominal value and for the HD dose group 107.0% and 110.1% of the nominal value. The coefficients of variation (COV) of the different sampling locations (top, middle, bottom) were 13.6% and 10.8% in the LD dose group, 8.9% and 13.0% in the MD dose group and 4.7% and 4.5% in the HD dose group. All samples were homogenous, as COV was below or equal to the acceptance criterion of 20%.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: Females were paired for cohabitation in batches in order to regularise the number of animals for terminal sacrifice on a particular day. The subsequent morning and each morning thereafter, the vaginal smear of each female was checked until positive evidence of mating was confirmed.
- Proof of pregnancy: The day on which sperms were observed in the vaginal smear was considered as gestation day ‘0’. Mated females were assigned in an unbiased manner to the control and treatment groups ensuring that the mean body weights were comparable to each other.
- Any other deviations from standard protocol: The mating resulted in 23 sperm-positive females in the control and 24 each in the LD, MD and HD group. Non sperm-positive females were excluded from the study without any further observations.
Duration of treatment / exposure:
Day 5 - 19 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
Until Day 20 of gestation / post mating
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22 pregnant females (control)
21 pregnant females (LD)
23 pregnant females (MD)
20 pregnant females (HD)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: According to the results of the dose range finding study (BSL study No. 143124) and in consultation with the sponsor doses of 100, 300 and 1000 mg/kg bw/day were selected for the 3 dose groups (LD = low dose, MD = medium dose, HD = high dose).
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily, preferably at the same time each day, animals were observed for spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Sperm-positive females on Gestation Days 0, 5, 8, 11, 14, 17 and 20. Males were only weighed once prior to mating.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption of pregnant females was measured on Gestation Day 5, 8, 11, 14, 17 and 20.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: At the time of termination or death during the study, the dam (presumably pregnant female) was examined macroscopically for any structural abnormalities or pathological changes which may have influenced the pregnancy. Uteri that appeared non-gravid were further examined by staining with 10% ammonium sulphide solution to confirm the non-pregnant status.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
A statistical assessment of the body weight and food consumption results, prenatal parameters and litter weight data was performed by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Fetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were analysed using a Fisher’s exact test. Litter incidence was the primary unit for the statistical analysis and interpretation. The statistics were performed with GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).
Historical control data:
Historical control data from the Test Facility were not provided.
Clinical signs:
no effects observed
Description (incidence and severity):
No test item-related clinical signs were observed in any of the treated groups. A few spontaneous clinical signs were observed in a few animals, but no effect on overall health, body weight and food consumption was observed in these animals.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All animals survived to the scheduled necropsy and no mortality was observed in this study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight and body weight gain were unaffected by test item administration during the gestation period when compared with the controls. Throughout the treatment period, body weights and body weight gain increased as the study progressed and were within the normal range of variation for this strain.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effect on food consumption was observed during the treatment period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed in terminal body weight, gravid uterine weight, and adjusted maternal weight.
No gross pathological changes were observed during the macroscopic examination of females of the control, the LD and the MD group. However, in the HD group fluid distension of the uterus was observed in one female, and in another female white discoloured areas on the liver, white to yellow discolouration of the left side of the oesophagus/trachea, yellow fluid content in the thoracic cavity and enlarged adrenal glands were observed at necropsy. Due to the isolated incidence in only two animals, these gross pathological findings were considered to be spontaneous in nature and as such not considered to be a systemic effect due to test item administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed in resorptions, percent preimplantation loss and percent postimplantation loss. There were no statistically significant differences.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed in implantations, resorptions, percent preimplantation loss and percent postimplantation loss. There were no statistically significant differences.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed in resorptions. There were no statistically significant differences.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
Statistical analysis of litter data revealed no treatment-related effects on group mean number of live fetuses and dead fetuses when compared with the controls.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
Successful mating resulted in 21/24 pregnancies in the LD group, 23/24 in the MD group and 20/24 in the HD group, compared to 22/23 pregnancies in the control group. Low pregnancy rate in the LD and HD group was considered to be a biological variation and of no toxicological relevance.
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
All animals survived to the scheduled necropsy and no mortality was observed in this study. No test item-related clinical signs were observed in any of the treated groups. A few spontaneous clinical signs were observed in few animals, but no effect on overall health, body weight and food consumption was observed in these animals. The mean body weight and body weight gain were unaffected by test item administration during the gestation period when compared with the controls. Throughout the treatment period, body weights and body weight gain increased as the study progressed and were within the normal range of variation for this strain. No treatment-related effect on food consumption was observed during the treatment period. No treatment-related effects were observed in terminal body weight, gravid uterine weight, adjusted maternal weight, number of corpora lutea, implantations, resorptions, percent preimplantation loss and percent postimplantation loss. There were no statistically significant differences. Successful mating resulted in 21/24 pregnancies in the LD group, 23/24 in the MD group and 20/24 in the HD group, compared to 22/23 pregnancies in the control group. Low pregnancy rate in the LD and HD group was considered to be a biological variation and of no toxicological relevance. No gross pathological changes were observed during the macroscopic examination of females of the control, the LD and the MD group. However, in the HD group fluid distension of the uterus was observed in one female, and in another female white discoloured areas on the liver, white to yellow discolouration of the left side of the oesophagus/trachea, yellow fluid content in the thoracic cavity and enlarged adrenal glands were observed at necropsy. Due to the isolated incidence in only two animals, these gross pathological findings were considered to be spontaneous in nature and as such not considered to be a systemic effect due to test item administration.
Key result
Dose descriptor:
NOAEL
Remarks:
maternal general toxicity
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed at this dose level
Key result
Dose descriptor:
NOAEL
Remarks:
maternal developmental toxicity
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed at this dose level
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effect on per litter data parameters including group litter mean weight, total litter weight and male litter weight was observed. However, statistically significantly lower female litter weight was observed in the LD group when compared with the controls. Due to lack of dose dependency and consistency, this effect on female litter weight was considered to be of no toxicological relevance.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Statistical analysis of litter data revealed no treatment-related effects on group mean number of live fetuses and dead fetuses, number of male and female fetuses, total number of fetuses or sex ratio when compared with the controls.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Statistical analysis of litter data revealed no treatment-related effects on sex ratio when compared with the controls.
Changes in litter size and weights:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effect on per litter data parameters including group litter mean weight, total litter weight and male litter weight was observed. However, statistically significantly lower female litter weight was observed in the LD group when compared with the controls. Due to lack of dose dependency and consistency, this effect on female litter weight was considered to be of no toxicological relevance.
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no external abnormalities considered to be of toxicological relevance in any of the dose groups. The statistical analysis showed no significant differences to the control group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Craniofacial examination by a razor blade serial sectioning technique revealed few findings (slightly dilated right or both lateral ventricles, right or left retinal fold and slightly dilated 3rd lateral ventricle) at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls. Statistical analysis of the data revealed no significant effect in any of these findings as compared to the control group. Therefore, these findings are considered to be not treatment related and spontaneous in nature. Skeletal examination of Alizarin red stained fetuses revealed a range of abnormalities in the treated groups which were of a type comparable to the control group or which occurred at an incidence either comparable to or lower or sometimes higher than in the control group. A statistically significant increase in the litter incidence of incomplete ossification of the interparietal bone in the LD group was observed when compared to the control group. Due to lack of dose dependency and consistency this findings was not assumed to be test item related. All remaining skeletal examinations revealed no significant alterations compared to the control group.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A range of visceral findings observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls, and litter incidences were statistically insignificant except significantly lower discolouration of the dexter lobe of the liver in the MD group when compared to the controls. As the observed finding was minor and lacked dose dependency and consistency, no toxicological significance can be attributed to it; this finding was considered to be spontaneous in nature. All remaining fetal visceral findings revealed no significant alterations compared to the control group.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Statistical analysis of litter data revealed no treatment-related effects on group mean number of live fetuses and dead fetuses, number of male and female fetuses, total number of fetuses or sex ratio when compared with the controls. No treatment-related effect on per litter data parameters including group litter mean weight, total litter weight and male litter weight was observed. However, statistically significantly lower female litter weight was observed in the LD group when compared with the controls. Due to lack of dose dependency and consistency, this effect on female litter weight was considered to be of no toxicological relevance. There were no external abnormalities considered to be of toxicological relevance in any of the dose groups. The statistical analysis showed no significant differences to the control group. A range of visceral findings observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls, and litter incidences were statistically insignificant except significantly lower discolouration of the dexter lobe of the liver in the MD group when compared to the controls. As the observed finding was minor and lacked dose dependency and consistency, no toxicological significance can be attributed to it; this finding was considered to be spontaneous in nature. All remaining fetal visceral findings revealed no significant alterations compared to the control group. Craniofacial examination by a razor blade serial sectioning technique revealed few findings (slightly dilated right or both lateral ventricles, right or left retinal fold and slightly dilated 3rd lateral ventricle) at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls. Statistical analysis of the data revealed no significant effect in any of these findings as compared to the control group. Therefore, these findings are considered to be not treatment related and spontaneous in nature. Skeletal examination of Alizarin red stained fetuses revealed a range of abnormalities in the treated groups which were of a type comparable to the control group or which occurred at an incidence either comparable to or lower or sometimes higher than in the control group. A statistically significant increase in the litter incidence of incomplete ossification of the interparietal bone in the LD group was observed when compared to the control group. Due to lack of dose dependency and consistency this findings was not assumed to be test item related. All remaining skeletal examinations revealed no significant alterations compared to the control group.
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at this dose level
Key result
Abnormalities:
effects observed, non-treatment-related
Key result
Developmental effects observed:
no

Table 1: Litter data – summary

Group

 

Mean litter weight (g)

Number of males

Number of females

Live foetuses

Dead foetuses

Sex ratio

Total litter weight (g)

Male litter weight (g)

Female litter weight (g)

 

C

 

Mean

3.86

5.18

5.68

10.86

0.00

0.98

42.26

20.46

21.80

SD

0.58

1.97

1.55

2.38

0.00

0.50

12.79

8.71

7.87

N

22

22

22

22

22

22

22

22

22

 

LD

 

Mean

3.67

5.33

4.62

9.95

0.00

1.40

35.84

20.00

15.84*

SD

0.44

2.24

2.16

3.23

0.00

1.12

10.99

9.07

6.63

N

21

21

21

21

21

20 a)

21

21

21

 

MD

 

Mean

3.83

5.26

5.17

10.43

0.00

1.18

39.67

20.27

19.40

SD

0.59

1.66

1.40

1.44

0.00

0.77

6.37

5.86

6.17

N

23

23

23

23

23

23

23

23

23

 

HD

 

Mean

3.83

4.95

5.70

10.60

0.05

1.01

40.34

19.44

20.90

SD

0.51

1.64

2.15

2.68

0.22

0.55

10.25

6.86

7.75

N

20

20

20

20

20

20

20

20

20

Asterisks indicate significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001.

C: Control

LD: Low dose

MD: Medium dose

HD: High dose

N: Number of pregnant females (dams)

a): One dam in the LD group with no female pup, the animal was therefore excluded from sex ratio calculation

Table 2: Fetal skeletal findings – summary

 

Skeletal findings

Group

1

2

3

4

C

LD

MD

HD

 

 

Skull interparietal

incomplete ossification

 

No of Incidences

21

30

30

19

Total No of Observed Foetuses

125

109

123

104

% Foetus Incidence

16.80

27.52

24.39

18.27

No of Litters with at least 1 incidence

12

15*

14

8

Total No of Observed Litters

22

21

23

20

% Litter Incidence

54.55

71.43

60.87

40.00

Asterisks indicate significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001.

C: Control

LD: Low dose

MD: Medium dose

HD: High dose

Table 3: Fetal visceral findings – summary

 

Visceral findings

Group

1

2

3

4

C

LD

MD

HD

 

 

Liver dexter lobe discolored (dark)

 

No of Incidences

0

0

6

1

Total No of Observed Foetuses

114

100

117

102

% Incidence of Abnormality

0.00

0.00

5.13

0.98

No of Litters with at least 1 incidence

0

0

5*

1

Total No of Observed Litters

22

21

23

20

% Litter Incidence

0.00

0.00

21.74

5.00

Asterisks indicate significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001.

C: Control

LD: Low dose

MD: Medium dose

HD: High dose

Conclusions:
On the basis of this prenatal developmental toxicity study in pregnant female Wistar rats with 13-Docosenamide, (Z)- at dose levels of 100, 300, and 1000 mg/kg bw/day administered from gestation days 5 to 19 no test item related toxicological findings in dams or fetuses were revealed. Under the conditions of the study, 1000 mg/kg bw/day was considered as no observed adverse effect level (NOAEL) for both maternal and embryo-fetal toxicity of 13-Docosenamide, (Z)-.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP guideline study with a structurally related substance according to the criteria of Regulation (EC) No 1907/2006. Annex XI, paragraph 1.5. Reliability of study originally Klimisch 1, but reliability was changed to "2" according to the ECHA guidance document "Practical guide 6: How to report read-across and categories".
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

Effect on developmental toxicity: via oral route

There is no data available on developmental toxicity and teratogenicity for stearamide (CAS 124-26-5).

In order to fulfil the standard information requirements set out in Annex IX, 8.7.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from a structurally related substance is conducted. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 13).

 

In the available key study (BSL, 2015) the structurally-related test substance (Z)-Docos-13-enamide (CAS 112-84-5, erucamide) was investigated for prenatal developmental toxicity after repeated oral administration conducted according to OECD TG 414, and in compliance with GLP. Groups of 21 (low dose), 23 (medium dose) and 20 (high dose) pregnant female Crl:WI(Han) rats per dose were administered doses of 100, 300 and 1000 mg/kg bw/day via oral gavage. Animals treated with the vehicle (corn oil) served as controls. Treatment was carried out once daily during the gestation period between Day 5 to Day 19. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed twice daily (except weekends). Body weight was recorded on gestation days 0, 5, 8, 11, 14, 17 and 20. Upon sacrifice on gestation day 20 the dam (presumably pregnant female) was examined macroscopically for any structural abnormalities or pathological changes which may have influenced the pregnancy. The ovaries and uterine content were examined after termination. Fetuses were subjected to external and either soft tissue and head or skeletal examination. 

All animals survived to the scheduled necropsy, and no mortality was observed in this study. No test item-related clinical signs were observed in any of the treated groups. A few spontaneous clinical signs were observed in few animals, but no effect on overall health, body weight and food consumption was observed in these animals. The mean body weight and body weight gain were unaffected by test item administration during the gestation period when compared with the controls. No treatment-related effects were observed in terminal body weight, gravid uterine weight, adjusted maternal weight, number of corpora lutea, implantations, resorptions, percent preimplantation loss and percent postimplantation loss. There were no statistically significant differences. No gross pathological changes were observed during the macroscopic examination of females of the control, the low-dose (LD) and the mid-dose (MD) group. However, in the high-dose (HD) group fluid distension of the uterus was observed in one female, and in another female white discoloured areas on the liver, white to yellow discolouration of the left side of the oesophagus/trachea, yellow fluid content in the thoracic cavity and enlarged adrenal glands were observed at necropsy. Due to the isolated incidence in only two animals, these gross pathological findings were considered to be spontaneous in nature and as such not considered to be a systemic effect due to test item administration. In conclusion, no maternal toxic effects were observed after administration of the test substance. Statistical analysis of litter data revealed no treatment-related effects on group mean number of live fetuses and dead fetuses, number of male and female fetuses, total number of fetuses or sex ratio when compared with the controls. No treatment-related effect on per litter data parameters including group litter mean weight, total litter weight and male litter weight was observed. However, statistically significantly lower female litter weight was observed in the LD group when compared with the controls. Due to lack of dose dependency and consistency, this effect on female litter weight was considered to be of no toxicological relevance. There were no external abnormalities considered to be of toxicological relevance in any of the dose groups. A range of visceral findings observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls, and litter incidences were statistically insignificant except significantly lower discolouration of the dexter lobe of the liver in the MD group when compared to the controls. As the observed finding was minor and lacked dose dependency and consistency, no toxicological significance can be attributed to it; this finding was considered to be spontaneous in nature. All remaining fetal visceral parameters revealed no significant alterations compared to the control group. Craniofacial examination by a razor blade serial sectioning technique revealed few findings (slightly dilated right or both lateral ventricles, right or left retinal fold and slightly dilated 3rd lateral ventricle) at frequencies generally comparable to or in some cases slightly higher or lower compared to the controls. Statistical analysis of the data revealed no significant effect in any of these findings as compared to the control group. Therefore, these findings are considered to be not treatment related and spontaneous in nature. Skeletal examination of Alizarin red stained fetuses revealed a range of abnormalities in the treated groups which were of a type comparable to the control group or which occurred at an incidence either comparable to or lower or sometimes higher than in the control group. A statistically significant increase in the litter incidence of incomplete ossification of the interparietal bone in the LD group was observed when compared to the control group. Due to lack of dose dependency and consistency this finding was not assumed to be test item related. All remaining skeletal examinations revealed no significant alterations compared to the control group.

In summary, administration of (Z)-Docos-13-enamide (CAS 112-84-5) at doses of 100, 300 or 1000 mg/kg bw/day by oral gavage to pregnant female Wistar rats from gestation days 5 to 19 resulted in significant lower female litter weight as well as lower discolouration of the dexter lobe of the liver and significant increase in the litter incidence of incomplete ossification of the interparietal bone. These findings were considered to be not test item related and of no toxicological relevance due to lack of dose dependency and consistency. Therefore, both the maternal and embryo-fetal No-Observed-Adverse-Effect-Levels (NOAEL) were considered to be ≥ 1000 mg/kg bw/day.

The utilisation of such surrogate data from a structurally related substance for regulatory purposes is reasonable and justified according to Regulation (EC) No 1907/2006, Annex XI, article 1.5, especially in the light of animal welfare and considering the physico-chemical and toxicokinetic similarities of Stearamide and (Z)-Docos-13-enamide. Therefore, no individual prenatal developmental toxicity study in the rat with Stearamide is proposed.

 

Justification for classification or non-classification

Based on the results for the structurally related substance erucamide, and according to the criteria of Regulation (EC) No 1272/2008, the substance stearamide does not have to be classified for reproductive toxicity.

Additional information