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EC number: 938-147-6 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
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- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
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- Dissociation constant
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- Endpoint summary
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- Environmental data
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
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- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
The registration substance Hostapon SG (70% Sodium N-cocoyl glycinate) was investigated for its reproduction toxicity according to the Guideline OECD 421. The test material, composed of 70% sodium cocoyl glycinate and 20 % sodium chloride, was dissolved in water and was administered to rats via gavage at dosages of 0, 62.5, 250, and 1000 mg/kg bw/day. It was given to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the offsprings reached day 4 post partum.
At high dose, the body weight and the food consumption of males and females were reduced. These effects were considered as not adverse for parental animals, because the relative difference to the control values were within 10% and seemed to stagnate with the treatment progression. No other effect was noted for parental animals.
With respect to the reproduction performance no effects on mating performance, fertility, corpora lutea count or duration of gestation were observed at any dose level. At high dose, the numbers of alive pups at first check and on lactation day 4 were reduced. It is well-known that high salt maternal intake is associated with adverse health effects(i.e. reviewed by EPA 2003: "Drinking Water Advisory: Consumer Acceptability Advice and Health Effects Analysis on Sodium).The reduction of alive pups is considered as consequence of reduced food uptake and high salt content of the test material and therefore not considered as evidence of specific reproduction toxicity of Sodium N-cocoyl glycinate.
The NOAEL of 250 mg/kg bw/day was established for reproduction toxicity of Hostapon SG.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Composition of the test material:
68.1 % N-cocoyl glycine sodium salt
19.6% Sodium chloride
4.4 % Glycine
6.9% Fatty acid - Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories BV
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: 199 - 233 g (males), 133 - 154 g (females)
- Fasting period before study: yes (overnight)
- Housing: in groups of 5 in Makrolon type-4 cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: yes
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10 - 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hour dark / light cycle - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): n.a.
- Mixing appropriate amounts with (Type of food): n.a.
- Storage temperature of food: n.a.
VEHICLE
- Justification for use and choice of vehicle (if other than water): purified water
- Concentration in vehicle: 0 - 100 mg/mL
- Amount of vehicle (if gavage): 10 mL (dose volume) - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of copulation (up to 14 days pairing period)
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- 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
- Duration of treatment / exposure:
- Males: minimum 4 weeks
Females: approximately 7 weeks - Frequency of treatment:
- once daily
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 62.5 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 11 per sex per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on dose-range-finding study
- Rationale for animal assignment: random - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: daily from start of treatment to day of necropsy
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a. - Sperm parameters (parental animals):
- Parameters examined in [all/P/F1/F2] male parental generations:
No abnormal microscopic findings during sperm staging regarding completeness of stages and maturation of cell populations. - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] 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; possible cause of death was determined for pups born or found dead - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after treatment for 28 days.
- Maternal animals: All surviving animals on day 21 post coitum (if birth did not occur at that day, the dam was sacrificed on day 25 post coitum).
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS - Postmortem examinations (offspring):
- SACRIFICE
The F1 offspring were sacrificed at 4 days of age.
GROSS NECROPSY
No test item related findings in any pubs at any dose level observed. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At the dose level of 1000 mg/kg bw/day, bedding in mouth was observed in all males starting from day 5 of the treatment and in all females starting from day 8 of the treatment until the completion of the treatment.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males:
At the dose level of 1000 mg/kg bw/day, statistically significant reduction in body weights and body weight gains were noted in males. Reduction in body weights was noted from day 5 of the pre-pairing period until the completion of the study, reduction in body weight gain was noted from day 5 to 14 of the pre-pairing period. During pairing period, body weight gain of males at the high dose level was similar to the body weight gain in the control group.
Females:
At the dose level of 1000 mg/kg bw/day, lower body weights (not statistically significantly) and lower body weight gain (statistically significant on individual days) were noted during gestation.
The effect found for food consumption and body weight were considered as treatment related but not adverse, because the relative differecen to terminal body were not severe (less than 10%) and seemed to stagnate with the progression of the treatment. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- For males in pre-pairing Period:
At the dose level of 1000 mg/kg bw/day, statistically significant reduction in food consumption was noted in males. Mean food consumption over the pre-pairing period was 21.2 g/animal/day compared to 25.2 g/animal/day in the control group.
For females in pre-pairing, gestation and lactation periods:
At the dose level of 1000 mg/kg bw/day, statistically significant reduction in food consumption was noted in females during the pre-pairing and gestation periods. During the lactation period, food consumption remained lower but not statistically significantly. Mean food consumption during the pre-pairing, gestation and lactation periods was at the high dose level: 16.0, 19.8 and 21.7 g/animal/day, compared to the respective values of 18.3, 22.9 and 25.0 g/ animal/day in the
control group.
The effect found for food consumption and body weight were considered as treatment related but not adverse, because the relative differecen to terminal body were not severe (less than 10%) and seemed to stagnate with the progression of the treatment. - Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- At dose of 1000 mg/kg/day the number of pups born alive and the number of pups on LD4 were reduced.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- reproductive performance
- Remarks on result:
- other:
- Remarks:
- The findings of reduced number of alive pups at first check and on lactation day 4 are not considered as evidence of reproduction toxicity of sodium cocoyl glycinate. - At dose of 1000 mg/kg/day, the body weight and the food consumption of males and females were reduced. These effects were considered as not adverse nature for parental animals, because the relative difference of body weight to the control values were within 10% and seemed to stagnate with the treatment progression. Nevertheless, it is reasonable to consider the reduced viability of offspings as the consequence of reduced food uptake during pregnancy and laction of dams. - The test material contained 20% NaCl and the animals were in fact treated with NaCl up to 200 mg/kg/day. It is well-known that high salt maternal intake is associated with adverse effects on the offspring (i.e. Maruyama K et al., Lif Sci.2015 Sep 1; 136:42-51). The reduced viability of offsprings could be related to the high salt intake of dams as well. In conclusion, the effects found at 1000 mg/kg/day is not to be interpreted as the evidence of reproduction toxicity of sodium cocoyl glycinate.
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, the numbers of pups alive at first check and on LD4 were reduced.
- Body weight and weight changes:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- Remarks on result:
- other:
- Remarks:
- The findings of reduced number of alive pups at first check and on lactation day 4 are not considered as evidence of reproduction toxicity of sodium cocoyl glycinate. - At dose of 1000 mg/kg/day, the body weight and the food consumption of males and females were reduced. These effects were considered as not adverse nature for parental animals, because the relative difference of body weight to the control values were within 10% and seemed to stagnate with the treatment progression. Nevertheless, it is reasonable to consider the reduced viability of offspings as the consequence of reduced food uptake during pregnancy and laction of dams. - The test material contained 20% NaCl and the animals were in fact treated with NaCl up to 200 mg/kg/day. It is well-known that high salt maternal intake is associated with adverse effects on the offspring (i.e. Maruyama K et al., Lif Sci.2015 Sep 1; 136:42-51). The reduced viability of offsprings could be related to the high salt intake of dams as well. In conclusion, the effects found at 1000 mg/kg/day is not to be interpreted as the evidence of reproduction toxicity of sodium cocoyl glycinate.
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects as a secondary non-specific consequence of other toxic effects
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- The reproduction toxicity of sodium N-cocoyl glycinate was investigated according to the Guideline OECD 421. No significant reproducton toxicity was found for sodium N-cocoyl glycinate.
- Executive summary:
The registration substance Hostapon SG (70% Sodium N-cocoyl glycinate) was investigated for its reproduction toxicity according to the Guideline OECD 421. The test material, composed of 70% sodium cocoyl glycinate and 20 % sodium chloride, was dissolved in water and was administered to rats via gavage at dosages of 0, 62.5, 250, and 1000 mg/kg bw/day. It was given to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the offsprings reached day 4 post partum.
At high dose, the body weight and the food consumption of males and females were reduced. These effects were considered as not adverse nature for parental animals, because the relative difference to the control values were within 10% and seemed to stagnate with the treatment progression. No other effect was noted for parental animals.
With respect to the reproduction performance no effects on mating performance, fertility, corpora lutea count or duration of gestation were observed at any dose level. At high dose, the numbers of alive pups at first check and on lactation day 4 were reduced. It is well-known that high salt maternal intake is associated with adverse health effects (i.e. reviewed by EPA 2003: "Drinking Water Advisory: Consumer Acceptability Advice and Health Effects Analysis on Sodium). The reduction of alive pups is considered as consequence of reduced food uptake and high salt content of the test material and therefore not considered as evidence of specific reproduction toxicity of Sodium N-cocoyl glycinate.
The NOAEL of 250 mg/kg bw/day was established for reproduction toxicity of Hostapon SG.
- Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Referenceopen allclose all
Table 1: Summary of Food Consumption of Males
Doses [mg/kg /day] |
|
Food Consumption of Males [g]; n = 11 |
|
Pre-paring Day 1-8 |
Pre-paring Day 8-14 |
||
0 |
Mean |
24.9 |
25.5 |
S.D. |
1.4 |
1.5 |
|
62.5 |
Mean |
24.7 |
24.8 |
S.D. |
2.4 |
2.3 |
|
250 |
Mean |
24.2 |
23.8 |
S.D. |
2.4 |
2.5 |
|
1000 |
Mean |
20.7 ** |
21.7 ** |
S.D. |
3.7 |
3.4 |
*/**: DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**)
Table2: Summary of Food Consumption of Females; Prepairing, Gestation and Lactation
Doses [mg/kg /day] |
|
Food Consumption of Females [g] |
|||||||
Pre-pairing |
|
Gestation |
|
Lactation |
|||||
Day 1-8 |
Day 8-14 |
GD 0-7 |
GD 7-14 |
GD 14-21 |
LD 1-4 |
||||
0 |
Mean |
18.1 |
18.4 |
22.8 |
23.5 |
22.4 |
25.0 |
||
S.D. |
1.3 |
1.6 |
1.7 |
1.9 |
1.4 |
6.7 |
|||
n |
11 |
11 |
8 |
8 |
8 |
9 |
|||
62.5
|
Mean |
17.8 |
18.2 |
21.8 |
22.4 |
21.1 |
26.2 |
||
S.D. |
1.3 |
1.1 |
1.2 |
0.7 |
1.0 |
4.4 |
|||
n |
11 |
11 |
10 |
10 |
10 |
11 |
|||
250 |
Mean |
18.4 |
18.7 |
22.3 |
23.1 |
21.5 |
26.9 |
||
S.D. |
2.7 |
1.9 |
2.2 |
2.2 |
2.4 |
3.4 |
|||
n |
11 |
11 |
11 |
11 |
11 |
11 |
|||
1000 |
Mean |
15.6 * |
16.4 * |
19.6 ** |
20.0 ** |
19.8 * |
21.7 |
||
S.D. |
2.0 |
1.7 |
2.2 |
2.9 |
2.2 |
5.6 |
|||
n |
11 |
11 |
10 |
10 |
10 |
10 |
*/**: DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**)
Table 3: Summary of Body Weights of Males
Doses [mg/kg /day] |
|
Body weight of males [g]; n = 11 |
|||||
Pre-pairing period |
Pairing period |
||||||
1d |
8d |
14d |
1d |
8d |
15d |
||
0 |
Mean |
311 |
335 |
354 |
350 |
367 |
381 |
S.D. |
8 |
12 |
12 |
12 |
13 |
13 |
|
62.5 |
Mean |
310 |
332 |
349 |
348 |
362 |
379 |
S.D. |
8 |
7 |
11 |
13 |
13 |
12 |
|
250 |
Mean |
310 |
330 |
345 |
343 |
360 |
376 |
S.D. |
8 |
12 |
15 |
14 |
18 |
21 |
|
1000 |
Mean |
310 |
318** |
332** |
328** |
346* |
363* |
S.D. |
8 |
17 |
19 |
19 |
18 |
18 |
*/**: DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**)
Table 4: Summary of Body Weights of Females; Pre-mating
Doses [mg/kg /day] |
|
Body weight [g]; n = 11 |
||
1d |
8d |
14d |
||
0 |
Mean |
195 |
203 |
209 |
S.D. |
8 |
10 |
10 |
|
62.5 |
Mean |
194 |
204 |
211 |
S.D. |
6 |
8 |
11 |
|
250 |
Mean |
196 |
205 |
210 |
S.D. |
6 |
7 |
8 |
|
1000 |
Mean |
197 |
201 |
207 |
S.D. |
8 |
11 |
11 |
*/**: DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**)
Table 5: Summary of Body Weights of Females; Gestation and Lactation
Doses [mg/kg /day] |
|
Body weight [g] |
||||||
GD0 |
GD7 |
GD14 |
GD21 |
|
LD1 |
LD4 |
||
0 |
Mean |
211 |
240 |
268 |
345 |
|
240 |
252 |
S.D. |
11 |
16 |
15 |
19 |
|
14 |
17 |
|
n |
8 |
8 |
8 |
8 |
|
9 |
9 |
|
62.5
|
Mean |
211 |
240 |
268 |
337 |
|
244 |
256 |
S.D. |
11 |
12 |
13 |
14 |
|
15 |
13 |
|
n |
10 |
10 |
10 |
10 |
|
11 |
11 |
|
250 |
Mean |
216 |
244 |
269 |
334 |
|
245 |
258 |
S.D. |
11 |
10 |
13 |
22 |
|
16 |
10 |
|
n |
11 |
11 |
11 |
11 |
|
11 |
11 |
|
1000 |
Mean |
214 |
234 |
261 |
329 |
|
238 |
251 |
S.D. |
15 |
14 |
16 |
16 |
|
18 |
15 |
|
n |
10 |
10 |
10 |
10 |
|
10 |
10 |
One female group 1 and one female group 2: mating not detected, therefore body weight for gestation missing
Table 6. Summary of reproductive parameters
Dose (mg/kg bw) |
0 |
62.5 mg/kg/day |
250 mg/kg/day |
1000 mg/kg/day |
|
|
|
|
|
Number of females paired
|
11 |
11 |
11 |
11 |
Number of females mated (confirmed by vaginal smear) |
10 |
10 |
11 |
11 |
Number of females pregnant (confirmed at littering/necropsy) |
9 |
11 |
11 |
10 |
Dystocia death |
0 |
0 |
0 |
0 |
Number of females with live litters |
9 |
11 |
11 |
10 |
Precoital interval (days) |
2.4 ± 1.3 (n = 10) |
2.4 ± 1.0 (n = 10) |
4.3 ± 3.3 (n = 11) |
4.7 ± 4.0 (n = 11) |
Gestation length (days) |
21.6± 0.5(n= 8) |
21.3± 0.5(n=10) |
21.5 ± 0.5(n= 11) |
21.6 ± 0.5(n = 10) |
Corpora lutea |
14.1 ± 1.2 (n= 9) |
14.0 ± 1.3 (n=11) |
14.3 ± 1.4 (n= 11) |
14.2± 1.9 (n=10) |
Implantation sites |
13.8 ± 1.3 (n= 9) |
13.0 ± 1.1 (n=11) |
13.1 ± 3.2 (n= 11) |
13.3 ± 2.3 (n=10) |
Post implantation loss |
0.6 ± 0.7(n= 9) |
0.7 ± 1.1(n= 11) |
1.5 ± 2.1(n= 11) |
2.7 ± 2.8(n= 10) |
Viable litter size at first check |
13.2 ± 1.4(n= 9) |
12.3 ± 1.6(n= 11) |
11.6 ± 3.7(n= 11) |
10.6 ± 2.0(n= 10) * |
Dead pups at first check |
0.0 |
0.1 ± 0.3(n= 11)a |
0.0 |
0.6 ± 1.9(n= 10)b |
Viable litter size LD4 |
13.2 ± 1.4(n= 9) |
11.9 ± 1.8(n= 11) |
11.5 ± 3.6(n= 11) |
9.4 ± 3.3(n= 10) * |
|
|
|
|
|
Total number born alive pups at first check |
119 |
135 |
128 |
106 |
% of males/females of born alive pups at first check |
54/46 |
49/51 |
50/50 |
42/58 |
Total number alive pups on LD 4 |
119 |
131 |
127 |
94 |
|
|
|
|
|
Body weight of pups (g) on LD1 |
5.9 ± 0.7 (n = 9) |
5.7 ± 0.6 (n = 11) |
6.0 ± 0.6 (n= 11) |
5.7 ± 0.9 (n = 10) |
Body weight of pups (g) on LD4 |
8.1 ± 1.4 (n = 9) |
8.6 ± 1.0 (n = 11) |
8.8 ± 1.3 (n = 11) |
8.2 ± 1.5 (n = 10) |
|
|
|
|
|
One female group 1 and one female group 2: mating not detected, therefore gestation length missing
*/**: Steel Test, significant at 5% (+), 1% (++)
a) One pup found dead.
b) Six pups found dead, whereas only one litter (animal no. 83) was affected. Additionally eight alive pups were found at first check for this litter.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 250 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- One valid guideline study
Additional information
.
Effects on developmental toxicity
Description of key information
The developmental toxicity of the registration substance Hostapon SG was assesses via read-across to Sodium N-Lauroyl-Sarcosinate.
The developmental toxicity of Sodium N-Lauroyl-Sarcosinate in rats was investigated according to the Guideline OECD 414. Time mated pregnant rats were treated at doses of 0, 30, 100 and 250 mg/kg/day. Reduced food consumption at 250 mg/kg/day and reduced body weight gain was noted at doses of 100 and 250 mg/kg/day. Sloughing on the non-glandular region of the stomach was found at 250 mg/kg/day. No effect was found for fetuses. NOAEL of 250 mg/kg/day was determined for overall developmental toxicity.
Likewise, Hostapon SG is expected to be of no developmental toxicity.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- other information
- Justification for type of information:
- Justification is provided in Chapter 13.
- Reason / purpose for cross-reference:
- assessment report
- Conclusions:
- The developmental toxicity the registration substance Hostapon SG is derived based on the read-across to sodium N-lauroyl sarcosinate. Hostapon is expected to be of no developmental toxicity.
- Executive summary:
The developmental toxicity of the registration substance Hostapon SG was assesses via read-across to Sodium N-Lauroyl-Sarcosinate.
The developmental toxicity of Sodium N-Lauroyl-Sarcosinate in rats was investigated according to the Guideline OECD 414. Time mated pregnant rats were treated at doses of 0, 30, 100 and 250 mg/kg/day. Reduced food consumption at 250 mg/kg/day and reduced body weight gain was noted at doses of 100 and 250 mg/kg/day. Sloughing on the non-glandular region of the stomach was found at 250 mg/kg/day. No effect was found for fetuses. NOAEL of 250 mg/kg/day was determined for overall developmental toxicity.
Likewise, Hostapon SG is expected to be of no developmental toxicity.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04 Aug - 05 Dec 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 22 January 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted August 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSa No 8147, 24 November 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD® (SD)IGS BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Margate, UK
- Age at study initiation: not specified in report, animals purchased time-mated
- Weight at study initiation: 197-268 g (females on arrival, prior to GD3)
- Housing: individual in solid-floor propylene cages with stainless steel lids in a single air-conditioned room, bedding with softfood flakes
- Diet: pellet diet (Rodent 2018C Teklad Global Certified Diet, Harlan; Oxon; UK) ad libitum, environmental enrichment provided in the form of wooden chew blocks and cardboard fun tunnels
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 04 Aug 2013 (first day of treatment) To: 22 Aug 2013 (final day of necropsy) - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
the test item was prepared at the appropriate concentrations as a solution in distilled water.
VEHICLE
- Concentration in vehicle: 6, 20 and 50 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test item concentration in the test samples was determined by high performance liquid chromatography (HPLC/UV) using an external standard technique.The formulations investigated during the study were found to comprise test item in the range of 101% to 104% and, thus, the required content limit ± 10% with reference to the nominal content was met. The test item was found to be stable in the formulations when kept for twenty one days in the refrigerator due to results which met the variation limit of 10% from the time-zero mean. Thus, the results indicate the accurate use of the test item and distilled water as vehicle during this study. The formulations were found to be homogeneously prepared, and sufficient formulation stability under storage conditions was approved.
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
- Duration of treatment / exposure:
- Gestation Day 5-19
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- until Gestation Day 20 (terminal sacrifice)
- Remarks:
- Doses / Concentrations:
30, 100 and 250 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 24 P females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were chosen based on previous toxicity data.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked included: following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioural changes once daily during the gestation period. An additional observation was also performed five hours after dosing during the normal working week. All observations were recorded.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: individual body weights were recorded for each surviving individual animal at Day 3, 5, 6, 7, 8, 11, 14, 17 and 20 (termination kill) of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined: Yes, at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily by visual inspection of water bottles
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: ovaries and uteri of pregnant females, full external and internal examination; any macroscopic abnormalities were recorded; the stomach was retained from all females - Ovaries and uterine content:
- The ovaries and uterine content were 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
- Other: fetal sex, placental weight, position and type of intrauterine implantation - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No - Statistics:
- Group mean values were calculated to include data from all females with live fetuses on Day 20 of gestation. As the litter was the standard unit of assessment, values were first calculated within the litter, and group mean values represent the mean of these individual litter values.
The following parameters were analyzed statistically, where appropriate, using the test methods outlined below:
Female body weight change, food consumption and gravid uterus weight: Bartlett´s test for homogeneity of variance and one way analysis of variance, followed by Dunnett´s multiple comparison test or, if unequal variances were observed, an alternative multiple comparison test.
All caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis non-parametric analysis of variance and Mann-Whitney ‘U’ test.
Probability values (p) demonstrating different levels of significance were chosen as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p>=0.05 (not significant) - Indices:
- Pre implantation loss: [(number of corpora lutea-number of implantations) / number of corpora lutea] x 100;
Post-implantation loss: [(number of implantations–number of live foetuses)/number of implantations] x 100;
Sex ratio: % male fetuses (sex ratio)= [Number of male foetuses / Total number of foetuses] x 100 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 250 mg/kg bw/day: the female found dead on Day 10 did not show any clinical signs prior to Day 10. The female found dead on Day 18 had noisy respiration on Days 10 and 17 and increased salivation and pilo-erection on Day 17.
5/22 females showed incidences of increased salivation between Days 10 and 19 and 3/22 females also showed noisy respiration on either Day 6 or 7.
100 mg/kg bw/day: 1/24 females showed increased salivation on Day 18 and 1/24 females had noisy respiration on Day 13.
Observations of this nature are commonly observed following the oral administration of an unpalatable or irritant test item formulation and are considered not to represent true systemic toxicity.
Control: 1/24 females had fur loss on Day 18. In the absence of treatment this was considered of no toxicological importance. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 250 mg/kg bw/d: One female treated was found dead on Day 10 and another female was found dead on Day 18.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 250 mg/kg bw/day: body weight gain of the females was lower throughout the treatment period and cumulative body weight gain to Day 14 (where body weight is not greatly influenced by the weight of the gravid uterus) was 24% lower than the corresponding control value. By termination on Day 20, cumulative body weight gain was 15% lower than the corresponding control values. When final body weight was adjusted for the gravid uterus, an overall body weight gain reduction was evident during gestation.
100 mg/kg bw/day: females showed a slight reduction in cumulative body weight gain from Day 7 onwards. When final body weight was adjusted for the gravid uterus, an overall body weight gain reduction was evident during gestation. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 250 mg/kg bw/day: females showed a reduction in food consumption throughout the treatment period. Statistically significant reductions were evident between Days 8 and 11 (p < 0.001) and Days 14-17 (p< 0.05) compared with the control group.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Description (incidence and severity):
- The female treated with 250 mg/kg bw/day that was found dead on Day 10 had gaseous distention in the stomach and gastro-intestinal tract. The other interim death female had sloughing on the non-glandular region of the stomach, seven dead foetuses in the right uterine horn and five dead foetuses in the left uterine horn. The remaining females treated with 250 mg/kg bw/day that were terminated on Day 20 all had sloughing on the non-glandular region of the stomach.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- Females from all treatment groups showed a statistically significant reduction (p<0.05 - p<0.01) in the number of corpora lutea. The intergroup differences did not show a true dose related response and were considered to be incidental and unrelated to treatment due to ovulation and mating occurring prior to the administration of the test item. As a consequence of incidentally lower number of corpora lutea in treated females litter size was statistically significantly reduced (p<0.05) in all treated females. The intergroup differences did not show a true dose related response and in the absence of any effect on post-implantation loss and mean fetal weights it supports the assumption that the intergroup differences in litter size was considered to be incidental and of no toxicological importance.
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There was no obvious adverse effect of maternal treatment on litter data as assessed by the mean number of implantations, early and late embryonic/fetal deaths and live fetuses or sex ratio, as assessed by percentage male.
For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of visceral or skeletal anomalies. The types of external, visceral and skeletal anomalies were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effect on developmental toxicity observed at the highest tested dose level.
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Sodium N-Lauroyl-sarcosinate was investigated according to the Guideline OECD 414. NOAEL of 250 mg/kg/day was determined.
- Executive summary:
The developmental toxicity of the registration substance Hostapon SG was assesses via read-across to Sodium N-Lauroyl-sarcosinate.
The developmental toxicity of Sodium N-Lauroyl-sarcosinate in rats was investigated according to the Guideline OECD 414. Time mated pregnant rats were treated at doses of 0, 30, 100 and 250 mg/kg/day. Reduced food consumption at 250 mg/kg/day and reduced body weight gain was noted at doses of 100 and 250 mg/kg/day. Sloughing on the non-glandular region of the stomach was found at 250 mg/kg/day. No effect was found for fetuses. NOAEL of 250 mg/kg/day was determined for overall developmental toxicity.
Likewise, Hostapon SG is expected to be of no developmental toxicity.
Referenceopen allclose all
All treated females showed statistically significant reduction of corpora lutea and in consequence reduced litter sizes. The intergroup differences did not show a true dose related response and were considered to be incidental and unrelated due to ovulation and mating occurring prior to the administration of the test item starting on GD5. The absence of any effect on post-implantation loss and mean fetal weights supports the assumption that these intergroup differences in litter size were considered to be incidental and of no toxicological importance. Foetuses of the 250 mg/kg bw/day group showed a statistically significant increase in the percent of foetuses showing one or more ossified forepaw phalanges. Due to the isolated occurrence of this observation it is not considered to be a true developmental effect and it is therefore of no biological importance.
Table A: Group Mean Litter Data Values (Mean ± SD)
Dose Level (mg/kg bw/day) |
Number of Litters |
Number of Corpora Lutea |
Number of Implants |
Number of Embryonic/Fetal Deaths |
Number of Live Implants |
||||
Early |
Late |
Total |
Male |
Female |
Total |
||||
0 (control) |
23 |
15.2 ± 1.8 |
13.9 ± 1.6 |
0.1 ± 0.3 |
0.1 ± 0.6 |
0.3 ± 0.7 |
6.9 ± 1.8 |
6.8 ± 1.9 |
13.7 ± 2.1 |
30 |
21 |
14.3* ± 1.8 |
13.1 ± 2.0 |
1.0 ± 2.4 |
0.1 ± 0.4 |
1.0 ± 2.5 |
6.0 ± 2.7 |
6.1 ± 2.4 |
12.1* ± 3.4 |
100 |
24 |
13.7* ± 1.9 |
13.0 ± 1.8 |
0.6 ± 1.3 |
0.2 ± 0.7 |
0.8 ± 1.4 |
6.5 ± 2.1 |
5.6 ± 1.7 |
12.1* ± 2.5 |
250 |
22 |
13.9** ± 1.2 |
13.2 ± 1.1 |
0.5 ± 1.4 |
0.2 ± 0.9 |
0.7 ± 1.6 |
6.5 ± 2.0 |
6.0 ± 1.9 |
12.5* ± 2.2 |
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 not significant
Table A: Group Mean Litter Data Values (continued) (Mean ± SD)
Dose Level (mg/kg bw/day) |
Implantation Loss (%) |
Male foetuses (%) |
Mean Male Fetal Weight (g) |
Mean Female Fetal Weight (g) |
Mean Fetal Weight (g) |
Mean Placental Weight (g) |
Litter Weight (g) |
Total Placental Weight (g) |
|
Pre |
Post |
||||||||
0 (control) |
8.4 ± 7.4 |
2.3 ± 7.2 |
50.4 ± 11.3 |
4.117 ± 0.260 |
3.935 ± 0.264 |
4.026 ± 0.257 |
0.564 ± 0.047 |
54.883 ± 8.672 |
7.667 ± 1.141 |
30 |
8.0 ± 10.0 |
8.4 ± 19.4 |
48.6 ± 15.2 |
4.152 ± 0.405 |
3.881 ± 0.372 |
4.005 ± 0.365 |
0.578 ± 0.155 |
48.345 ± 13.761 |
6.729 ± 1.942 |
100 |
5.0 ± 5.2 |
6.9 ± 12.2 |
53.7 ± 12.8 |
4.166 ± 0.339 |
3.886 ± 0.269 |
4.036 ± 0.289 |
0.542 ± 0.060 |
49.142 ± 11.318 |
6.540 ± 1.503 |
250 |
4.8 ± 5.3 |
5.5 ± 12.5 |
52.2 ± 13.7 |
4.221 ± 0.347 |
4.033 ± 0.327 |
4.126 ± 0.320 |
0.540 ± 0.057 |
51.237 ± 8.200 |
6.744 ± 1.369 |
Table B: Group Mean Cumulative Body Weight Change Values (Mean ± SD)
Dose Level (mg/kg bw/day) |
Number of Animals |
Cumulative Body Weight Change (g) from GD5 |
||||||
GD6 |
GD7 |
GD8 |
GD11 |
GD14 |
GD17 |
GD20 |
||
0 (control) |
23 |
4.0 ± 3.4 |
7.6 ± 3.7 |
13.0 ± 5.1 |
33.6 ± 6.6 |
51.6 ± 8.1 |
82.3 ± 10.4 |
127.8 ± 14.9 |
30 |
21 |
5.1 ± 5.4 |
7.1 ± 8.2 |
12.9 ± 10.2 |
34.0 ± 12.9 |
53.5 ± 15.5 |
82.2 ± 19.2 |
127.0 ± 23.4 |
100 |
24 |
2.3 ± 5.3 |
6.1 ± 5.5 |
8.8 ± 7.5 |
27.6 ± 9.9 |
44.8 ± 13.8 |
74.2* ± 12.4 |
114.3* ± 17.2 |
250 |
24/22+ |
0.5 ± 9.0 |
3.6 ± 10.1 |
7.3 ± 11.2 |
21.7** ± 14.6 |
39.3* ± 17.8 |
68.2** ± 20.0 |
109.1** ± 24.7 |
+ = n=23 on GD10, n=22
on GD18
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 not significant
Table C: Group Mean Gravid Uterus Weight , Adjusted Body Weight and Body Weight Change Values (Mean ± SD)
Dose Level (mg/kg bw/day) |
Number of Animals |
Body Weight (g) on Days of Gestation |
Body Weight Change (g) during GD5-20 |
Gravid Uterus Weight (g) |
Adjusted Body Weight (g) GD20 |
Adjusted Body Weight (g) Change GD5-20 |
|
GD5 |
GD20 |
||||||
0 (control) |
23 |
262.6 ± 20.6 |
390.4 ± 29.8 |
127.8 ± 14.9 |
84.663 ± 12.502 |
305.8 ± 23.4 |
43.2 ± 8.2 |
30 |
21 |
261.7 ± 12.9 |
288.7 ± 27.3 |
127.0 ± 23.4 |
75.544 ± 18.733 |
313.2 ± 28.6 |
51.5 ± 22.7 |
100 |
24 |
260.6 ± 14.4 |
374.9 ± 24.8 |
114.3** ± 17.2 |
75.893 ± 15.615 |
299.0 ± 20.7 |
38.4* ± 14.6 |
250 |
24/22+ |
257.6 ± 15.5 |
368.1 ± 32.4 |
109.1** ± 24.7 |
77.535 ± 11.935 |
290.6 ± 25.0 |
31.6** ± 18.7 |
+ = n=23 on GD10, n=22
on GD18
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 not significant
Table D: Group Mean Food Consumption Values (Mean ± SD)
Dose Level (mg/kg bw/day) |
Number of Animals |
Food Consumption (g/rat/day) between Days of Gestation |
|||||
3-5 |
5-8 |
8-11 |
11-14 |
14-17 |
17-20 |
||
0 (control) |
23 |
23.0 ± 3.1 |
25.1 ± 2.5 |
26.5 ± 2.6 |
26.1 ± 2.8 |
25.9 ± 3.0 |
28.0 ± 2.4 |
30 |
21 |
23.6 ± 3.7 |
24.5 ± 3.9 |
27.1 ± 3.7 |
26.5 ± 3.7 |
26.0 ± 4.2 |
28.7 ± 3.8 |
100 |
24 |
22.8 ± 2.9 |
23.9 ± 2.8 |
24.9 ± 3.3 |
24.6 ± 3.7 |
24.5 ± 3.4 |
27.5 ± 2.9 |
250 |
24/22+# |
22.3 ± 3.4 |
22.4 ± 5.3 |
21.5*** ± 4.7 |
23.3 ± 4.3 |
22.6* ± 4.2 |
25.4 ± 3.8 |
+ = n=23 on GD10, n=22
on GD18
# = Food consumption not performed on GD 8 and 11 for female Nos. 85 to
90 due to technician error
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 not significant
In conclusion the oral administration of the test substance to pregnant rats by oral gavage during gestation at dose levels of 30, 100 and 250 mg/kg bw/day resulted in treatment related effects detected in females treated with 250 and 100 mg/kg bw/day. The NOAEL was therefore considered to be 30 mg/kg bw/day.
No toxicological significant changes were detected in the offspring parameters measured. The NOEL for developmental toxicity was therefore considered to be 250 mg/kg bw/day.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 250 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- One valid guideline study on the read-across source substance
Justification for classification or non-classification
No indication of reproduction toxicity was found in the reproduction toxicity screening test on the registration substance and in the developmental toxicity study on the read-across source chemical. No classification is assigned to the registration substance.
Additional information
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