Fatty acids, coco derivs., reaction products with glycine, potassium salts

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

other: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2012-2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium cocoyl glycinate (SCG) [INCI]

IUPAC Name:

Sodium cocoyl glycinate (SCG) [INCI]

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

62.5 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

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

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

Examinations

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.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
No mortality occurred. No significant test item-related clinical signs were noted at any dose level.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
A reduction of food consumption at the dose level of 1000 mg/kg body weight per day was noted in males and females. A related but not statistically significant reduction in body weights was noted only in male animals but not in females.

REPRODUCTIVE FUNCTION:
No effects observed.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No abnormal lesions noted during microscopic staging regarding completeness of stages and maturation of cell populations.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
No effects on mating performance or fertility was observed at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS):
No changes in organ weights considered to be test item-related were noted at any dose level.

GROSS PATHOLOGY (PARENTAL ANIMALS):
Individual findings in male animals were within the range of the normal background of animals from this strain. No test item-related findings were noted in females at any dose level.

HISTOPATHOLOGY (PARENTAL ANIMALS):
No histopathological findings attributable to the treatment with the test item could be observed. No test item related findings related to ovaries, testes and epididymides could be detected.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING):
Mean value of living pubs per dam at first litter check was in the range of historical controls.

CLINICAL SIGNS (OFFSPRING):
No test item-related observations were noted in pubs during the first litter check or during lactation at any dose level.

BODY WEIGHT (OFFSPRING):
No effects on pub body weights were noted at any dose level.

GROSS PATHOLOGY (OFFSPRING):
No test item-related findings were found in pubs at any dose level.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results, the NOAEL of Hostapon SG for general toxicity in male and female parental animals is considered to be 1000 mg/kg body weight per day. A test item related influence on the offspring with regard to an increased post-implantation and postnatal loss observed in this study cannot be excluded. However, these effects are most probably attributable to the high sodium chloride content of the test item and thus are not considered to reflect substance specific toxicity.

Executive summary:

Hostapon SG Dried was administered in highly purified water as vehicle at dosages of 62.5, 250, and 1000 mg/kg body weight/day, and controls received the vehicle only. Hostapon SG Dried was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum. Test item-related effects were observed at the dose level of 1000 mg/kg bw/day, no of them was considered to be adverse.

Treatment with the test item at the high-dose level caused also a reduction in food consumption of males and females. In males, reduction in food consumption was accompanied by a reduction in body weights observed during the entire study period and a reduction in body weight gain which was significant during the pre-pairing but recovered during the pairing period. In females no effects on body weights or body weight gain were noted. The effects on food consumption, body weights and body weight gain at the high dose level were considered not to be adverse.

During necropsy and following histopathological examination no significant test item-related findings were noted in males and females at any dose level. There were no microscopic abnormal lesions encountered during sperm staging regarding completeness of stages and maturation of cell populations. There were no findings noted that could be attributed to treatment with the test item, Hostapon SG. The findings observed were within the range of normal background lesions which may be recorded in animals of this strain and age.

No effects on mating performance, fertility, corpora lutea count or duration of gestation were observed at any dose level. At the dose level of 1000 mg/kg bw/day, higher incidences of post-implantation loss and higher postnatal loss as well as lower litter size at first litter check and on day 4 post partum were noted.

No test item-related findings were noted at first litter check and during lactation in pups at any dose level.

Based on the results, the NOAEL of Hostapon SG for general toxicity in male and female parental animals is considered to be 1000 mg/kg body weight per day. A test item related influence on the offspring with regard to an increased post-implantation and postnatal loss observed in this study cannot be excluded. However, these effects are most probably attributable to the high sodium chloride content of the test item and thus are not considered to reflect substance specific toxicity.