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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to GLP
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
No. of animals per sex per dose:
10
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
only high dose
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
only high dose
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
only high dose
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: only high dose during pre.mating period
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
only high dose related to general maternal toxicity
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): At the highest dose one male and one female animal died. Additionally dyspnea, loss of weight, soft stools, dilation of the abdomen occurred. In mid and low sose animals no clinical signs or deaths.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No effects at mid and low dose. Decrease of body weight in high dose animals in the first week of tretament.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Lower mean daily food consumption during pre-mating in males of the high dose. No effects in mid and low dose.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No changes in testicular stages as evaluated of stages of spermatogenesis.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Mating and fertility indices slightly lower in high dose animals. No changes at all in mid and low dose.

ORGAN WEIGHTS (PARENTAL ANIMALS): Lower weight of epididymides in high dose animals without histopathological correlate. No changes in mid and low dose.

GROSS PATHOLOGY (PARENTAL ANIMALS): No changes noted.

HISTOPATHOLOGY (PARENTAL ANIMALS): Histology of Fo testes, epididymides and ovaries did not show compound related changes. No changes seen in the testicular stages of spermatogenesis.
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
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
No differences on F1 pubs survival during the first 4 days of lactation between control and treated groups. No significant differences in body weight.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Reproductive effects observed:
not specified
Conclusions:
Based on the results of this study it was concluded that the NOAEL is 125 mg/kg body weight per day for both, the dams and their offspring.
Executive summary:

The study used as source investigated reproductive toxicity.The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

 

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

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

Constituent 1
Chemical structure
Reference substance name:
Quaternary ammonium compounds, bis(hydrogenated tallow alkyl)dimethyl, chlorides
EC Number:
263-090-2
EC Name:
Quaternary ammonium compounds, bis(hydrogenated tallow alkyl)dimethyl, chlorides
Cas Number:
61789-80-8
Molecular formula:
R2Me2N(+)Cl(-) whereas R = mainly C16, 18-alkyl molecular weight range is based on R=14 (lower limit value) and R=18 (higher limit value)
IUPAC Name:
N,N-Dimethyl-N,N-di-n-alkyl(C16-18)-ammoniumchloride
Details on test material:
- Name of test material (as cited in study report): Genamin DSAC
- Physical state: yellowish powder

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia
- Age at study initiation: 8 weeks (males, females)
- Weight at study initiation: 225 - 250 g (males), 200 - 225 g (females)
- Fasting period before study: no data
- Housing: makrolon cages
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: daily

VEHICLE: corn oil
- Justification for use and choice of vehicle (if other than water): corn oil is a recommended vehicle for this type of test
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 7 evenings/week for a maximum of 14 evenings (16 hours at a time)
- Proof of pregnancy: 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: no data
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration was determined with two-phase titration according to ISO 2271
Duration of treatment / exposure:
Daily administration to the F0 males from day 14 prior to the mating phase until the end of mating until the maximum total dosing period of 28 days. Daily administration to females for 14 days before the start of the mating period and throughout the mating period. Treatment continued during pregnancy up until day 3 of lactation.
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg body weight per day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
62.5 mg/kg body weight per day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
125 mg/kg body weight per day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg body weight per day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on pretest
- Rationale for animal assignment (if not random): random
Positive control:
no

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (males), weekly (females during pregnancy), day 0 and day 4 (F1 animals)

Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
no effects on postnatal survival, no effects on body weight
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals the day after the end of treatment
- Maternal animals: All surviving animals on day 4 of lactation with their pubs

GROSS NECROPSY
- Gross necropsy consisted of external examinations

HISTOPATHOLOGY / ORGAN WEIGHTS
- Ovaries and uteri (including horns, cervix and vagina), testes, epididymides, accessory sex organs
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 4 days of age.

GROSS NECROPSY
- Gross necropsy consisted of external examinations

Statistics:
- Heterogeneity test
- Fisher`s exact test
- Trend test
- Log-rank test
- ANOVA and Dunnett`s test
Reproductive indices:
Mating index (F0), fertility index (F0), pregnancy index (F0), pre-coital interval (F0), pregnancy period (F0), post-implantationen loss, mean value per litter
Offspring viability indices:
Birth index, mean body weight (F1), viability index on day 4

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
only high dose
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
only high dose
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
only high dose
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: only high dose during pre.mating period

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
only high dose related to general maternal toxicity
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): At the highest dose one male and one female animal died. Additionally dyspnea, loss of weight, soft stools, dilation of the abdomen occurred. In mid and low sose animals no clinical signs or deaths.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No effects at mid and low dose. Decrease of body weight in high dose animals in the first week of tretament.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Lower mean daily food consumption during pre-mating in males of the high dose. No effects in mid and low dose.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No changes in testicular stages as evaluated of stages of spermatogenesis.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Mating and fertility indices slightly lower in high dose animals. No changes at all in mid and low dose.

ORGAN WEIGHTS (PARENTAL ANIMALS): Lower weight of epididymides in high dose animals without histopathological correlate. No changes in mid and low dose.

GROSS PATHOLOGY (PARENTAL ANIMALS): No changes noted.

HISTOPATHOLOGY (PARENTAL ANIMALS): Histology of Fo testes, epididymides and ovaries did not show compound related changes. No changes seen in the testicular stages of spermatogenesis.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
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:
no mortality observed
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)

No differences on F1 pubs survival during the first 4 days of lactation between control and treated groups. No significant differences in body weight.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study it was concluded that the NOAEL is 125 mg/kg body weight per day for both, the dams and their offspring.
Executive summary:

For dioctadecyldimethylammonium chloride ( 96.8% active compound) a GLP conform Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 421 had been performed. Groups of 10 rats (CRL:CD (SD) BR) per sex were treated with dosages of 0, 62.5, 125, and 500 mg/kg bw/day by gavage (administration volume 10 ml/kg bw/day) using corn oil as a vehicle for the control group. Males were treated daily from two weeks before mating, during mating and until a dosing period of a total of 28 days had been completed. Females were treated daily from two weeks before mating until the 4 th day of lactation. Subsequently these females were sacrificed with their pups. At daily doses of 500 mg/kg bw one male and one female died after 12 respectively 10 treatments. Clinical observations revealed dyspnea, soft stools in all females and almost all males. Half of the females also showed slight to moderate dilation of the abdomen. Body weight loss was observed in both sexes during the first week of treatment in high dose animals. Further, statistically significantly lower mean daily food consumption in high dose animals was observed in the males during the premating period and in the dams during the first week of pregnancy. Statistically significantly lower mean dam body weights were observed after 14 and 20 days of gestation and at the day of birth after delivery in the high dose. No toxicologically relevant effects were observed at dosages of 125 and 62.5 mg/kg bw/day. At sacrifice of the parental animals no significant differences were found on the organ weights of uterus, ovaries, testes and epididymides. Histopathology of testes, epididymides and of the ovaries of the animals of the 500 mg/kg dose groups did not show any compound related changes. No substance related changes were reported for the evaluation of testicular stages of spermatogenesis performed in the PAS-hematoxylin stained sections. At the dosages of 62.5 and 125 mg/kg/day all of the 10 paired females revealed to be sperm positive after mating, all revealed to be pregnant and all delivered live litters. The numbers of corpora lutea had not been evaluated during this study. At 500 mg/kg/day, from the 9 paired females 7 revealed to be sperm positive (77 %) after mating, 6 out of 9 (67 %) revealed to be pregnant, and 5 out of 6 (83 %) delivered live litters. One animal revealed to have fully resorbed. Mean pre-coital time was longer in this group (about 6.1 days) when compared to the controls and the lower dosage groups (1.5 to 2.1 days). After birth, for the animals treated with 62.5 or 125 mg/kg/day there were no substance related biological differences in their pregnancy outcome in comparison to the control group. At 500 mg/kg /day, the percentage of postimplantation losses was increased to 19 % per litter in comparison to about 6 % per litter in the controls and in the lower treatment groups, thus resulting in a statistically significantly lower rate of live borns of 83 % in comparison to 94 % in the controls and in the lower treatment groups. Viability index on postnatal day 4 was in the range of those of the controls and the lower treatment groups. For all dose groups under investigation no statistically significant differences were found for the body weights of male and female pups at birth and on postnatal day 4. External abnormalities have not been reported. Based on the findings of this study it was concluded that the NOAEL regarding reproductive toxicity is 125 mg/kg body weight.