N-[3-(dimethylamino)propyl]stearamide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From Jul. 02, 1984 to Aug. 03, 1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

animals were treated during the period of organogenesis (Day 7-18 of presumed gestation) while the guideline recommends dosing through the entire period of gestation to the day before caesarean section.

GLP compliance:

yes

Remarks:

(according to U.S. FDA principles of GLP)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-[3-(dimethylamino)propyl]stearamide

EC Number:

231-609-1

EC Name:

N-[3-(dimethylamino)propyl]stearamide

Cas Number:

7651-02-7

Molecular formula:

C23H48N2O

IUPAC Name:

N-[3-(dimethylamino)propyl]octadecanamide

Details on test material:

- Name of test material: Stearamidopropyl dimethylamine
- TSIN: G0250.01
- Substance type: pure active substance
- Physical state: Waxy Flake; Cream colored
- Stability under test conditions: Not reported
- Storage condition of test material: Ambient (50 to 90 ⁰F)
- Solubility: 5% w/w in water; 5% w/w in ethanol; 10% w/w in mineral oil
- The responsibility of test substance characterization and stability was assumed by sponsor.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Approximately 30 week
- Weight at study initiation: 2.94 – 5.01 kg
- Housing: Individually in stainless steel cages (30x24x16 inches) with grid flooring suspended over absorbent paper liners; in units of eight cages per rack.
- Diet: Certified Rabbit Chow #5322(Ralson Purina); Each rabbit was given 150 g diet /Day (during acclimation); 180 g diet/Day (during presumed gestation).
- Water: Reverse osmosis treated water containing 0.0-0.6 ppm chlorine; ad libitum
- No identified contaminates on either the fed or water were known to interfere with results of this study.
- Acclimation period: Approximately 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 71 ± 3 °F
- Humidity: 47 - 76%
- Air changes: 12 to 15 air changes per hour of 100% fresh air which was passed through 99.97% hepa filters.
- Photoperiod: 12 hour artificial fluorescent light/12 hour dark cycle per day

IN-LIFE DATES: From: Jul. 09, 1984 To: Aug. 03, 1984

Administration / exposure

Route of administration:

dermal

Vehicle:

other: 30% isopropanol and 70% reverse osmosis membrane processed deionized water (R.O. water)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in vehicle at a concentration such that all dosage was administered to rabbit at a volume of 2 mL/kg bw day. After preparation dosing solution was stirred for 30 minutes (using stir-bar and a magnetic stir plate) prior to application
- Rate of preparation of dosing solutions (frequency): Dosing solutions were prepared and used daily.

TEST SITE
- Area of exposure: 10 cm X 15 cm area in the back, clipped free of hairs by oster clippers
- Type of wrap if used: None
- Time intervals for clippings: Day prior to first administration and repeated at three day intervals (performed after washing of applied dosage).
Method of treatment: The appropriate dosage or vehicle was applied to the shaven back of the animal as evenly as possible using 10cc syringe.

EXPOSURE PERIOD: 2 hour

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes; During a 2-hour exposure period, an Elizabethan collar was worn by each animal to prevent access to the applied material.

REMOVAL OF TEST SUBSTANCE
- Washing: Yes, the application site was rinsed with warm R.O. water. The application area on the back of each rabbit and surrounding fur was blotted dry using soft cloth.
- The interior of each cage was wiped with a warm damp cloth, to remove any test article possibly deposited by animal during the exposure period.
- Time after start of exposure: 2 hours

TEST MATERIAL
- Amount(s) applied: 2 mL/kg bw/day The dose volume was applied daily on the basis of observed body weight.
- Concentration: 0, 2.5, 50 and 100 mg/mL
- Constant concentration used: Yes

VEHICLE
- Justification for use and choice of vehicle : Not reported
- Concentration: 30% isopropanol and 70% reverse osmosis membrane processed deionized water (R.O. water)

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

DETAILS ON MATING:
- Impregnation procedure: Artificial insemination; Does were artificially inseminated with spermatozoa from untreated proven male rabbits specially used for breeding.
- Approximately three hour prior to artificial insemination, all animals were intravenously administered 20 USP Units/Kg bw of HCG.
- Each female received an estimated 0.25 mL of semen which was diluted with normal saline to a concentration of 6.0 x 10 (6) spermatozoa/0.25 mL of saline.
- Verification of same strain and source of both sexes: Yes, the spermatozoa were obtained from male rabbits of same source and strain as female rabbits.
- Proof of pregnancy: The Day of artificial insemination was performed was designated as Day 0 of presumed gestation.

Duration of treatment / exposure:

Day 7-18 of presumed gestation

Frequency of treatment:

Daily

Duration of test:

23 days (Day 7-29 of presumed gestation)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 100 and 200 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

20 female rabbits/dose group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Not reported
- Rationale for animal assignment: Post acclimation, 80 rabbits that appeared to be in good health were assigned to 4 experimental groups by computer-generated (weight ordered) randomization procedure.
- Assignment of animals: The animals were assigned into following control and treatment groups:
Group 1 (vehicle control): 0 mg/kg bw/day
Group 2 (low dose group): 5 mg/kg bw/day
Group 3 (mid dose group): 100 mg/kg bw/day
Group 4 (high dose group): 200 mg/kg bw/day
- Rationale for selection of route of administration: The topical route was selected because it is intended route of human exposure.

Examinations

Maternal examinations:

MORTALITY/MORBIDITY: Yes
- Time schedule: Twice daily (during entire presumed gestation period)

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (during entire presumed gestation period)
- Cage side observations included: General appearance

CLINICAL OBSERVATIONS: Yes, animals were observed for signs of toxicity, skin irritation, and abortion.
- Time schedule: Several times a day (during dosage and post dosage period (Day 7 through 29 of presumed gestation))

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during the acclimation period, twice during the pre-dosage period and daily during the dosage and post dosage period.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Daily during the acclimation period by estimating to nearest of 25% of feed consumed. For Day 0 to 29 of presumed gestation, feed consumption was recorded and calculated in the terms of gram food consumed.

WATER CONSUMPTION AND COMPOUND INTAKE: No

DERMAL IRRITATION: During dosage and post dosage period (Day 7 through 29 of presumed gestation) rabbits were scored for degree of skin irritation using the system of Nixon et. al. 1983. For details refer to scoring scale provided in ‘Any other information on materials and methods incl. tables’ section.

POST-MORTEM EXAMINATIONS: Yes, On the same calendar day on which a rabbit died/sacrificed. This necropsy procedure was also followed as part of the caesarean-sectioning and for the rabbits which aborted and delivered.
- Sacrifice on gestation day # 29 of presumed gestation, all surviving animals were killed with T-61 Euthanasia solution administered intravenously.
- Organs examined: A complete gross necropsy examination was performed, which also included the brain. Gross maternal lesions were saved in neutral buffered 10% formalin.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number and placement of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of live and dead fetus: Yes

Fetal examinations:

- External examinations: Yes: all per litter; each caesarean derived fetus was weighed and subsequently examined for gender and gross external abnormalities.
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes; all per litter: brain was opened with free-hand cross section and examined
- Abnormal fetal tissue considered appropriate for retention was preserved in neutral buffered 10% formalin.
- all fetuses which were obtained after a minimum of 27 days of gestation were examined externally, eviscerated, stained with alizarin red-S and evaluated for skeletal variation
- Late resorption was examined to the extent possible, as autolysis often prevented the full evaluation.

Statistics:

Maternal body weight changes, feed consumption, corpora lutea, implants, resorptions, live fetuses and fetal body weights were analyzed using Bartlett’s test of homogeneity of variances and the Analysis of Variance. Provided that Bartlett’s test of homogeneity of variance was not significant, treated groups were compared to the control group, using the least significant difference (LSD) criterion. If Bartlett’s test was significant, comparisons with the control group were made by a technique which made allowances for unequal variances. In this latter case, Wilcoxon’s rank sum test was also applied. Regression analysis on dose level was performed; this analysis included test for linear regression and lack of fit.

The chi-squared, 2X2 contingency test, followed by Fisher’s exact test was used to evaluate the discrete data, such as indices of pregnancy, dead fetuses, fetuses with variations and individual fetal abnormalities and variations.

Indices:

Not reported

Historical control data:

Not reported

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

- Clinical signs attributed to administration of the test substance included alopecia (all treated groups), excess lacrimation (mid and high dose groups), ungroomed coat and green-colored matted fur around mouth and rump (high dose group).
- Statistically significant (P≤ 0.05 to P≤ 0.01) increases in the incidence of rabbits with these signs occurred only for the middle and high dosage groups, as compared to the control groups. Other clinical signs (anorexia, soft or liquid feces, red exudates in cage pan) were not attributed to the test material; they were either were single events which were not-dosage-dependant or occurred in the absence of administration of the test material (red exudates in cage pan).
- Two low dosage group rabbits aborted on Day 21 of gestation. As the incidence of abortion was not dosage-dependant, these events were not attributed to administration of the test material.
- One high dosage group doe delivered its litter on Day 28 of gestation. As premature delivery frequently occurs in one rabbit in a population of 80 rabbits, this event was not attributed to administration of the test material.

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

- All skin reactions demonstrated dosage-dependant onset, incidence and severity with recovery evident during the dosage and post dosage periods.
- Atonia, desquamation and fissuring was observed in mid and high dose groups. One high dose group rabbit had eschar present, attributed to the treatment.
- All other findings were consistent among treatment and control groups.

Mortality:

no mortality observed

Description (incidence):

- No death was recorded during course of the study

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- Administration of the test substance at mid and high dose levels inhibited average body weight gain.
- High dose group rabbits had a significant decrease (P≤0.01) in average body weight during treatment, and continued to have lower average body weights than control rabbits during the post dosage period.
- As compared to control average daily body weight gain was significantly less for the mid dose (P≤0.05) and high dose (P≤0.01) group rabbits.
- Administration of the 5 mg/kg/day dosage of the test substance did not adversely affect the expected pattern of average maternal body weight gain.- During the pre-administration period, average maternal body weight gain was similar for rabbits in all dosage groups.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

- Maternal feed consumption was affected at mid and high dose levels, as compared with the control. The effect was slight for the mid dose group rabbits and moderate for the high dose group rabbits.
- As compared with control values, average daily feed consumption of the high dose group rabbits was generally significantly decreased (P≤0.05 to P≤0.0.1) from Day 15 through Day 21 of gestation. After the completion of the dosage period, a small rebound effect on feed consumption occurred for rabbits in the middle and high dosage groups. Rabbits generally consumed slightly more feed per day during this period than did the control does. However, this observation did not demonstrate statistically significant differences (p> 0.05).

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

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Neuropathological findings:

not examined

Maternal developmental toxicity

Number of abortions:

effects observed, treatment-related

Description (incidence and severity):

- Two low dosage group rabbits aborted on Day 21 of gestation and one high dosage group rabbit delivered on Day 28 of gestation. As a result, caesarean-delivery observations were based on 20, 15, 17, and 15 rabbits from control, low, middle, and high dosage groups, respectively.

Other effects:

no effects observed

Description (incidence and severity):

- All control rabbits, 17 (85.0%) rabbits in each of the low and mid dosage groups, and 16 rabbits (84.2%) of the high dosage group were pregnant.
- Administration of the 200 mg/kg/day of the test material may have slightly impaired implantation, as the average number of implantation sites per pregnant doe was slightly lower for rabbits in this dosage group, as compare to the control group. However; the effect was not statistically significant (p>0.05). As the result of the slightly lower implantation value, the average litter size for the high dosage group was also slightly decreased, as compared with the control values. All of the values were within expected historical control values.
- Administration of test material did not adversely affect pregnancy incidence or average numbers of corpora lutea or resorption. Values for these parameters were not significantly different (P>0.05) among the four dosage groups and did not demonstrate dosage-dependency.

Effect levels (maternal animals)

1

Dose descriptor:

NOEL

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

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): no effects observed

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

- Viable fetus(es) were present in 20, 14, 17, and 14 litters from control, low, middle, and high dosage groups, respectively. Litter data were based on these values. 1 rabbit each from low and high dose group had all implantation resorbed.

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

- As compared with the control, treatment with test substance did not result in increased incidence of fetuses with observed variations. The incidence of specific fetal malformations and/or developmental changes did not demonstrate dosage-dependency and/or were not significantly more frequent (P>0.05) in litters from treatment group, as compared with litters from control group.

Skeletal malformations:

no effects observed

Description (incidence and severity):

- Average numbers of ossification sites per fetus were similar for litters in all dosage groups. None of the fetal ossification sites demonstrated significant differences (P>0.05) among the four dosage groups.

Visceral malformations:

no effects observed

Description (incidence and severity):

- As compared with the control, treatment with test substance did not result in increased incidence of fetuses with observed variations. The incidence of specific fetal malformations and/or developmental changes did not demonstrate dosage-dependency and/or were not significantly more frequent (P>0.05) in litters from treatment group, as compared with litters from control group.

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Viable fetus(es) were present in 20, 14, 17, and 14 litters from control, low, middle, and high dosage groups, respectively. Litter data were based on these values. 1 rabbit each from low and high dose group had all implantation resorbed.
- Totals of 138, 105, 94, and 80 live Day-29 fetuses which were Caesarean-delivered from 20, 14, 17, and 14 control, low, middle, and high dosage group litters, respectively, were examined for gross external, soft tissue and skeletal variations. Statistical analyses were based on these litters and specimens. In addition to these caesarean-delivered Day-29 fetuses, 3 late resorptions from the control group and 6 late resorptions from the mid dose group were also examined to the extent possible.
- Treatment with test material did not adversely affect average fetal body weights per litter or the average percentage of male fetuses per litter. Incidence values for these parameters were not significantly different (P>0.05) among the four dosage groups.

Effect levels (fetuses)

Dose descriptor:

NOEL

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no developmental toxicity

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

Table 1: Caesarean Delivery Summary (Study# 33077) Maternal parameters Vehicle Control 5 mg/kg bw/day (Low dose group) 100 mg/kg bw/day (Mid dose group) 200 mg/kg bw/day (High dose group) Animals Treated (#) 20 20 20 19 Pregnant [# (%)] 20 (100%) 17 (85.0%) 17 (85.0%) 16 (84.2%) Aborted (#) 0 2 0 0 Died (#) 0 0 0 0 Premature delivery (#) 0 0 0 1 Animals delivered by caesarean section on Day 29 of gestation (#) 20 15 17 15 Corpora Lutea (mean±S.D.) 11.6 ± 3.1 10.9 ± 3.0 11.3 ± 2.5 11.2 ± 3.4 Implantation (mean±S.D.) 7.7 ± 3.4 7.7 ± 3.9 7.4 ± 2.7 6.3 ± 3.3 Litter size (mean±S.D.) 6.9 ± 3.5 7.0 ± 3.2 5.5 ± 2.4 5.3 ± 3.4 Live fetus (#) 138 105 94 80 Dead fetus (#) 0 0 0 0 Resorption (mean±S.D.) 0.8 ± 1.5 0.7 ± 1.2 1.8 ± 2.0 1.0 ± 1.8 Early resorption (#) 12 7 24 13 Early resorption (mean±S.D.) 0.6 ± 1.5 0.5 ± 0.7 1.4 ± 1.6 0.8 ± 1.8 Late resorption (#) 4 3 7 2 Late resorption (mean±S.D.) 0.2 ± 0.7 0.2 ± 0.8 0.4 ± 1.2 0.1 ± 0.4 Does with any resorption (%) 7 (35.0%) 5 (33.3%) 12 (70.6%) 7 (46.7%) Does with all implantation resorbing [# (%)] 0 1 (6.7) 0 1 (6.7) Does with viable fetus [#(%)] 20 (100) 14 (93.3%) 17 (100%) 14 (93.3%) Table 2: Variation observed in fetuses – Summary (Study# 33077) Fetal parameters* Vehicle Control 5 mg/kg bw/day (Low dose group) 100 mg/kg bw/day (Mid dose group) 200 mg/kg bw/day (High dose group) Litters evaluated 20 14 17 14 Fetuses Evaluated 138 105 94 80 Litters with fetuses with any variation observed [N (%)] 8 (40.0%) 8 (57.1%) 11 (64.7%) 6 (42.8%) Fetuses with any variation observed [N (%)] 13 (9.4%) 13 (12.4%) 23 (24.5%) 10 (12.5%)

Applicant's summary and conclusion

Conclusions:

Percutaneous application of Stearamidpropyl dimethylamine to New Zealand White rabbits from Days 7 through 18 of presumed gestation at dose levels of 0, 5, 100 and 200 mg/kg bw/day did not produce any evidence of developmental toxicity. The NOAEL for developmental toxicity was determined to be 200 mg/kg bw/day.

NOEL for maternal toxicity was determined to be 5 mg/kg bw/day, the NOAEL was 100 mg/kg bw/d (based on variations in body weight and food consumption data).

Executive summary:

The purpose of the study was to determine the developmental toxicity of Stearamidpropyl dimethylamine administered topically at dose levels of 0, 5, 100 and 200 mg/kg bw/day (dose volume 2 mL/kg bw) to artificially inseminated rabbits for 12 consecutive days (during Days 7 through 18 of presumed gestation).

A total of 80 female New Zealand white rabbits (Source: Dutchland Laboratories, Pennsylvania) weighing 2.94 – 5.01 kg were housed individually in stainless steel cages (30x24x16 inches) with grid flooring. The animals were maintained under standard laboratory conditions (temperature: 71 ± 3 °F, humidity: 47 - 76%, 12 h light/12 h dark cycle per d) and fed on certified rabbit chow #5322. The animals were acclimatized for approximately 4 weeks prior to test.

The test substance was applied topically as a solution in 30% isopropanol and 70% reverse osmosis membrane processed deionized water (vehicle) at a dose volume of 2 mL/kg bw/day. The actual dose volume was calculated daily on the basis of observed body weight.

Post acclimation rabbits that appeared to be in good health were randomly assigned to 3 treatments and 1 control group (20 rabbits/group). Approximately three hours prior to artificial insemination, all animals were intravenously administered 20 USP Units/Kg bw of HCG. Rabbits were artificially inseminated by spermatozoa from male rabbits used specifically for breeding purpose. Day of artificial insemination was considered as Day 0 of presumed gestation.

- Assignment of animals: The animals were assigned into following control and treatment groups:

Group 1 (vehicle control): 0 mg/kg bw/day

Group 2 (low dose group): 5 mg/kg bw/day

Group 3 (mid dose group): 100 mg/kg bw/day

Group 4 (high dose group): 200 mg/kg bw/day

Prior to the first day of topical dosage, a 10 cm X 15 cm area on back of each animal was clipped using Oster clipper(clipping was repeated at three day intervals). The appropriate dosage or vehicle was applied to the shaven back of the animal as evenly as possible using a 10cc syringe. During exposure period, an Elizabethan collar was worn by each animal to prevent access to the applied material.

After a 2 hour exposure period, the application site was rinsed with warm R.O. water. The application area on the back of each rabbit and surrounding fur was blotted dry using a soft cloth.

Rabbits were observed daily during the dosage and postdosage periods for signs of toxicity, skin irritation, abortion, delivery, death, body weight and feed consumption. Skin irritation levels were determined approximately 24 hours after each dosage or at 24-hour intervals, after dosage was discontinued. On Day 29 of presumed gestation all rabbits were sacrificed, and a complete gross necropsy was performed, including examination of the brain. The abdomen of each rabbit was opened, and the uterus was examined for pregnancy, number of implantations, live and dead fetuses and early and late resorptions. Corpora lutea were counted. Each fetus was weighed and subsequently examined for gross external variations and gender, prior to examination for soft tissue and skeletal variations.

No does died during the course of the study. Clinical signs attributed to administration of the test material included alopecia (5, 100, 200 mg/kg/day doses), excess lacrimation (100 and 200 mg/kg/day dosages), ungroomed coat and green-colored matted fur around mouth and rump (200 mg/kg/day dosage). Statistically significant (p≤0.05 to p≤0.01) increases in the incidences of rabbits with these signs occurred only in the mid and high dosage groups, as compared with the control group.Other signs (anorexia, soft or liquid feces, red exudates in cage pan) were not attributed to the test material; they were either were single events which were not-dosage-dependant or occurred in the absence of administration of the test material (red exudates in cage pan).

All skin reactions demonstrated dosage-dependant onset, incidence and severity with recovery evident during the dosage and post dosage periods. Atonia, desquamation and fissuring was observed in mid and high dose groups. One high dose group rabbit had eschar present, attributed to the treatment.

Two low dosage group rabbits aborted on Day 21 of gestation. As the incidence of abortion was not dosage-dependant, these events were not attributed to administration of the test material. One high dosage group doe delivered its litter on day 28 of gestation. As premature delivery frequently occurs in one rabbit in a population of 80 rabbits, this event was not attributed to administration of the test material.

As compared to control, average daily body weight gain was significantly less for the mid dose (P≤0.05) and high dose (P≤0.01) group rabbits. High dose group rabbits had a significant decrease (P≤0.01) in average body weight during treatment, and continued to have lower average body weights than control rabbits during the post dosage period. Body weight/bodyweight gain of low dose group rabbits followed expected pattern of average maternal body weight gain.

Maternal feed consumption was affected at mid and high dose levels, as compared with the control. The effect was slight for the mid dose group rabbits and moderate for the high dose group rabbits. As compared with control values, average daily feed consumption of the high dose group rabbits was generally significantly decreased (P≤0.05 to P≤0.0.1) from Day 15 through Day 21 of gestation.

All control rabbits were pregnant, 17 (85.0%) rabbits in each of the low and middle dosage groups were pregnant, and 16 (84.2%) of the high dosage group rabbits were pregnant. Two low dosage group rabbits aborted and one high dosage group rabbit delivered prior to scheduled Caesarean section. As a result, Caesarean-delivery observations were based on 20 control, 15 low, 17 middle, and 15 high dosage group rabbits.

Administration of the 200 mg/kg/day dosage of the test material may have slightly impaired implantation, as the average number of implantation sites per pregnant doe was slightly lower for rabbits in this dosage group, as compare to the control group. The effect was not statistically significant (p>0.05). As the result of the slightly lower implantation value, the average litter size for the high dosage group was also slightly decreased, as compared with the control values. All of the values were within expected historical control values.

Administration of these dosages of the test material did not adversely affect pregnancy incidence or average numbers of corpora lutea or resorptions. Values for these parameters were not significantly different (P>0.05) among the four dosage groups and did not demonstrate dosage-dependency.

Viable fetus(es) were present in 20, 14, 17, and 14 litters from control, low, middle, and high dosage groups, respectively. Litter data were based on these values.1 rabbit each from low and high dose group had all implantations resorbed.Total of 138, 105, 94, and 80 live Day-29 fetuses which were Caesarean-delivered from 20, 14, 17, and 14 control, low, middle, and high dosage group litters, respectively, were examined for gross external, soft tissue and skeletal variations. Statistical analyses were based on these litters and specimens.

No fetal variations at gross external, soft tissue or skeletal examination were attributed to the treatment with test substance. Incidence of variations observed either were not dosage-dependant or were not significantly different (P> 0.05) among the four dosage groups.

In conclusion, percutaneous application of Stearamidpropyl dimethylamine to New Zealand White rabbits from Days 7 through 18 of presumed gestation at dose levels of 0, 5, 100 and 200 mg/kg bw/day did not produce evidence for developmental toxicity.

NOEL for maternal toxicity was determined to be 5 mg/kg bw/day; the NOAEL was 100 mg/kg bw/d (based on variations in body weight and food consumption data).

This developmental toxicity/teratogenicity study was classified as acceptable, and satisfies the guideline requirements of OECD 414 method.