Dimethyldioctylammonium chloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no studies available to assess the reproductive toxicity potential of the substance. However, there is a reliable two-generation study on rats available for a structurally similar substance. Exposure of rats to the substance at concentrations of 300, 750 aand 1500 ppm in the diet for two generations resulted in well-defined parental and postnatal toxicity at 1500 ppm without any adverse effects on reproductive performance. The NOEL was 750 ppm for both parents and offspring, indicating that there was no increased risk to the offspring in the absence of indications of adult toxicity based on body weight gain effects in the F1 generation.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 May 1988 - 15 August 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: B-1889

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Twenty eight male and 28 female weanling rats (F0 generation) were exposed to the substance by dietary inclusion for a total of 10-week pre-breed exposure period. Exposures continued through mating, gestation, parturition and lactation. Exposures continued through mating, gestation, parturition and lactation of the second litters.

Details on mating procedure:

Following a 10-week pre-breed exposure period the F0 rats were randomly paired within dose groups for a three week mating period to produce the F1A generation. At least 10 days after the weaning of the F1A litters, the Fo parents were paired again (with different male-female pairing within the dose groups than employed for the F1A breed) for 3 weeks to produce the F1B generation.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of the substance in the test diets was determined using gas chromatography. For the first 4 weeks of teh study, test diets from all diets were analysed for concentrations of the substance prior to administration of the diets to the animals. For the remaining 60 weeks of teh study, all test diets from every fourth preparation were analysed after administration of the diets to the study animals. Homogeneity and stability analyses of the substance in the diets were performed prior to the start of the test diet administration.

Details on study schedule:

Following a 10-week pre-breed exposure period the F0 rats were randomly paired within dose groups for a three week mating period to produce the F1A generation. At least 10 days after the weaning of the F1A litters, the F0 parents were paired again (with different male-female pairing within the dose groups than employed for the F1A breed) for 3 weeks to produce the F1B generation. After the F1B pups were weaned, the F0 animals were necropsied and high dose and control animals were examined for histopathologic lesions. At weaning, 28 F1B weanlings/sex/group were randomly selected as parents of the subsequent generation. Selected F1 parents were exposed to the same dietary concentrations of the substance as their parents for at least 10 weeks. After their pre-breed exposure the F1 animals were paired to produce F2A and F2B offspring.

Dose / conc.:

0 ppm

Dose / conc.:

300 ppm

Dose / conc.:

750 ppm

Dose / conc.:

1 500 ppm

No. of animals per sex per dose:

28/sex/dose

Control animals:

yes, plain diet

Details on study design:

Twenty eight F0 rats/sex/dose were bred twice to produce F1A and F1B litters. Selected males and females from F1B litters were used as parents of the F2 generation. Twenty eight F1 pups/sex/dose, exposed to the same dietary concentration of the substance as their parents, were subsequently bred twice to produce F2A and F2B litters.

Parental animals: Observations and examinations:

PARAMETERS EXAMINED
The following parameters were examined in F0 to produce F1A/F1B litters and F1 to produce F2A/F2B litters: Mating index (males), mating index (males), fertility index (females) and fertility index (males).

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1A/F1B / F2A/F2B offspring: gestational index, live birth index, 4-day survival index (precull and postcull), 14-day survival index, 21-day survival index, lactation index, 28-day survival index.
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, other:]

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]

Statistics:

The unit of comparison was the male, pregnant female or the litter. Results of the qunatitative continuous variables (e.g. body weights, food consumption, organ weights, etc) were intercompared for the three treatment groups and one control group by use of Levene's test for equal variances; analysis of variance (ANOVA) and t-tests. When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used for pair-wise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by the separate variance t-test for pairwise comparisons. The significance levels for the t-tests comparisons were corrected by the Bonferroni method. Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons when appropriate. Frequency data were compared using the Fisher's exact test. For all statistical tests, the fidcial limit of 0.5 (two-tailed) was used as the criterion for statistical significance.

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced body weight and body weight gain at the top concentration begining one week after treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Substantial reductions in food consumption were observed throughout the pre-breed period in F0 animals at the top concentration.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

Gestational length as well as mating, fertility and gestational indices were unaffected by treatment. Body weights and bodyu weight gains at 300 and 750 ppm were essentially equivalent to control values throughout gestation. Gestational food consumption was unaffected by treatment. There were no differences across the groups for reproductive parameters for F0 parents for the F1A and F1B breeds.

Clinical signs:

effects observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males and females at 1500 ppm exhibited consistently reduced body weights throughout the entire treatment period. Significant weight gain depression was noted at 1500 ppm.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption for the F1 males and females was reduced at 1500 ppm throughout the treatment period. No effects on food consumption were noted in F1 males and females at 300 and 750 ppm.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

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

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

Maternal gestational body weights, but not weight gains, were reduced at 1500 ppm.

Key result

Dose descriptor:

NOEL

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Effect level:

1 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

not determinable due to absence of adverse toxic effects

Clinical signs:

effects observed, non-treatment-related

Mortality / viability:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Pup body weights and body weight gains were unaffected by treatment though lactational day 7. From day 14 through weaning on lactational day 21, and postweaning, on day 28, body weights of male and female pups at 1500 ppm were reduced. Corresponding body weight gains for lactational days 7-21 and 21-28 (postweaning) were reduced at 1500 ppm. Body weights and weight gains of pups at 750 and 300 ppm were unaffected by treatment.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reproductive performance

Remarks on result:

not determinable due to absence of adverse toxic effects

Clinical signs:

effects observed, non-treatment-related

Mortality / viability:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

F2B pup body weights per litter were equivalent through lactational day 4. From lactational day 7 through weaning on day 21, and postweaning, on day 28, body weights of F2B pups at 1500 ppm were reduced. Concurrent F2B pup weight gain reductions were observed at 1500 ppm from day 4-28. There were no observable effects of treatment on body weight at 750 and 300 ppm.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOEL

Generation:

F2

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

1 500 ppm

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Reproductive effects observed:

no

Lowest effective dose / conc.:

1 500 ppm

Treatment related:

no

Conclusions:

Exposure of rats to the substance at concentrations of 300, 750 aand 1500 ppm in the diet for two generations resulted in well-defined parental and postnatal toxicity at 1500 ppm without any adverse effects on reproductive performance. The NOEL was 750 ppm for both parents and offspring, indicating that there was no increased risk to the offspring in the absence of indications of adult toxicity.

Executive summary:

The potential of the substance to produce alterations in parental fertility, maternal pregnancy and lactation, and growth and development of the offspring for two generations and two litters per generation was evaluated in Sprague Dawley rats. The substance was administered via the diet at concentrations of 300, 750 aand 1500 ppm. A well-defined parental and postnatal toxicity as evidenced by body weight reductions occurred at 1500 ppm without any adverse effects on reproductive performance. The NOEL was 750 ppm for both parents and offspring, indicating that there was no increased risk to the offspring in the absence of indications of adult toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 500

Study duration:

subchronic

Species:

rat

Quality of whole database:

Sufficient to address requirements.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

In a reliable developmental toxicity study the substance were administered to pregnant rats for 10 days at doses of 10, 25 and 50 mg/kg bw/day. There were no deleterious effects on gestation, but the substances did cause more dams to resorb one or more fetuses at the 50 mg/kg bw/day dose level. No teratological findings could be ascribed to the substances employed at doses up to 50 mg/kg bw/day in rats when dosed during GD 6 to 15.

In a reliable developmental toxicity study for a structurally similar substance, rats were administered the substance by oral gavage on GD 6 to 15 at doses of 1, 10 and 20 mg/kg bw/day. Treatment related clinical signs of toxicity was observed at 10 and 20 mg/kg bw/day. These adverse effects were audible respiration and gasping  at 10 and 20 mg/kg bw/day, and reduced body weight and food consumption at 20 mg/kg bw/day. The NOEL for maternal toxicity was 1 mg/kg bw/day. The NOEL for developmental toxicity was at least 20 mg/kg bw/day (the highest dose tested).

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not specified.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Specific details on test material used for the study:

Lot numbers:
Bardac-20: B35307 (25%)
Bardac-LF: B3414 (50%)

Species:

rat

Strain:

Wistar

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Adult female rats were mated with young adult males and detection of the vaginal sperm plug was considered to occur on day 0 of gestation.

Duration of treatment / exposure:

GD 6 to 15

Frequency of treatment:

Once daily.

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

Dose / conc.:

25 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Bardac-20:
10 mg/kg bw/day - 25 females
25 and 50 mg/kg bw/day - 24 females

Bardac-LF:
10 mg/kg bw/day - 26 females
25 mg/kg bw/day - 23 females
50 mg/kg bw/day - 26 females

Control animals:

yes, concurrent vehicle

other: Aspirin (250 mg/kg bw/day)

Maternal examinations:

Body weights were recorded on days 0, 6, 11, 15 and 20 of gestation. All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects.

Ovaries and uterine content:

Uterine contentts were examined and the number of implantation sites for each uterine horn were recorded. Number of live pups, dead pups and resorption sies were also recorded. The weight of each pup and number of corpora lutea was recorded.

Fetal examinations:

The urogenital tract was examined for signs of gross abnormality. One third of the pups in each litter were randomly chosen and fixed in Bouin's solution and these animals were examined for soft tissue abnormalities. All pups showing any gross abnormality were included in this preparation.

Statistics:

Incidence of occurrence ratios of treated groups were compared with the ratio for the control group using confidence Belts for Proportions (confidence coefficient of 0.95). Fetus weights were evaluated by analyses of variance and compared to the control value sing Scheffe's test.

Clinical signs:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

effects observed, non-treatment-related

Early or late resorptions:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

not specified

Key result

Dose descriptor:

NOEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

number of abortions

total litter losses by resorption

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 specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The most common abnormalities were hemorrhagic thorax and abdomen and gastroschisis. The incidence of accurrence was no greater in substance ttreated groups than in the controls.

Key result

Dose descriptor:

NOEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

skeletal malformations

visceral malformations

Key result

Developmental effects observed:

no

Lowest effective dose / conc.:

50 mg/kg bw/day

Conclusions:

No teratological findings could be ascribed to the substances employed at doses up to 50 mg/kg bw/day in rats when dosed during GD 6 to 15.

Executive summary:

The substance was administered to pregnant rats for 10 days at doses of 10, 25 and 50 mg/kg bw/day. There were no deleterious effects on gestation, but the substances did cause more dams to resorb one or more fetuses at the 50 mg/kg bw/day dose level. No teratological findings could be ascribed to the substances employed at doses up to 50 mg/kg bw/day in rats when dosed during GD 6 to 15.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 February 1990 - 23 February 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

1981

Qualifier:

according to guideline

Guideline:

EPA OPP 83-3 (Prenatal Developmental Toxicity Study)

Version / remarks:

1984

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: B-1889

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions: Stability was assessed prior to the start of the study. Solutions were prepared twice during the study and were analysed for test substance content prior to use.
- Solubility and stability of the test substance in the solvent/vehicle: Soluble in deionised water.

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: males - 63 days old; females - 56 days old.
- Weight at study initiation: males - 250 - 300 g; females - 175 - 200 g
- Housing: stainless steel wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-82°F
- Humidity (%): 40-74%
- Photoperiod (hrs dark / hrs light): 12 hour light period.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Purity of substance was 80.8% and the dosing was adjusted to take into account the purity.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability was assessed prior to the start of the study. Solutions were prepared twice during the study and were analysed for test substance content prior to use employing gas chromatography.

Duration of treatment / exposure:

GD 6 to GD 15

Frequency of treatment:

Once daily

Dose / conc.:

1 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

Dose / conc.:

20 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Twenty five pregant females/dose

Control animals:

yes, concurrent vehicle

Maternal examinations:

Clinical observations were recorded daily and twice daily during dosing. Maternal body weights were recorded for all females on GD 0, 6, 9, 12, 15, 18 and 21. Maternal food consumption was measured at 3-day intervals throughout gestation, GD 0-21.

Ovaries and uterine content:

At scheduled sacrifice on GD 21, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea and number and status of implantation sites (i.e., early and late resorptions, dead fetuses, live fetuses).

Fetal examinations:

All live fetuses were dissected from the uterus, counted, sexed, weighed and examined for external malformations (including cleft palate) and variations. Approximately one-half of the fetuses in each litter were examined for visceral (including carniofacial) malformations and variations. The remaining one-half of the fetuses were evaluated for skeletal malformations and variations.

Statistics:

The unit of comparison was the pregnant female or the litter. Results of the quantitative continous variables (e.g. maternal body weights, organ weights, fetal weights etc) were intercompared for teh three treatment groups and vehicle control group by use of Levene's test for equal variance analysis of variance (ANOVA) and t-tests and Bonferroni probabilities for pairwise comparisons. When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by the separate variance t-test. Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons when appropriate. Incidence data were compared using the Fisher's exact test. For all statistical tests, the probability value of P<0.05 (two-talied) was used as the critical level of significance.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

This included audible respiration and gasping at 20 mg/kg bw/day and audible respiration at 10 mg/kg bw/day. At 20 mg/kg bw/day, audible respiration was observed subsequent to the treatment period as well.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a reduction in maternal body weight for says 12, 15, 18 and 21 at 20 mg/kg bw/day, bjt this was not statistically significant. Body weight gains also appeared to be decreased for days 9 to 12, 12 to 15 and 6-15 at 20 mg/kg bw/day and body weight gains appear reduced for the entire gestational period, day 0-21.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reductions in food consumption at 20 mg/kkg bw/day for days 9 to 12, 12 to 15 and 6 to 15 correlate well with reductions in body weight and severity of clinical signs during the treatment period.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

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:

no effects observed

Description (incidence and severity):

Gravid uterine weight and liver weight were unaffected by treatment.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Ulceration of the stomach and gas-filled intestines at 20 mg/kg bw/day.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

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 specified

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 specified

Changes in number of pregnant:

not specified

Key result

Dose descriptor:

NOEL

Effect level:

1 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

clinical signs

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 specified

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not specified

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There were two skeletal variations, poorly ossified cervical centrum and majority of proximal hindlimb phalanges unossified were significantly decreased in the 10 and 20 mg/kg bw/day groups, respectively. However, these were not considered to be related to treatment.

Visceral malformations:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Developmental effects observed:

no

Conclusions:

Administration of the substance by oral gavage to Sprage Dawley rats during organogenesis (GD 6 to 15) at doses of 1, 10 and 20 mg/kg bw/day resulted in characteristic maternal toxicity at 10 and 20 mg/kg bw/day. These adverse effects were audible respiration and gasping at 10 and 20 mg/kg bw/day, and reduced body weight and food consumption at 20 mg/kg bw/day. The NOEL for maternal toxicity was 1 mg/kg bw/day. The NOEL for developmental toxicity was at least 20 mg/kg bw/day (the highest dose tested).

Executive summary:

The potential of the substance to cause developmental toxicity was evaluated in Sprague Dawley rats. The animals were administered the substance by oral gavage on GD 6 to 15 at doses of 1, 10 and 20 mg/kg bw/day. Treatment related clinical signs of toxicity was observed at 10 and 20 mg/kg bw/day. These adverse effects were audible respiration and gasping  at 10 and 20 mg/kg bw/day, and reduced body weight and food consumption at 20 mg/kg bw/day. The NOAEL for maternal toxicity was 1 mg/kg bw/day. The NOEL for developmental toxicity was at least 20 mg/kg bw/day (the highest dose tested).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sufficient to address requirements.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the findings of a reliable two generation reproductive toxicity study and a developmental toxicity study conducted on a structurally similar substance, together with the findings from a reliable developmental toxicity study conducted on the substance itself, classification of the substance is not justified.