Methyl (R)-2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Additional documentation provided in IUCLID assesment reports (Chapter 13) supports the read across approach

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Additional documentation provided in IUCLID assesment reports (Chapter 13) supports the read across approach

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOEL

Effect level:

1 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

maternal abnormalities

Key result

Remarks on result:

other: Oral administration of the test substance was not teratogenic to rats at doses up to 7.5 mg/kg bw/day.

Key result

Developmental effects observed:

no

Conclusions:

Rat NOEL: 1.0 mg/kg/day (maternal effects)
Oral administration of the test substance was not teratogenic to rats at doses up to 7.5 mg/kg bw/day.

Executive summary:

The objective of this study was to evaluate the embryotoxic and teratogenic potential of repeated oral administration of the test substance during organogenesis in rats. Bred rats were given 0, 0.1, 1.0, or 7.5 mg test substance /kg/day by gavage on days 6 through 15 of gestation.

Slight maternal toxicity was observed in the 7.5 mg/kg group as evidenced by decreased weight gain and food consumption early in gestation. No evidence of embryotoxicity or teratogenicity was observed in rats.

In conclusion, oral administration of the test substance during organogenesis was not teratogenic in rats at dose levels as high as 7.5 mg/kg/day.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Reference 2

Reference Type:

other company data

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of at least 30 bred rats were given the test substance by gavage on days 6 through 15 of gestation at a level of 0.1, 1.0 and 7.5 mg/kg of test substance/day. Test animals were sacrificed by carbon dioxide inhalation on gestation day 21 and observed for alterations.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyphenoxy]propanoic acid

Cas Number:

95977-27-8

Molecular formula:

C15H11ClF3NO4

IUPAC Name:

(2S)-2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyphenoxy]propanoic acid

Specific details on test material used for the study:

DOWCO 453 acid
Lot # AGR 192975
Purity: 99.7%

Test animals

Species:

rat

Strain:

Fischer 344

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Weight at breeding: Approximately 175-220 g
- Diet: Certified Laboratory animal Chow, ad libitum
- Water: Muncipal tap water, ad libitum
- Acclimation period: At least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 22°C
- Humidity: Approximately 50%
- Photoperiod: 12 hrs dark /12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionized distilled

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- The sodium salt of test substance was prepared in deionized-distilled water by adding 1.0 N sodium hydroxide solution to dissolve the acid. The sample was back titrated with hydrochloric acid solution to a pH between 6 and 7. Solutions of test substance-sodium salt were prepared such that a dose volume of 4 mL/kg of body weight/day yielded the appropriate acid equivalent for each dose level. Fresh solutions of test substance-sodium salt were prepared as required based upon the previously reported 14 day stability data.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The mean analytical concentration of the dosing solutions used was 93-95% of the target concentration.

Details on mating procedure:

- Impregnation procedure: Adult virgin female rats were bred to adult males (one female to one male) from the same strain. The day sperm were found in a vaginal smear was considered day zero of gestation.

Duration of treatment / exposure:

GD6-GD15

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.1 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

1 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

7.5 mg/kg bw/day

No. of animals per sex per dose:

30, 31, 31 and 30 dams in the control, 0.1, 1.0 and 7.5 mg/kg/day groups, respectively

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

OBSERVATIONS
- Time schedule: Daily

BODY WEIGHT
- Time schedule for examinations: Body weights were recorded on gestation days 6 through 16 and on day 21 of gestation

POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 21

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number and position of fetuses: Yes
- Number of live and dead fetus: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Sex, body weight and crown-rump length of each fetus: Yes

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [all per litter]

Statistics:

Maternal body weights, food and water consumption, absolute and relative organ weights, and fetal weight and length were evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, a Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. Corpora lutea, implantations, and litter size were analyzed by the Wilcoxon Rank-Sum test with Bonferroni's correction. For food consumption, statistical outliers were identified by a sequential method and excluded from analysis. Pregnancy rate was analyzed by the Fisher Exact Probability test. Evaluation of the neonatal sex ratio was done using the binomial distribution test. The frequency of alterations, resorptions, and other incidence data were analyzed by the Wilcoxon test, using the litter as the experimental unit.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Description (incidence and severity):

no treatment-related effects on general appearance or demeanor were observed among bred rats given 0, 0.1, 1.0, or 7.5 mg/kg/day on days 6 through 15 of gestation.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreases in body weight gain during days 6 through 8 of gestation, was observed in the 7.5 mg/kg/day group

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Decreases in food consumption during days 6 through 8 of gestation, was observed in the 7.5 mg/kg/day group

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

effects observed, treatment-related

Description (incidence and severity):

Water consumption in the top dose group was increased on days 12 through 20 of gestation.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Only liver weights were observed; Absolute and relative liver weights among the treated groups were comparable to controls

Maternal developmental toxicity

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

The incidence of implantations undergoing resorption among the treatment groups was comparable to the control group indicating that the test substance was not embryolethal in rats.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOEL

Effect level:

1 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

maternal abnormalities

Results (fetuses)

Fetal body weight changes:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence of individual malformations was not significantly increased for any of the treated groups compared to controls

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No skeletal malformations were observed in any group including controls. A significant increase in the incidence of delayed ossification of the centra of the thoracic vertebrae was observed in the 7.5 mg/kg/day group. A slight increase in the incidence of unfused thoracic centra was also observed in this group. The deffects may be indicative of a slight fetotoxic effect which is probably secondary to the slight maternal toxicity observed in this group.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence of individual malformations was not significantly increased for any of the treated groups compared to controls

Effect levels (fetuses)

Key result

Remarks on result:

other: Oral administration of the test substance was not teratogenic to rats at doses up to 7.5 mg/kg bw/day.

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Table 1: Body weights and weight changes (g) of pregnant rats (significant observations)

Gestation day	0 mg/kg/day	0.1 mg/kg/day	1.0 mg/kg/day	7.5 mg/kg/day
16	236±13	231±12	232±10	228±14*
21	274±19	261 ±20	267±19	260±23*
6-8	6±3	5±4	6±3	4±3*

*Statistically different from the control value by Dunnett's test,α=0.05.

 

Table 2: Food consumption (g/rat/day) of pregnant rats (significant observations)

Gestation day	0 mg/kg/day	0.1 mg/kg/day	1.0 mg/kg/day	7.5 mg/kg/day
6-8	14±1	14±1	14±1	13±1*

*Statistically different from the control value by Dunnett's test,α=0.05.

 

Table 3: Water consumption (g/rat/day) of pregnant rats (significant observations)

Gestation day	0 mg/kg/day	0.1 mg/kg/day	1.0 mg/kg/day	7.5 mg/kg/day
12-14	27±5	28±4	28±3	32±10*
15-17	34±4	33±4	33±4	40±14*
18-20	28±3	29±4	30±3	33±5*

*Statistically different from the control value by Dunnett's test,α=0.05.

 

Table 4: Incidence of Fetal Alterations Among Litters of Pregnant Rats (significant observations)

Skeletal observations		0 mg/kg/day	0.1 mg/kg/day	1.0 mg/kg/day	7.5 mg/kg/day
Delayed ossification of thoracic centra	F	1(2)	2(4)	1(2)	6 (11)*
	L	8(2)	12(3)	4(1)	33 (8)*

Number Fetuses (Number Litters) Examined

*Statistically different from the control value by a modified Wilcoxon test,α=0.05.

 

Applicant's summary and conclusion

Conclusions:

Rat NOEL: 1.0 mg/kg/day (maternal effects)
Oral administration of the test substance was not teratogenic to rats at doses up to 7.5 mg/kg bw/day.

Executive summary:

The objective of this study was to evaluate the embryotoxic and teratogenic potential of repeated oral administration of the test substance during organogenesis in rats. Bred rats were given 0, 0.1, 1.0, or 7.5 mg test substance/kg/day by gavage on days 6 through 15 of gestation.

Slight maternal toxicity was observed in the 7.5 mg/kg group as evidenced by decreased weight gain and food consumption early in gestation. No evidence of embryotoxicity or teratogenicity was observed in rats.

In conclusion, oral administration of the test substance during organogenesis was not teratogenic in rats at dose levels as high as 7.5 mg/kg/day.