2-Propenoic acid, γ-ω-perfluoro-C8-14-alkyl esters

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study is a scientific publication and well documented. The read across hypothesis is based on the assumption that due to its characteristic as ester, after ingestion in mammalians the ester bound of the target chemical will be subject to metabolic cleavage into its corresponding alcohols and the acrylic acid. Thus FTAC (target) and its associated alcohols (perfluoro-alkylethanol) n:2 FTOH mixture are considered to form not only a group of structurally related analogues, but are also closely related based on metabolic pathway considerations. For details see section 13 of this IUCLID document.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the reproductive and developmental toxicity of a fluoroalkylethanol mixture

Author:

Mylchreest, E., Ladics, G.S., Munley, S.M., Buck, R.C., and Stadler, J.C.

Year:

2005

Bibliographic source:

Drug Chem. Toxicol. 28 (2005): 159-175

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

fluoroalkylethanol mixture

IUPAC Name:

fluoroalkylethanol mixture

Constituent 2

Reference substance name:

65530-60-1

EC Number:

613-814-1

Cas Number:

65530-60-1

IUPAC Name:

65530-60-1

Test material form:

other: medium tan waxy solid

Details on test material:

- The fluoroalkylethanol [also known as fluorotelomer alcohol, F(CF2CF2)nCH2CH20H, n = 3 to 6] mixture (CAS no. 65530-60-1) as commercially produced was supplied as a pale to medium tan waxy solid by DuPont Chemical Solutions Enterprise (Deepwater, NJ, USA).
- The purity of the test substance was 95%.
- The test substance contained 2% residual fluoroalkylethyl iodide [F(CF2CF2)nCH2CH2I, n =3 to 6], which is the chemical precursor to the fluorotelomer alcohol.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Nulliparous, time-mated females were received from Charles River Breeding Laboratories. The rats were 63 days old upon receipt and were at
either GD 1, 2, or 3. Body weights recorded on the day that evidence of copulation was observed (GD 0) were provided by the vendor and ranged from 226 to 260 g. The rats were housed individually in wire-mesh cages throughout the developmental toxicity study. Animal rooms were maintained on a timer-controlled, 12-hour light/12hour dark cycle (fluorescent light). Environmental conditions of the rooms were targeted to be within a temperature range of 22 ± 3°C and a relative humidity range of 50 ± 20%. Tap water and PMI Nutrition International, Inc., Certified Rodent LabDiet 5002 were available ad libitum.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous methylcellulose

Details on exposure:

Formulated suspensions of the test substance in 0.5% aqueous methylcellulose were prepared daily and were administered at a volume of 10 mL/kg throughout the study.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Nulliparous, time-mated females were received from Charles River Breeding Laboratories. The rats were 63 days old upon receipt and were at
either GD 1, 2, or 3. Rats were assigned to lots according to their gestation day and then randomized within their respective lots on the basis of GD 0 body weights. They were assigned either to the control or to an experimental group by random sampling from a ranked list, so that means and standard deviations were similar across dose groups.

Duration of treatment / exposure:

treatment on gestation days 6 to 20.

Frequency of treatment:

daily treatment on gestation days 6 to 20.

Duration of test:

gestation days 4 to 21.

Doses / concentrations

Remarks:

Doses / Concentrations:
50, 200 and 500 mg/kg bw/d
Basis:
nominal conc.

No. of animals per sex per dose:

22 mated and pregnant females/group

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Body weights were recorded daily during the intubation period (GD 6-20) and on the day of sacrifice (GD 21). Clinical signs were recorded daily in the morning for each animal on study. Afternoon clinical observations were recorded during the intubation period (GD 6-20).

Ovaries and uterine content:

All dams were sacrificed on GD 21 and examined grossly for external and internal alterations. The gravid uteri were removed and weighed to permit calculation of the final maternal body weight adjusted for the weight of the uterine contents. The fetuses were removed from each uterus and individually identified.

Fetal examinations:

Each fetus was weighed, sexed, and examined for external alterations.
- Approximately half of the fetuses were subjected to fresh visceral (Staples, 1974) and fixed head (Barrow and Taylor, 1969) examinations.
- All fetuses were examined for skeletal alterations.
- Stages of renal papillary development were determined as described by Woo and Hoar (1972)

Statistics:

Sequential trend tests were applied until no dose response was detected (Selwyn, 1995). Continuous data (maternal body weight, weight change, and feed consumption) were analyzed using a linear contrast of means from analysis of variance (ANOVA) (Snedecor and Cochran, 1967). For litter count data and fetal alteration data, Jonckheere's test was applied in a sequential fashion (Jonckheere, 1954).
Where litter effects (pup/fetal weight, sex ratio) must be considered, a linear contrast of least square means from ANCOVA was sequentially applied; litter size and sex ratio were considered covariates for pup/fetal weight analyses, and litter size was considered a covariate for sex ratio analysis (Dempster et al., 1984).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: reduced body weigth were observed at the 500 mg/kg/bw/d group

Details on maternal toxic effects:
Reduced body weigth and increased perineal fur staining were observed at the 500 mg/kg/bw/d group.

Effect levels (maternal animals)

1

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: increased fetal skeletal alterations (variations but no malformations) were observed at 500 mg/kg/d

Details on embryotoxic / teratogenic effects:
Increased fetal skeletal alterations (variations but no malformations) were observed at 500 mg/kg/d

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Exposure of pregnant rats to the test substance at levels of 0, 50, 200, or 500 mg/kg/day did not produce any test substance-related mortality neither in maternal rats nor in the pups.

Evidence of maternal and developmental toxicity was detected at 500 mg/kg/day (Table 1). At 500 mg/kg/ day, there were reductions in mean absolute and adjusted final body weights (about 5 %) and weight gain (about 15 %) (calculated for the entire intubation period: GD 6 through 21). The reduced weight gains were most pronounced during the first week of intubation. There were also increased occurrences of perineal fur staining at 500 mg/kg/day; 9 of 22 animals from this level were affected at some point during the study.

With regard to developmental toxicity, there were increased incidences of fetal skeletal alterations (delayed skull and pelvic bone ossification and wavy ribs) accompanied by a slight decrease in mean fetal weight (about 3%). At 200 and 500 mg/kg/day, there were some instances in the data where effects occurred that were considered test substance-related.

At 200 mg/kg/day, maternal weight gains were reduced early in the treatment period; however, the magnitude of the reductions was small and transient, because the reduced gains had no appreciable impact on final body weight. Similarly, feed consumption was reduced at the beginning of treatment at both the 200 and 500 mg/kg/day doses. These reductions were not considered adverse because they were transient and had no appreciable impact on overall feed consumption.

Mean fetal weight was slightly reduced at 200 and 500 mg/kg/day; however, the magnitude of the reduction was minimal (3% lower than for controls) and thus was not considered adverse. The significant increase in the incidence of retarded skull bone ossification at 200 mg/kg/day was not considered test substance-related because it was within the relevant historical control range, and the statistical significance appeared to be the result of a relatively low value for the concurrent control group. There were no test substance-related effects observed at 50 mg/kg/day.

Table 1:              Summary of maternal toxicity and reproductive outcome

	Dose (mg/kg bw/d)
	0	50	200	500
Maternal Toxicity endpoints^a
Clinical observation	—	—	—	Increased perineal staining
Absolute final body weight	416.8 (27.86)^b	415.9 (23.54)	407.5 (28.74)	399.4 (28.51)*
Net final body weight^C	319.0 (19.75)	315.3 (17.44)	310.9 (21.05)	303.4 (18.99)*
Dosing period weight gain	156.7 (22.42)	151.4 (15.78)	143.2 (21.08)*	133.1 (27.54)*
Net dosing period weight gain^C	58.9 (14.88)	50.8 (12.39)	46.6 (15.74)*	37.1 (18.48)*
Dosing period food consumption	26.6 (4.71)	25.9 (2.67)	24.9 (2.13)	25.4 (1.91)
Reproductive outcome and litter data
No. mated	22	22	22	22
No. pregnant	22	22	22	22
Means per litter
Corpra lutea	16.7 (1.93)	16.6 (2.32)	16.6 (3.02)	15.8 (1.77)
Implantations	14.2 (1.31)	14.8 (1.82)	14.2 (2.29)	14.4 (1.81)
Resorptions (combined)	0.4 (0.58)	0.4 (0.59)	0.2 (0.39)	0.4 (0.91)
-        Early resorptions	0.4 (0.58)	0.3 (0.57)	0.2 (0.39)	0.4 (0.91)
-        Late resorptions	0	0.1 (0.29)	0	0
Dead fetuses	0	0	0	0
Live fetuses	13.9 (1.49)	14.4 (1.71)	14.0 (2.44)	14.0(2.24)
Sex ration (% males)	45	45	49	46
Fetal weight (g)	5.53 (0.30)	5.52 (0.26)	5.36 (0.20)	5.38 (0.44)*

^a: AII weights are in grams (body weight and weight gain) or grams/day (food consumption).

^b: Mean (standard deviation)

^C: Products of conception excluded from maternal body weight

*:Statistically significant trend (p < 0.05) by linear contrast of means from ANOVA.

**:Statistically significant trend (p < 0.05) by linear contrast least square means from ANCOVA (litter size and sex ratio covariates).

Applicant's summary and conclusion

Executive summary:

In order to evaluate the pre-natal developmental toxicity of the mixed fluorotelomer alcohol, groups of time-mated Sprague-Dawley female rats were administered the test substance by oral gavage in 0.5% methylcellulose as vehicle at daily dosages of 0, 50, 200, or 500 mg/kg/d on gestation days 6-20. In the developmental toxicity study, reduced maternal body weight parameters, increased perianal fur staining and increased fetal skeletal alterations (variations but no malformations) were observed at 500 mg/kg/d. There was no maternal or developmental toxicity at 50 or 200 mg/kg/d. Minimal fetal weight reduction in the 500 mg/kg/d group were considered secondary to maternal toxicity. Thus, the no-observed-adverse effect level (NOAEL) for maternal and developmental toxicity was considered to be 200 mg/kg/d.