2-Hydroxypropyl-β-cyclodextrine ethers

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2010

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Pregnant females were dosed during the period of organogenesis, followed by an assessment of fetal external, visceral,
and skeletal development.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

.beta.-Cyclodextrin, 2-hydroxypropyl cycloheptaamylose

IUPAC Name:

.beta.-Cyclodextrin, 2-hydroxypropyl cycloheptaamylose

Constituent 2

Reference substance name:

-

EC Number:

420-920-1

EC Name:

-

Cas Number:

128446-35-5

Molecular formula:

Hill formula: (C42H70-nO35)(C3H7O)n; n(mittel)=5,25

IUPAC Name:

5,10,15,25-tetrakis(hydroxymethyl)-40,44,47,49-tetrakis(2-hydroxypropoxy)-20,30,35-tris[(2-hydroxypropoxy)methyl]-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.2³,⁶.2⁸,¹¹.2¹³,¹⁶.2¹⁸,²¹.2²³,²⁶.2²⁸,³¹]nonatetracontane-36,37,38,39,41,42,43,45,46,48-decol

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): hydroxypropylated .beta.-cyclodextrin
- Physical state: White powder
- Analytical purity: >95%
- Lot/batch No.: 74B008
- Expiration date of the lot/batch: 31 December 2002
- Stability in water: At least 96 h
- Stability under storage conditions: Stable
- Storage condition of test material: At room temperature in the dark

Specific details on test material used for the study:

Cargill, Cedar Rapids, IA

Test animals

Species:

rabbit

Strain:

other: HRA:[NZW]SPF

Details on test animals or test system and environmental conditions:

Timed-mated HRA:[NZW]SPF rabbits aged between 5 and 6 months of age at initiation of dosing and weighing between 2.7 and 3.8 kg were obtained from Covance Research Products (Denver, PA). The female rabbits were mated at the supplier and the day of mating was designated GD 0. Rabbits were uniquely identified by tattoo and ear tag and were individually housed in suspended injection-molded plastic cages. Rabbits were acclimated to laboratory conditions before initiation of dosing. Approximately 140 g of Certified high fiber rabbit diet 5325 (PMI Nutrition International) and 10g of Certified rabbit stix (Bio-Serv, Frenchtown, NJ) was offered daily and reverse osmosis purified water was provided ad libitum. The room in which the animals were housed was maintained at 61–721F, relative humidity 30–70%, and had a 12-h light/dark cycle. The use of animals in this study followed the guide- lines provided in the NRC Guide for the Care and Use of Laboratory Animals (1996) and the Animal Welfare Act. This study was approved by the facility’s Institutional Animal Care and Use Committee and was conducted in an Association for the Assessment and Accreditation of Laboratory Animal Care accredited facility.

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

Control or vehicle articles were administered once daily by oral gavage on GD 7–19 (N520 animals/group).

Analytical verification of doses or concentrations:

not specified

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

500 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20/group

Control animals:

yes, historical

Examinations

Maternal examinations:

Maternal body weights were recorded on GD 0, 7, 10, 13, 16, 19, 22, 25, and 29. Food consumption was visually estimated such that a value of 0 indicated that the rabbit ate 0–19% of food offered; a value of 1 indicated that the rabbit ate 20–79% of food offered; a value of 2 indicated that the rabbit ate 80–100% of food offered. Food consumption was visually estimated daily from 2 days after arrival (GD 1 to 5) through GD 29. All females were observed once daily for physical signs of toxicity on the day of arrival through the day of necropsy on GD 29. During the dosing interval (GD 7–19), females were also observed 1–3 h after dosing. Females were euthanized on GD 29 by an intravenous injection of Beuthanasia-D-Special (Schering-Plough) and the uterus of each female was examined to determine pregnancy status. Corpora lutea were counted and recorded as left and right and the total number per female are presented. A gross examination of the thoracic and abdominal cavities was performed on all F0 females in all dose groups.

Ovaries and uterine content:

Uterine implants were counted and each was classified as a live fetus, dead fetus, or resorption (early or late), and the total number per animal are presented. Placental morphology was evaluated by gross evaluation.

Fetal examinations:

All fetuses were weighed and examined externally. After external examination, each fetus was euthanized by intraperitoneal injection of Beuthanasia-D-Special (Schering- Plough). The heads of all fetuses were examined after fresh, free-hand coronal sectioning, and a fresh visceral examination was performed on all fetuses using a modified Staples’ technique (Stuckhardt and Poppe, 1984). The gender of each fetus was determined by visceral examination of the gonads. All fetuses were subsequently fixed in 95% ethanol and stained with alizarin red for skeletal examination. Fetal observations were recorded in general accordance with internationally developed terminology (Wise et al., 1997).

Statistics:

The adult animal or litter was considered as the experimental unit and was evaluated by identifying biologically significant changes and/or using comparative statistical methods. Descriptive statistics are presented as the mean7 standard deviation (SD), unless otherwise noted. Continuous variables including body weight gain, food consumption, number of corpora lutea, and number of implantation sites were analyzed using a one-way analysis of variance (Scheffe, 1959). If these analyses revealed significant differences, pairwise comparisons were performed using Dunnett’s test (Miller, 1981). Noncontinuous variables including % pre-implantation loss, % post-implantation loss, % affected fetuses per litter for total external, visceral and skeletal malformations were analyzed using a Kruskal–Wallis non-parametric analysis of variance (Kruskal and Wallis, 1952). If these analyses revealed significant differences, pairwise comparisons were performed using Dunn’s test (Dunn, 1964). A probability value of Pr0.05 was considered statistically significant.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In the rabbit teratology study, both the 500 and 1,000 mg/kg HPbCD groups exhibited stool findings (loose and/or scant stool) and concomitant effects on food consumption and body weight, when compared with MC. Owing to this excessive maternal toxicity, four rabbits in the 500 mg/kg and three rabbits in the 1,000 mg/kg HPbCD groups were euthanized for humane reasons on GD 16–20. In addition to these mortalities described above, one additional rabbit each in the 500 and 1,000 mg/kg HPbCD groups was euthanized because of abortion, which was attributed to maternal toxicity (scant stool, decreased food consumption, and body weight loss).

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Individual rabbits in the 500 and 1,000 mg/kg HPbCD groups exhibited decreases in body weight gain during GD 7–19, when compared with MC (data not shown). This finding correlated with decreased food consumption and stool findings. During the post-dosing interval, mean body weights and food consumption in these HPbCD groups exhibited evidence of recovery and were comparable to the MC group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

effects observed, non-treatment-related

Description (incidence and severity):

In the rabbit teratology study, two rabbits in the 1,000mg/kg HPbCD group exhibited enlarged gallbladders (data not shown), and one of these two rabbits had aborted.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Number of abortions:

effects observed, treatment-related

Description (incidence and severity):

Due to maternal toxicity as described above.

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:

no effects observed

Changes in number of pregnant:

no effects observed

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

< 500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

other: effects on the digestive tract

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test HP-beta-CD did not show embryonal toxicity or teratogenic effects in rats.