2-Hydroxypropyl-β-cyclodextrine ethers

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

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

Principles of method if other than guideline:

HPbCD were administered orally before/during mating, and on gestation Day (GD) 0–7, followed by an assessment of embryonic development on GD 14.

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:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

For the rat fertility study, CRL:CDs[SD] female rats aged between 9 and 11 weeks of age at initiation of dosing and weighing between 279 and 355 g (males) and between 203 and 264 g (females) were obtained from Charles River Laboratories (Kingston, NY). Rats were uniquely identified by tattoo and were individually housed in suspended stainless steel wire-bottom cages. Rats were acclimated to laboratory conditions before initiation of dosing. Certified rodent Labdiet 5002 (PMI Nutrition International; Brentwood, MO) and reverse osmosis purified water was provided ad libitum. The room in which the animals were housed was maintained at 72741F, relative humidity 30–70%, and had a 12-h light/dark cycle.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Control or vehicle articles were administered once daily by oral gavage to females for 2 weeks before and during mating (up to 3 weeks) and on GD 0–7. Since there were no histopathological or organ weight changes in the reproductive organs in a previous 1-month general toxicology repeat dose rat study with these vehicle articles, the control and vehicle articles were administered once daily by oral gavage to males for 3 weeks before mating and during mating (up to 3 weeks) and for 3 weeks after mating.

Details on mating procedure:

During the initial mating phase, one male was housed with one female of the same group for up to 2 weeks. If there was no evidence of mating during this 2-week interval (sperm-positive vaginal smear or observation of a copulatory plug), the female was placed with a proven male from the same dose group for one additional week. Evidence of mating was designated as GD 0, and the male and female mating pair were separated. Therefore, the mating interval was completed within 3 weeks.

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)

Control animals:

yes, historical

Examinations

Oestrous cyclicity (parental animals):

Estrous cyclicity was assessed in all females for 2 weeks before initiation of dosing through the day of mating via vaginal smear, which was taken by lavage. The stages identified were proestrus (round or spindal shaped epithelial cells with granular cytoplasm and few leukocytes), estrus (mostly large cornified epithelial cells without a distinct nucleus), metestrus (cornified epithelial cells, round/spindle shaped epithelial cells and leukocytes), and diestrus (predominantly leukocytes and few epithelial cells). From the smear data, mean estrous cycle length was determined as the number of days from estrus to the next estrus or proestrus to the next proestrus.

Postmortem examinations (parental animals):

All females were euthanized on GD 14 by carbon dioxide (CO2) asphyxiation 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. Uterine implants were counted and classified as a live fetus, dead fetus, or resorption (early or late), and the total number per animal are presented. A gross examination of the thoracic and abdominal cavities was carried on all F0 females in all dose groups. All males were euthanized within 3 weeks after the completion of the mating phase and a gross examination of the thoracic and abdominal cavities and reproductive organs was carried on all F0 males in all dose groups.

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: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Effect levels (P0)

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 absence of adverse toxic effects

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test HP-beta-CD did not impair the fertility in rats.