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Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study, to GLP

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006
Reference Type:
secondary source
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Alkanes, C14-17, chloro
EC Number:
287-477-0
EC Name:
Alkanes, C14-17, chloro
Cas Number:
85535-85-9
Molecular formula:
Substance is a range of chlorinated isomers of C14 to C17 paraffin
IUPAC Name:
Alkanes, C14-17, chloro
Details on test material:
- Name of test material (as cited in study report): Cereclor S52
- Substance type: technical product
- Physical state: clear slightly yellow viscous liquid
- Analytical purity: 100%
- Composition of test material, percentage of components: C14-17 chlorinated n-alkane, 52% chlorinated
- Purity test date: no data
- Impurities (identity and concentrations): none
- Lot/batch No.: 1883/2
- Expiration date of the lot/batch: May 2006
- Stability under test conditions: storage life 2 years below 40oC
- Storage condition of test material: -20oC protected from light

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Charles River, Margate, Kent UK- Age at study initiation: (P) 9-10 weeks- Weight at study initiation: (P) males 311-362 g; females 218-256 g- Fasting period before study: no- Housing: pre-mating, males after mating - stainless steel; mating, females during gestation, littering and lactation - polypropylene- Diet (e.g. ad libitum): SDS VRF1 powdered ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 19-23- Air changes (per hr): filtered air, no recirculation- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 2005-11-21 To: 2006-02-05

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION- Rate of preparation of diet (frequency): weekly- Mixing appropriate amounts with (Type of food): SDS VRS1- Storage temperature of food: ambient temperature
Details on mating procedure:
- M/F ratio per cage: 1: 1- Length of cohabitation: up to 2 weeks- Proof of pregnancy: vaginal plug / sperm in vaginal smear; referred to as day 0 of pregnancy- After successful mating each pregnant female was caged (how): singly in solid-bottom polypropylene cage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC analysis with electron capture detection (ECD) following acetonitrile extraction.
Duration of treatment / exposure:
Males - 9 weeks; females approx 11-12 weeks (PND 21)
Frequency of treatment:
Continuous in diet
Details on study schedule:
F0 males and females maintained on diets for 4 weeks prior to pairing, during pairing, gestation and lactation until termination. Males killed on day 4 of lactation and females on day 21 of lactation.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:0, 21, 44 and 84 mg/kg bw/dayBasis:actual ingestedMales - pre-pairing
Remarks:
Doses / Concentrations:0, 23, 47 and 99 mg/kg bw/day Basis:actual ingestedFemales pre-pairing
Remarks:
Doses / Concentrations:0, 25, 49 and 104 mg/kg bw/dayBasis:actual ingestedFemales - gestation
Remarks:
Doses / Concentrations:0, 64, 121 and 212 mg/kg bw/day Basis:actual ingestedFemales - during lactation
No. of animals per sex per dose:
12 with 5 extra in each control and top dose (1200 ppm) group
Control animals:
yes, plain diet
Details on study design:
no data
Positive control:
no

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: continuousDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: 2x dailyBODY WEIGHT: Yes - Time schedule for examinations: Males - weekly; Females - weekly until mating detected, then on days 0, 6, 13 and 20 after mating and on days 1, 4, 7, 14 and 21 of lactation. The F1 offspring were weighed on Days 1, 4, 7, 11, 14 and 21 of age.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Oestrous cyclicity (parental animals):
pre-coital interval assessed
Sperm parameters (parental animals):
no data
Litter observations:
Mortality and consequent changes in litter size monitored daily from days 1-21 of age.The sex ratio of each litter recorded on days 1, 4 and 21 of age.Individual offspring bodyweights recorded on days 1, 4, 7, 11, 14 and 21 of age.
Postmortem examinations (parental animals):
SACRIFICE- Male animals: All surviving animals at PND 4 - Maternal animals: All surviving animals at PND 21GROSS NECROPSY- Gross necropsy consisted of an internal examinations of all exposed organs including the cervical, thoracic, and abdominal viscera.- For F0 females, the numbers of implantation sites in each uterine horn was counted.HISTOPATHOLOGY / ORGAN WEIGHTSLivers were weighed and prepared for microscopic examination
Postmortem examinations (offspring):
SACRIFICE- The F1 offspring were sacrificed at day 21 of age. - The animals were subjected to a macroscopic postmortem examination and any abnormalities in position/size of organs noted- Liver weights were recorded- Blood samples were taken from one male and one female pup from the satellite groups at days 1, 2, 4, 8 and 12 and from all main groups at day 21
Statistics:
mean +/- standard deviation calculated where appropriate
Reproductive indices:
Percentage mating, conception rate and fertility index determined
Offspring viability indices:
Post implantation survival index, live birth index, viability index and lactation index calculated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

No effects related to treatment were seen on any of the parameters assessed.Gestation lengths of females at 300, 600 or 1200 ppm were within the expected range of 22-23 days and were considered to be unaffected by treatment.Females receiving 1200 ppm had marginally higher absolute and relative mean liver weights when compared with controls.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on fertility; C14-17 chlorinated paraffin (52% chlorinated)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

No effects related to treatment were seen in any of the parameters assessed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on survival and growth of offspring up to weaning; C14-17 chlorinated paraffin (52% chlorinated)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The dietary administration to male and female rats for 4 weeks before pairing, during mating, gestation and lactation of Cereclor S52 (a C14-17 n-alkane, 52% chlorinated), at levels up to 1200 ppm, had no adverse effects on reproduction and for pre- and post-natal survival, growth and development of the F1 offspring up to weaning and can be considered the no-observed-adverse-effect level (NOAEL) for these effects in this study.
Executive summary:

In a one-generation study conducted according to OECD (421) guidelines (and to GLP), groups of twelve F0 male and twelve female CD-strain rats were maintained on a diet containing 0, 300, 600 or 1200 ppm Cereclor S52 (a C14-17 chlorinated paraffin; 52% chlorinated) for 4 weeks before pairing, and throughout pairing, gestation and lactation until termination. F0 males were terminated after nine weeks of treatment, whilst F0 females were allowed to litter and rear their offspring and were killed on Day 21 of lactation. Additional groups of control and top dose F0 animals (5/group) were included to furnish blood, liver and milk samples for further analysis. The calculated intakes of Cereclor S52 during the various stages of the study were: F0 males pre-pairing 0, 21, 44 and 84 mg/kg bw/day; F0 females pre-pairing 0, 23, 47 and 99 mg/kg bw/day; F0 females during gestation 0, 25, 49 and 104 mg/kg bw/day and F0 females during lactation 0, 64, 121 and 212 mg/kg bw/day for the control, 300, 600 and 1200 ppm dose groups, respectively.

There were no adverse effects of treatment on the clinical condition, body weight gain or food intake of F0 males and females prior to pairing or, for F0 females during gestation and lactation. Oestrous cycles, mating performance, pre-coital interval, fertility and gestation lengths were unaffected by treatment. However, F0 females receiving 1200 ppm had marginally higher absolute and relative mean liver weights compared with controls.

The number of implantations and subsequent litter size, sex ratio and offspring survival were unaffected by treatment, as were the clinical condition of the male and female offspring and offspring body weights, body weight gains to weaning, macropathology findings, and liver weights.

Therefore, the no-observed-adverse-effect level (NOAEL) for reproduction and for post-natal offspring mortality, growth and development to weaning in this study was 1200 ppm, equivalent to a parental intake of Cereclor S52 of approximately 100 mg/kg bw/day prior to birth, and (for dams only) 212 mg/kg bw/day during lactation.