Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental 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: GLP and guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Isooctene
EC Number:
234-294-9
EC Name:
Isooctene
Cas Number:
11071-47-9
Molecular formula:
C8H16
IUPAC Name:
2-methylhept-1-ene
Details on test material:
Isooctene, purity: 99.9% (gas chromatography); 99.84 area% (gas chromatography)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH; Sandhofer Weg 7, 97633 Sulzfeld
- Age at study initiation: about 4 weeks
- Housing: During the period when the rats were not exposed they were housed singly in wire cages (type DK III, Becker & Co., Castrop-Rauxel, FRG
(floor area about 800 cm²)). Underneath the cages, waste trays were fixed containing bedding material (type 3/4 dust free embedding, supplied by
SSNIFF, Soest, FRG). The following exceptions were made:
1. For the overnight mating, the females were put into the cages of the males.
2. From day 18 p.c. until sacrifice, the dams and their litters were housed in Makrolon type M III cages (floor area about 800 cm2). The M III cages
were also supplied by BECKER & CO. Pregnant females were provided with nesting material (cellulose wadding) towards the end of pregnancy. The
motor activity measurements were conducted in Polycarbonate cages with wire covers from Ehret, Emmendingen, FRG (floor area about 800 cm²) and bedding. The room was completely disinfected using a disinfector ("AUTEX", fully automatic, formalinammonia-based terminal disinfector) before
the start of the study. Usually, each week the floor and the walls were cleaned with water containing about 1 % Mikroquat®.
- Diet (e.g. ad libitum): The animals were maintained on milled mouse/rat laboratory diet “GLP” (Provimi Kliba SA, Kaiseraugst, Basel Switzerland) ad
libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
During exposure and motor activity measurements food and water were withdrawn.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): relative humidity in the range of 30 - 70%
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): A light/dark rhythm of 12 hours was maintained:
• 06.00 a.m. - 06.00 p.m. light
• 06.00 p.m. - 06.00 a.m. dark
Deviations from these ranges did not occur.

IN-LIFE DATES: From: 13.06.2006 To: 10.10.2006

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
The mean cohabitation time (duration until sperm was detected (i.e. day 0 p.c.)) amounted to 2.8 days/2.8 days/2.0 days/3.0 days (0, 1, 5 and 15 g/m³). All sperm positive rats delivered pups with the following exceptions: one control female did not generate F1 pups nor had it implantations. One
low dose female did not generate F1 pups but had 1 implantation. Therefore, the fertility indices were 90% in the control group and 100% in all
exposed groups.The mean duration of gestation was comparable in all test groups. The gestation index was 100% in mid and high dose groups (5
and 15 g/m³), 89% in the control group (0 g/m³) and 90% in the low dose group (1 g/m³). The number of liveborn and stillborn pups was comparable between all test groups. Thus, the live birth index amounted to 100% in the mid dose group (5 g/m³), 99% in the high dose group (15 g/m³), 98% in
the control group (0 g/m³) and 96% in the low dose group (1 g/m³). The mean number of delivered F1 pups/dam and the rate of live- and stillborn F1 pups was not affected by the test substance. The observed differences did not show any relation to dosing and were without any biological
relevance. The total average of delivered F1 pups/dam was 10.7, 11.8, 11.1 and 11.3 pups/dam in test groups 0-3 (0, 1, 5 and 15 g/m³).
Duration of treatment / exposure:
The males were treated for approx. 13 weeks (10 weeks premating, 3 weeks mating and post mating). In females treatment was performed during
premating (10 weeks), mating and gestation through day 4 after delivery (approx. 15 weeks).
Frequency of treatment:
6 hours per day on 5 days per week
Details on study schedule:
After ten weeks of exposure, the parental animals were mated to produce a litter. Mating pairs were formed from the same concentration group. The parental animals were examined for their mating and reproductive performances. The pups were sexed and were weighed on the day after birth and on day 4 post partum. Their viability was recorded. All pups were underwent necropsy on day 4 post partum and were examined macroscopically for external and visceral findings.
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 5 and 15 g/m3
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: yes

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
1 000 mg/m³ air
Sex:
male/female
Basis for effect level:
other: male kidney (α2µ)

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
> 15 000 mg/m³ air
Sex:
male/female
Basis for effect level:
other: no influence on fertility and pre/postnatal development

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

15 g/m3 dose group

• Slight ataxia from study day 9 onward • Slight salivation during and after exposure from day 8 to day 42 • Slight salivation during exposure from study day 43 onward • Ataxia and salivation during exposure in all F0 females on gestation days 0 to 18 • Decreased body weight of the males -9% to -12.8% from study day 14 onward • Decreased body weight gain of the males -17.9% to 22.3% from study day 7 onward • Decreased food consumption on study day 7 (male -13.1 %, female -7.5 %) • Decreased food efficiency of the male animals on study day 7 (-11 %), 14 (-14 %), 28 (-26 %) and 35 (-19 %). • Increased γ-glutamyltransferase activity in both sexes • Increased globulin, cholesterol, potassium and calcium levels in both sexes • Decreased prothrombin time in both sexes • Increased alanine aminotransferase activity as well as increased platelet counts and bilirubin, total protein, albumin and magnesium levels in the males • Decreased glucose levels in the males • Increased triglyceride levels in the females • Decreased urea and creatinine levels in the females • Increased absolute liver weight (+24 %) in the males • Increased relative liver weight (+42 %) in the males • Increased absolute kidney weight (+19 %) in the males • Increased relative kidney weight (+35 %) in the males • Increased number of hyaline cast(s) in the kidney of the male animals • Basophilic tubules, in the kidney of the male animals • Increased protein storage (α-2u globulin) in the kidney of the male animals

5 g/m3 dose group

• Increased cholesterol levels in the rats of both sexes • Increased total protein, potassium and magnesium levels in the males • Decreased prothrombin time as well as decreased glucose levels in the males • Increased absolute liver weight (+12 %) in the males • Increased relative liver weight (+17%) in the males • Increased absolute kidney weight (+14 %) in the males • Increased relative kidney weight (+19 %) in the males • Increased number of hyaline cast(s) in the kidney of the male animals • Basophilic tubules, in the kidney of the male animals • Increased protein storage (α-2u globulin) in the kidney of the male animals

1 g/m3 dose group

• No observed adverse effect

Applicant's summary and conclusion