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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
other: Data sharing dispute
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
yes see "Principles of method if other than guideline"
Principles of method if other than guideline:
1. Manager of the Toxicology and Applied Pharmacology Department changed
2. The relative humidity in the animal room exceeded 70% for short periods and reached a maximum
of 88.7%
3. On 14 September 2006, temperature in the hight concentration exposure chamber was 24.1C
during the last minute of the exposure period.
4. Four instead of 3 rodent tube sections were used for goups A and D
5. Calculation of the pre-implantation loss was not described in the study plan
These deviations are considered not to have affected the validity of the study.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld Germany
- Age at study initiation: 9 -10 weeks
- Housing:- Diet (e.g. ad libitum): During acclimitization, pre-mating, animals were group housed in groups of hour animals. During mating, one male and one female were housed together. Mated
females were individually housed. Post-mating, males were group housed in groups of 4. Feed was provided ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 plus/minus 2 C
- Humidity (%): 40 - 70 %
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From: 23 August 2006 To: 9 October 2006

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
nose only
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The inhalation equipment was designed to expose rates to a continuous supply of fresh test atmosphere. Vapors of the test material for each test atmosphere were generated by pa ssing a flow of approximately 5 L/min air through U-tube evaporators in which a flow fo test material was injected using a peristaltic pump (Watson and Marlow, type 502S). The evaporators were pla ced in a temperature controlled bath, held at 29C . The flows of air were diverted from the mass flow controlled and humidified mainstream for each exposure chamber and after passage through the ev aporator reunited with the mainstream. The water container used form humidification of the mainstr eam was kept at a constant temperature of ca. 19.5 C. Each unit consists of a cylindrical column with a column of ca. 50 L, surrounded by a transparent hood. The test atmosphere was introduced at the top of the central column, and was exhausted at the bottom. For exposure to the animals of group B and C, each column included three rodent tube section of 20 ports each, for exposure of the animals of groups A and D four rodent tubes were necessary.
- Source and rate of air: 70, 51, 51 and 70 L/min for gourps A, B, C and D
- Method of holding animals in test chamber:Tubes
Details on mating procedure:
- M/F ratio per cage: one male per one female
- Length of cohabitation: 4 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test atmosphere was analyzed using a Total Carbon Analyzer. Readings were taken every minute duiring the exposure periods.
Duration of treatment / exposure:
Animals were dosed for 6 hours per day for the first 2 weeks for 5 days/week. Then the animals were exposed for 7 days/week during mating and female animals were exposed until gestation day 19. Male animals were exposed for 4 weeks and then sacrificed. Female animals were allowed to litter and were sacrificed at or shortly after lactation day 4.
Frequency of treatment:
Animals were dosed for 6 hours per day for the first 2 weeks for 5 days/week. Then the animals were exposed for 7 days/week during mating and female animals were exposed until gestation day 19. Male animals were exposed for 4 weeks and then sacrificed. Female animals were allowed to litter
and were sacrificed at or shortly after lactation day 4.
Doses / concentrations
Remarks:
See "Any other information on materials and methods including tables"
No. of animals per sex per dose:
12
Control animals:
yes
Details on study design:
- Frequency of observations and weighing: Observed daily and weighed weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology,

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: Daily observation

BODY WEIGHT:
- Time schedule for examinations: Weekly
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations: testis weight, epididymis weight
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: [number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies,
weight gain,

GROSS EXAMINATION OF DEAD PUPS: No
Reproductive indices:
Fertility and fecundity indices

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): Daily clinical observations did not reveal any test substance related effects. One animal was found dead after the second exposure. The test report states that the cause was most likely suffocation.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): A significant difference (decrease) in body weight change was seen in the mid dose (1000 ppm) males for week 3-4. No significant difference in mean body weights was seen in the males. For the females, body weights and body weight changes were comparable for the control and test substance treated animals.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS) REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS) All females except 1 animal in the 300 ppm group were mated within 4 days. Precoital time was comparable for all groups. The female fecundity index and the female fertility index were 100% in all groups.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): The male fertility index was 100% in all groups.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS) Mating index was 100% for all groups.

ORGAN WEIGHTS (PARENTAL ANIMALS): No statistical differences were found between the contr ol group and exposed groups in absolute and relative weights of the testes and epididymides.

GROSS PATHOLOGY (PARENTAL ANIMALS) Gross examination at necropsy did not show any exposure related findings.

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
>= 3 000 ppm
Sex:
male/female
Basis for effect level:
other: see Remark

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

VIABILITY (OFFSPRING) Number of litters with live born pup was 10, 10 10 and 12 for the control, 300, 1000 and 3000 ppm groups.

CLINICAL SIGNS (OFFSPRING) No clinical signs in the pups were noted.

BODY WEIGHT (OFFSPRING) Pup weight on PN 1 and weight change on PN 4 were comparable for all groups.

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
F1
Effect level:
0 ppm
Sex:
not specified
Basis for effect level:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEC for Reproductive Toxicity equals 3000 ppm
Executive summary:

Groups of 12 males and 12 females were exposed via inhalation to concentrations of 0, 300, 1000 and 3000 ppm for 6 hours per day during the first 2 weeks for 5 days per week, Thereafter, the animals were exposed until gestation day 19. Male animals were exposed for 4 weeks and then sacrificed. Females were allowed to litter and were sacrificed at or shortly after day 4 of lactation. No treatment related mortalities were seen. Body weights were comparable between the control and exposed animals during premating, gestation and lactation. Food consumption was comparable between the control and exposed animals. All females of the control and exposed groups, except one animal in the low dose group, became pregnant within 4 days. No treatment related effects were seen in any of the reproduction parameters. The number of litters with live born pups was 10, 10, 10 and 12 for the control 300, 1000 and 3000 ppm groups. The number of pups delivered and the number of pups alive on PN 4 were comparable in all groups. Pup weights on PN 1 and PN 4 were comparable in all groups. No treatment related observations were recorded. There were no treatment related differences observed between the control and exposed animals in absolute and relative testes and epididymides weights. No gross changes were noted at necropsy. The NOAEC by inhalation for parental toxicity, fertility, and developmental toxicity was at least 3000 ppm.