Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: several fertility parameters added to 90-d study
Type of information:
other: publication
Adequacy of study:
supporting study
Study period:
1987
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: The publication contains only a minor reference to 13 weeks studies in rat and mice.
Reason / purpose for cross-reference:
reference to other study
Reproductive effects observed:
not specified
Conclusions:
Based upon the provided information, no conclusion can be drawn.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Short description of key information:
In accordance with column 1 of REACH Annex IX, the 2-generation reproductive toxicity study (as required in section 8.7.3.) does not need to be conducted as the data from the available repeated dose toxicity studies do not indicate adverse effects on reproductive organs or tissues. Additionally, exposure of this substance to humans is expected to be limited.

Justification for selection of Effect on fertility via oral route:
Only one study is available (Klimisch 4). No NOAEL value is indicated.

Effects on developmental toxicity

Description of key information
In the key study pregnant rats received 485 mg/kg bw/ day of 4,4'-thiobis (6-t-butyl-m-cresol) for 10 days during gestation which caused increases in maternal mortality and a decreased percent of pup survival while not affecting the number of viable litters, the litter size, birth weight or weight gain of the pups. As only one dose was tested the LOAEL is <= 485 mg/kg bw/d for maternal and developmental toxicity. 
In a supporting study rabbits received up to 20 mg/kg bw/d during pregnancy. No significant increase in fetal abnormalities was noted. Maternal weight gain was retarded, leading to increased incidence of abortion in high-dose animals.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The evaluation of the study is hampered by lacking information concerning the Guidelines for testing and the purity of the tested substance; further the study is well documented and performed.
Qualifier:
no guideline followed
Principles of method if other than guideline:
screening test
In Phase I and II the LD10 is determined. In Phase III pregnant female mice were administered the test substance during gestation for 10 days (gestation day 6-15). Effects on litter and parental animals were recorded.
GLP compliance:
yes
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
sex: female

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: 6-8 wks
- Housing: individually polycarbonate shoe box
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -24
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Extracted by acetonitrile and analyzed by HPLC. Recovery in phase I: 80 - 105%; in phase II: 93 - 106%; in phase III: 76-96%.
Duration of treatment / exposure:
Phase I: 5 days
Phase II: 12 days
Phase III: gestation day 6-15
Frequency of treatment:
Phase I: once daily for 5 days
Phase II and III: once daily for 10 days
Remarks:
Doses / Concentrations:
10, 100, 1000 mg/kg bw/day
Basis:
actual ingested
Phase I
Remarks:
Doses / Concentrations:
0, 100, 310, 400, 500, and 630 mg/kg bw/day.
Basis:
actual ingested
Phase II repeated
Remarks:
Doses / Concentrations:
0, 485 mg/kg bw/day
Basis:
actual ingested
Phase III
No. of animals per sex per dose:
Phase I: three mice
Phase II: four mice
Phase III: 50 mice
Control animals:
yes, concurrent vehicle
Details on study design:
Other:
Phase I: range-finding study in non-pregnant mice dosing 5 days.
Phase II: because of the high mortality rate, a repeated Phase II was conducted with 100, 310, 400, 500, and 630 mg/kg bw/day, using pregnant mice dosing 10 days . Based on the mortality data, the predicted LD10 for 4,4'-thiobis(6-t-butyl-m-cresol) was 485 mg/kg bw/ day.
Phase III: 485 mg/kg bw/ day during 10 days.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: maternal moratlity and toxicity, twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: maternal body weights on days 6 - 15, 17 of gestation, and on day 0, 3 postpartum
Ovaries and uterine content:
no data
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring: number of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight when delivery was complete and on day 3.
Statistics:
An overall test for homogeneity of variance (Bartlett's test and F-test) was performed on the weight data of each group following randomization. Average body weight per group and average body weight change per group were calculated for treatment and control groups. Pro bit analysis of mortality and morbidity data generated in Phase II of the range finding study was used to determine the predicted LD10 for the Phase III.
Phase III maternal data:
- Random weights: ANOVA (2-tail) (all groups, pregnant dams) (all groups, viable litters only)
- Survival: Fisher's Exact Test (one-tail) (each group vs control, all dams) (each group vs control, pregnant only)
- Weight gains: Mann-Whitney U-Test (2-tail) (each animal, day 6 to day 0 postnatal) (each group vs control; viable litters only)
- Proportion of viable litters Fisher's Exact Test (one-tail) (each group vs control, pregnant only)
- Survival of pups Chi-Square Test (one-tail) (each group vs control)

The Mann-Whitney U-test (2-tail) was used to compare each group to the concurrent control.
- Number live pups/litter (day 0, day 3)
- Length of gestation
- Average pup weight (day 0, day 3)
- Average wt. gain/litter (day 3 - day 0)

The p-value listed is not corrected for multiple comparisons.
14
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: increased mortality

Details on maternal toxic effects:
4,4'-Thiobis (6-t-butyl-m-cresol) caused an increased maternal mortality.
Dose descriptor:
other: LD10
Effect level:
485 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: decreased survival

Details on embryotoxic / teratogenic effects:
4,4'-Thiobis (6-t-butyl-m-cresol) caused a decreased percent survival of the pups while having no effect on the
number of viable litters, the litter size, birth weight of the pups and weight gain of the pups.
Abnormalities:
not specified
Developmental effects observed:
not specified

Phase I:

4,4 1 -Thiobis (6-t-butyl-m-cresol) did not produce chemical related ·mortality when administered at

dose levels of 10, 100, and 1000 mg/kg/day. Therefore, the dose levels for the Phase II selected

were 600, 1200, 2400, 4800, and 9600 mg/kg/day.

Phase II: Because of the high mortality rate, a repeated Phase II was conducted with 100, 310,

400, 500, and 630 mg/kg bw/day. Based on the mortality data, the predicted LD10 for 4,4'-thiobis

(6-t-butyl-m-cresol) was 485 mg/kg bw/ day.

Conclusions:
In a screening study with female pregnant CD1 mice, the predicted median lethal dose for 4,4' -thiobis(6-t-butyl-m-cresol) was 485mg/kg/day. In
addition, 485 mg/kg bw/ day of 4,4'-thiobis (6-t-butyl-m-cresol) caused increases in rnaternal mortality and a decreased percent of pup survival while not affecting the number of viable litters, the litter size, birth weight or weight gain of the pups.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
485 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Study rated as Klimisch 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a screening study 4,4'-thiobis(6-tert-butyl-3-cresol) induced maternal toxicity in female Swiss mice upon oral administration of 485 mg/kg bw/day to pregnant mice on gestational days 6 -15. In addition, a decreased pup survival rate was reported, but 4,4'-thiobis(6-tert-butyl-3 -cresol) did not affect the number of viable litters, litter size, pup birth weight, or pup weight gain. In a supportive, development toxicity study with New Zealand White rabbits, no significant increase in fetal abnormalities was not noted upon treatment with 0.2, 2, 20 mg 4,4'-thiobis(6 -tert-butyl-3 -cresol) /kg/day during gestation. The only effect is retarded maternal weight gain due to maternal toxicity, leading to increased incidence of abortion in high-dose animals.


Justification for selection of Effect on developmental toxicity: via oral route:
Most reliable study (Klimisch 2).

Justification for classification or non-classification

Based on the studies available no classification is warranted.

Additional information