N-(1,1-dimethylethyl)bis(2-benzothiazolesulfen)amide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study, basic data given (abstract and tables)

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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 5% gum arabic

Details on mating procedure:

No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males 42 days, females 38 days (from 14 days prior to mating to day 3 of lactation)

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw and day
Basis:

No. of animals per sex per dose:

13 per dose and sex

Control animals:

yes

Dose descriptor:

NOAEL

Effect level:

ca. 40 mg/kg bw/day

Sex:

female

Basis for effect level:

other: no effects

Dose descriptor:

LOAEL

Effect level:

ca. 200 mg/kg bw/day

Sex:

female

Basis for effect level:

other: slight histopathological changes in kidney and in the liver

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day

Sex:

female

Basis for effect level:

other: no biologically relevant effects

Remarks on result:

other: Generation: fertility

Remarks on result:

other: no further infomation available

Reproductive effects observed:

not specified

Maternal toxicity:

40 mg/kg bw and day

no effects

200 mg/kg bw and day

temporary salivation after each administration at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed slight increase in the relative kidney weights slight hypertrophy of hepatocytes in the central zone

1000 mg/kg bw and day

temporary salivation after each administration food consumption was decreased prior mating and along with slight suppressiomn of body weight gain during pregnancy at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed slight increase in the relative kidney weights slight hypertrophy of hepatocytes in the central zone increase in relative liver weights deposition of brown pigment in the spleen (tended to increase but in many cases comparable to control group)

Fertility:

40 mg/kg bw/d:

No effects on copulation and ovulation, no dose-related abnormalities with regard to parturition and lactation Fertility index was lower than control level; however the low index observed seemed to be an accidental finding because all females in the

200 mg/kg bw/d group were found to be fertile, thus the authors concluded that this decreased is not biologically relevant

200 mg/kg bw/d:

No effects on copulation and ovulation, no dose-related abnormalities with regard to parturition and lactation no effects on fertility index

1000 mg/kg bw/d: No effects on copulation and ovulation, no dose-related abnormalities with regard to parturition and lactation Fertility indice was lower than control level, however, the relvance of this finding is questionable. This decrease was not reflected by other fertility parameter like the number of corpora lutea, number of implantation sites and implantation index (see table). The values noted at 1000 mg/kg bw and day were all within the variation range of the current negative control and were not statistically significant. Moreover, the decrease of the fertility index noted was not dose-dependent. No test substance-related adverse effects on the reproductive organs were indicated in the 90 day toxicity study (Monsanto Co 1985). Fetal: No adverse effects on viability, the sex ratio and body weights of pups in any of the treated animals. TBBS at the dose levels applied did not demonstrate teratogenicity

Summary of reproductive performance in parental rats

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There are 3 studies available that assess the effects of the read across substance TBBS on fertility.

 

The first study is a repeated dose study in which extra attention was given to the histology of the reproduction organs (Monsanto Co., 1985). This study showed no test substance-related adverse effects on the reproductive organs after a 90 day exposure period to dose levels of 100, 300 and 1000 mg/kg bw.d.

 

The second study is a combined repeat dose and reproductive/developmental toxicity screening study (MHWJ 1997), in which Sprague-Dawley rats were administered 40, 200 or 1000 mg/kg bw.d for 42 (males) or 38 (females) days.

Maternal toxicity was revealed by slight histopathological changes in the kidney and in the liver at 200 mg/kg bw and day and higher and a decrease of food consumption and body weight gain in treated females at 1000 mg/kg bw and day. A decrease in the fertility index was documented at 40 and 1000 mg/kg bw and day. This decrease noted was not dose-dependent as the effect could not be seen in animals dosed with 200 mg/kg bw.day, and was not supported by other parameter of fertility. It therefore seemed to be an accidental finding and the biological relevance of the decreased fertility index observed is questionable.

 

In the third study, Sprague-Dawley female rats were dosed with 50, 150 and 500 mg/kg bw.d from day 6 until day 15 of gestation. The Cesarian section observations revealed no biologically meaningful differences in the numbers of post-implantation loss, early resorptions, mean fetal body weight or fetal sex distribution compared to the control. A slight decrease in the mean numbers of corpora lutea, total implantations and the mean number of viable foetuses was noted in all three treatment groups, but these findings were not considered to be biologically meaningful as the values were comparable to the historical control value.

 

Overall, a NOAEL for fertility of 1000 mg/kg bw and day was suggested.

Justification for read-across:

TBSI and TBBS have common breakdown products (MBT and conjugates) via physical and biological processes. TBBS and MBT are therefore considered to be adequate source chemicals for target chemical TBSI. The read-across justification for TBSI was separately documented and attached to the dossier under Section 13.

Short description of key information:
The studies available on the read-across substance TBBS showed no test substance-related adverse effects on the reproductive organs and no biologically meaningful differences in fertility indicators such as post-implantation loss, early resorptions, mean fetal body weight et cetera.
A slight decrease in fertility index was noted, but this was considered to be an accidental finding as this effect was not dose dependent.

Justification for selection of Effect on fertility via oral route:
Most adequate endpoint

Effects on developmental toxicity

Description of key information

The studies available on the read-across substance TBBS showed no biologically meaningful differences in total numbers of fetuses or litters with malformations.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, comparable to guideline study with acceptable restrictions (purity of test substance not indicated)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

M/F ratio per cage: 1:1

Duration of treatment / exposure:

days 6-15 of gestation

Frequency of treatment:

daily

Duration of test:

days 6 tot 20 of gestation

No. of animals per sex per dose:

25 animals per dose

Control animals:

yes

Details on study design:

Sex: female

Dose descriptor:

NOAEL

Effect level:

ca. 500 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 500 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Clinical signs and mortality: No mortality occured in any of the treated animals 50 and 150 mg/kg bw/d: no biologically meaningfuldifferences in appearance or behavior in rats when compared to the control group Matting of the ventral or anogenital haircoat was noted in all four dosage groups with the greatest incidence occuring in rats in the 500 mg/kg bw/d dose group (4, 1, 2 and 10 respectively).A post-dose response of reduced activity was noted in two of these 10 rats of the highest dose group on gestation day 6 and 7. Incidentalfindings of hair loss and/or red matter on the nasal region were noted on several rats in the treated groups as well as the control group at various times during gestation

Necropsy observations at Cesarean section

control: 1/25 hydrometra

150 mg/kg bw/d: 1/25 ovarian cyst

500 mg/kg bw/d: 1/25 fibrinous pleuritis and congested lungs, 1/25 hydrometra, 1/25 ovarian cyst

Body weights

50 and 150 mg/kg bw/d: no biologically relevant differences compared to control 500 mg/kg bw/d: very slight decrease in mean maternal body weight gain (ca. 1 -2 %) during the treatment period. however, no differences were noted in comparing the corrected gestation day 20 body weights (gestation day 20 body weight minus uterus weight) of the treated groups to the control group

Cesarean section observations

50, 150, 500 mg/kg bw/d:no biologically meaningful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or fetal sex distribution compared to control Slight decrease were noted in the mean numbers of corpora lutea (4 %, 1%, 4 % at 50, 150 and 500 mg/kg bw/d, respectively)and total implantations in all three treatment groups (7 %, 6% amd 8 % at 50, 150 and 500 mg/kg bw/d). These decreases were attributed to random occurence as ovulation and implantation occur prior to treatment. A corresponding decrease in the mean numbers of viable fetuses in these groups was not considered biologically meaningful as the values were comparable to the historical control value.

Fetal morphological observations: 50, 150 and 500 mg/kg bw/d: no biologically meaningful differences in the total numbers of fetuses or litters with malformations compared to control A slight increase in the number of litters and fetuses with undeveloped renal papillae and/or distended ureters was noted in the three treated groups but was not considered biologically meaninful since this increase was within the range estabished in the historical control data. Renal papillae not developed and/or distended ureters:

control: fetuses: 3(1.7%), litters: 2( 8.3 %)

50 mg/kg bw/d:fetuses: 7(4.6 %), litters: 5( 22.7 %)

150 mg/kg bw/d:fetuses: 8(5.1 %), litters: 5( 21.7 %)

500 mg/kg bw/d:fetuses: 7(4.8 %), litters: 6( 27.3 %)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

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

Justification for selection of Effect on developmental toxicity: via oral route:
key study

Toxicity to reproduction: other studies

Additional information

There are 3 reliable studies available that give an insight in the developmental toxicity of the read across substance TBBS.

 

The key study assesses the developmental toxicity of TBBS (OECD TG 414). Pregnant Sprague-Dawley rats were used to determine the teratogenic potential of TBBS. Dosage levels of 0, 50, 150 and 500 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. Cesarean sections were performed on all surviving dams on gestation day 20. Increased matting of the ventral or anogenital haircoat and a very slight decrease in mean maternal body weight gain (ca. 1 to 2 %) was noted in the 500 mg/kg bw and day dosage group. Survival was 100 % in all groups. There were no other biologically meaningful differences in appearance or behaviour, maternal or foetal body weight, mean number of viable foetuses or post-implantation losses in any of the treatment groups when compared to the control group. In addition, there were no biologically relevant differences in the total numbers of foetuses or litters with malformation in any of the treatment groups when compared to the control group. A slight increase in the number of litters and foetuses with undeveloped renal papillae and/or distended ureters was noted in all three treatment groups but was not considered biologically relevant since this increase was within the range established in the historical control data (Monsanto 1981). Based on the findings of this study a NOAEL maternal/foetal of 500 mg/kg bw and day was suggested.

The two supporting studies corroborate with these findings.

Justification for read-across:

See above, as described for toxicity to reproduction.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (CLP).