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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1989
Reference Type:
publication
Title:
Developmental toxicity study of 2-mercaptobenzothiazole|(MBT) in two species
Author:
Rodwell, D.E. et al
Year:
1990
Bibliographic source:
Teratology, p. 587 (abstract).

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: EPA regulation (TSCA) guidelines (40 CFR Part 798.4700, September 1985, and revised edition May 1987)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
MBT, purity: 98.1 to 98.5 %

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Artificial insemination:
Proven resident New Zealand White male rabbits, purchased from the same supplier, were used as the semen donors. Semen was collected from seven male rabbits, using an artificial vagina and evaluated for volume, motility, and concentration. Prior to insemination, the semen was diluted with 0.9% physiologic saline and maintained in a water bath at approximately 37°C during the insemination procedure. Approximately 0.5 ml of the diluted semen was introduced into the doe¿s vagina. Semen collected from one male on a given day was used to inseminate an equal number of females in each study group. Immediately following the insemination, the females were administered human chorionic gonadotropin, via the marginal ear vein. The day of insemination was considered day 0 of gestation.
Duration of treatment / exposure:
Day 6-18 of gestation
Frequency of treatment:
daily
Duration of test:
up to gestation day 29
No. of animals per sex per dose:
20 per dose
Control animals:
yes
Details on study design:
Sex: female
Duration of test: up to Day 29 of gestation

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Analytical Chemistry Evaluations

The HPLC analyses determined that MBT was stable in 1% aqueous methycellulose f or a period of 7 days. Dosage suspensions were found to be homogeneous at concentrations similar to the lowest and highest levels. Analyses for concentration of the test article in the dosage suspensions revealed a recovery of the test article within ± 10% of targeted concentration.

Animal survival and pregnancy status

No treatment-related deaths occurred during the conduct of this study. One doe in the 150 mg/kg/day group died on gestation day 13. Mottled lungs and yellow semi-solid contents in the trachea indicated that this death was a result of intubation error. A single incidence of abortion was noted in the 150 mg/kg/day group on gestation day 19. One doe in the 300 mg/kg/day group delivered prematurely on gestation day 29 before the scheduled cesarean section. Pregnancy percentages were 95, 90, 85, and 100 in the control, 50, 150, and 300 mg/kg/day groups, respectively.

Clinical observations

There were no treatment-induced clinical signs observed in this study. Incidental findings occurred in all groups and included primarily soft stools, or mucoid stools, reduced feces, urine or fecal staining, and loss of hair.

Body weights gains

Mean maternal body weights and net maternal body weight gain were comparable between the groups. There were no statistically significant differences observed when body weight changes were calculated for the specified intervals. Treatment-related body weight losses were evident however, during the last days of treatment (gestation days 15 -19); several does lost in excess of 150 grams; this pattern was also observed in the range finding study. This weight loss attributed to much of the reduced mean weight gains during the treatment period (gestation days 6 - 19 300 mg/kg bw/d group - 63 % vs. control).

Food intake

Food consumption, calculated as g/animal/day or g/kg/day was comparable between groups for the duration of the study.

Necropsy observations

There were no treatment-induced lesions noted in the MBT groups. Incidental findings included hydrothorax and umbilical hernia in the control group, mottled lungs and semi-solid material in the trachea in the 150 mg/kg/day group (the doe died on gestation day 13). Absolute and relative liver weights from gravid does were slightly, increased in the 300 mg/kg/day group (absolute liver weight: 107 %, rel. liver weight: 104% vs. control)

Cesarean section observations

Parameters measured at cesarean section, including gravid uterine weight, the number of viable fetuses, early and late resorptions, fetal sex ratio and fetal weights were similar in all groups.

Fetal morphologic observations

No statistically or biologically significant differences were noted between the control and MBT groups with regard to malformations or variations. The malformations that occurred in this study are commonly seen in rabbits. Morphological variations were similar and occurred with comparable frequency in the control and treated groups

In summary, the present study was conducted to evaluate maternal and developmental toxicity of MBT in New Zealand White rabbits. Dosage levels of 50, 150, and 300 mg/kg/day were selected based upon results of a range-finding study conducted also on New Zealand white rabbits (CMA 1989). Treatment-related deaths occurred in the range-finding study at levels of 600 mg/kg/day and higher, while dose-dependent body weight loss was evident in all treated groups (150, 300, 600, 1000, and 1500 mg/kg/day) during the treatment period. A dosage level of 600 mg/kg/day as the highest dosage level was considered excessive for a definitive teratology study due to the magnitude of body weight loss and induced mortality. Similarly, dosage levels greater than 300 mg/kg/day were also considered inappropriate due to an anticipated excessively high magnitude of body weight loss and possible mortality. Therefore, 300 mg/kg/day of MBT was selected as the highest dosage level knowing that two does out of five had severe body weight loss during the treatment period. A dosage level of 150 was expected to induce minimal maternal toxicity and a dosage level of 50 mg/kg/day was selected to determine a no effect level for maternal and developmental toxicity.

Oral administration of MBT to pregnant rabbits at a level of 300 mg/kg/day induced maternal toxicity as expressed by slightly reduced body weight gain during treatment and slightly elevated liver weight, absolute or relative to final body weight. This toxicity became apparent upon visual inspection of individual body weight gain data particularly during the last days of treatment (gestation days 15-19) for this group when compared to the control group. During this period, six treated does had body weight losses greater than 150 grams while no control dam lost this magnitude of body weight. Lower dosage levels of MBT (50 and 150 mg/kg/day) did not produce any evidence of maternal toxicity. A single abortion was noted in the 150 mg/kg/day group on gestation day 19 and a premature delivery occurred in the 300 mg/kg/day group on gestation day 29, prior to the scheduled cesarean section. A single incidence of abortion was noted in the range-finding study at levels of 600 and 1000 mg/kg/day. However, the biological and toxicological significance of the abortion and premature delivery in the present study is equivocal, knowing that: abortions or premature deliveries are common in rabbits; a dose-related pattern was not evident (in particular, the time of occurrence); abortions were not noted in the range-finding study at levels of 150 or 300 mg/kg/day (2). One rabbit in the 300 mg/kg/day group died on gestation day 13. Postmortem findings indicated that the death occurred following an intubation error (semi-solid yellow contents in trachea).

The administration of MBT during the critical period organogenesis at dose levels of 50, 150, or 300 mg/kg/day did not induce any developmental toxicity or teratogenicity, in that all fetal data, including viability, mean body weight, malformations, and variations were comparable between the MBT and control groups.

In conclusion, oral administration of 50, 150, or 300 mg/kg/day of

MBT to pregnant New Zealand White rabbits during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at a level of 300 mg/kg/day as slightly decreased body weight gain and slightly elevated liver weight.

Applicant's summary and conclusion