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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the teratogenic potential of rubber accelerator bibenzthiazyl disulphide in rats
Author:
Ema, M.; et al.
Year:
1989
Bibliographic source:
Journal of Applied Toxicology, vol. 9(6), 413-417

Materials and methods

Principles of method if other than guideline:
other: developmental toxicity study
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
MBTS, purity: 97 to 98%

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: MBTS contained in the diet
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: 1: 1
- Length of cohabitation: overnight 15 h
Duration of treatment / exposure:
From day 0 to day 20 of pregnancy
Frequency of treatment:
Daily
Duration of test:
Dams killed on day 20 of gestation (dams killed: 16 control, 14 low dose group, 18 mid dose group, 13 high dose group); five to six pregant rats in each group were allowed to deliver spontaneously; these dams were killed on day 21 after birth; the offspring of these dams were reared until until 7 weeks after birth
Doses / concentrationsopen allclose all
Dose / conc.:
26 mg/kg bw/day
Remarks:
0.04% group
Dose / conc.:
127 mg/kg bw/day
Remarks:
0.2% group
Dose / conc.:
596 mg/kg bw/day
Remarks:
1% group
No. of animals per sex per dose:
15 to 19 per dose (dams kiled on day 20 of pregnancy); in an addition approach dams (5 to 6 per group) delivered offspring and were killed on day 21 after birth
Control animals:
yes, plain diet

Examinations

Maternal examinations:
Death, clinical sign od toxicity, body weight gain, food consumption, pregnancy rate.
Ovaries and uterine content:
Pre- and post implantation losses, numbers of corpora lutea per litter, implantations per litter, live fetuses per litter, sex ratio of live fetuses, fetal body weight of both sexes and placental weight.
Fetal examinations:
External, skeletal and internal malformations.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
596 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
127 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
596 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
596 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Maternal findings:

Mortality: no death occured during the study

Clinical signs: no clinical signs were noted in any of the treated animals or control animals

Body weight gain: maternal body weight gain during day 0 to 14 of pregnancy was significant reduced in the high dose group (1% MBTS in the diet) compared to control

Food consumption: no significant differences in food consumption was observed in treated females compared to control, however the food consumption was lower in the high dose group compared to control

Pregnancy rate: no significant differences were noted in the pregnancy rate in treated females compared to control

Table: maternal findings

 Dietary level of MBTS (%)  0  0.04  0.2     1
 No of rat (pregnant/copulated)  16/17  14/16  18/19     13/15
 Body weight gain during pregnancy (g)ab           
 Day 0 to day 7 of pregnancy  11 ± 8  12 ± 5  9 ± 8   7 ±  7
 Day 0 to 14 of pregnancy  38 ± 7  41 ± 7  36 ± 9 31 ± 10*
 Day 0 to day 20 of pregnancy  99 ± 14  107 ± 12  100 ± 15  94 ± 18
 Food consumption during pregnancy (g)ab        
 Day 0 to day 7 of pregnancy  89 ± 10 88  ± 14 88  ± 11  80 ± 14
 Day 0 to day 14 of pregnancy  206 ± 18  203 ± 23  200 ± 18  194 ± 24
 Day 0 to day 20 of pregnancy  329 ± 27  323 ± 37 324 ± 27 314  ± 30
 Daily intake of MBTS (mg kg bw/day)ab  -  26 ± 2  127 ± 14  596 ± 60

a: Expressed as mean ± SD

b: non-pregnant rats were excluded

* significant different from control

Reproduction findings:

There were no significant differences in the incidences of pre-and postimplantation losses, the number of corpora lutea per litter, implantations per litter and live fetuses per litter, the sex ratio of live fetuses, the fetuses body weight of both sexes and the placental weight.

Table: Reproductive findings in rats given dietary MBTS

Dietary level of MBTS (%)  0  0.04  0.2     1
 No. of litters  16  14  18  13
 No. of corpora lutea per littera  12.3 ± 1.6  11.7 ± 1.7  12.6 ± 1.8  13.1 ± 1.3
 No. of implantations per littera  11.6 ± 1.2  11.1 ± 1.7  11.6 ± 1.5  11.5 ± 2.0
 Preimplantation loss per litter (%)b  4.5  5.4 7.6   12.3
 Postimplantation loss per litter (%)c  9.2  2.3  9.5  7.8
 No. of live fetuses per littera  10.6 ± 1.9  10.8 ± 1.6  10.3 ± 1.2  10.6 ± 2.5
 Sex ratio of live fetuses (male/female)  75/94  69/82  94/92  72/66
 body weight of live fetuses (g)a        
 Male  4.29 ± 0.33  4.32 ± 0.23  4.27 ± 0.30  4.16 ± 0.17
 Female  3.99 ± 0.35  4.18 ± 0.24  4.06 ± 0.22  3.92 ± 0.19
 Placental weight (g)a  0.47 ± 0.05  0.49 ± 0.05  0.5 ± 0.07  0.5 ± 0.08

Offspring Morphological findings in fetuses of rats given dietary MBTS Table: morphological findings in fetuses Dietary level of MBTS (%)  0  0.04  0.2     1

b: b: (No. of corpora lutea minus no.of implantations/ no. of corpora lutea) X 100. c: (No. of implantations minus no. of live fetuses/ no. of implantations) X 100. Offspring Morphological findings in fetuses of rats given dietary MBTS Table: morphological findings in fetuses Dietary level of MBTS (%)  0  0.04  0.2     1

a: Expressed as mean ± SD b:

b: (No. of corpora lutea minus no.of implantations/ no. of corpora lutea) X 100.

c: (No. of implantations minus no. of live fetuses/ no. of implantations) X 100.

Offspring

Morphological findings in fetuses of rats given dietary MBTS:

No treatment-related effects for external, skeletal and internal malformation were noted. The incidences of the fetuses and litters that had skeletal variations or delayed ossifications were not significantly different between MBTS-treated animals and control group. There was no significant difference between the MBTS-treated and control group in the degree of ossification, indicated by the numbers of the caudal vertebrae.

Table: morphological findings in fetuses

Dietary level of MBTS (%)  0  0.04  0.2     1
 External examinationNo. of fetuses (litters) examined  169(16)  151(14)  186(18)  138(13)
 No of fetuses (litters) with anomalies  3(2)  0  1(1)
 Cleft palate  2(1)  0  1(1)  0
 General oedema  1(1)  0  0
 Skeletal examination        
 No. of fetuses (litters) examined  112(16)  101(14)  124(18)  92(13)
 No. of fetuses (litters) with anomalies  1(1)  0  0  0
 Fusion of the cervical vertebral arches  1(1)  0  0  0
 No. of fetuses (litters) with variations        
 Cervical ribs  9(4)  15(5)  8(6)  13(6)
 Shortening 13th ribs 4(3)   6(2)  1(1)  3(3)
 Asymmetry of the sternebrae  2(2)  0  1(1)  0
 Splitting sternebrae  1(1)  0  1(1)  0
 Lumbar ribs  2(2)  0  0  0
 Extralumbar vertebrae  2(2)  0  0  1(1)
 Splitting vertebral bodies  0  0  1(1)  0
 No. of fetuses (litters) with delayed ossification        
 Sternebrae  11(6)  7(4)  5(4)  6(3)
 Supraoccipital bone  0  0  1(1)  0
 Degree of ossification        
 No. of caudal vertebraea  4.5 ± 0.6  4.5 ± 0.6  4.3 ± 0.4  4.5 ± 0.4
 Internal examination        
 No. of fetuses (litters) examined  57(16)  50(14)  62(18)  46(13)
 No. of fetuses (litters) with anomalies  2(1)  0  1(1)  0
 Hydrocephaly  2(1)  0  1(1)  0

Postnatal findings in offspring of rats given dietary MBTS Table: postnatal findings in offspring ietary level of MBTS (%)  0  0.04  0.2     1

a: expressed as mean ± SD Postnatal findings in offspring of rats given dietary MBTS Table: postnatal findings in offspring ietary level of MBTS (%)  0  0.04  0.2     1

a: expressed as mean ± SD

Note: extra group (number of dams unclear, dams killed on day 21 after birth)

Postnatal findings in offspring of rats given dietary MBTS (extra group:offspring killed 7 weeks after birth)

No significant differences between the MBTS-treated animals and control groups were found in the gestation lengh of maternal rats, the numbers of implantation remnants per litter and live newborns per litter and the live birth index. The survival rate of the offspring before and after weaning was very high and almost constant in all groups. Autopsy of the dead offspring of the MBTS-treated groups revealed no consistent tendency, and the cause of death remained unclear. The body weights of offspring for both sexes was not signifcant different between MBTS treated animals and control up to week 7 (postnatal)

Table: postnatal findings in offspring

Dietary level of MBTS (%)  0  0.04  0.2     1
 No. of litters  6  5  6  6
 Length of gestation (day)a  21.0 ± 0  21.4 ± 0.5  21.2 ± 0.4  21.7 ± 0.5
 No. of implantation remnants per littera  10.2 ± 4.3  11.0 ± 1.9  10.8 ± 0.8  12.2 ± 2.1
 No. of live newborns per littera  9.5 ± 4.2  8.6 ± 3.6  9.7 ± 1.2  9.5 ± 1.4
 Live-birth index (%)b  94.0  76.9  89 -1  79 .7
 Survival rate of offspring (%)c        
 Day 7  95.8  100  95.8  100
 Day21  91.7  100  89.6  100
 Week 7  91.7  100  87.5  100
 Body weight of offspring (g)a        
 Day 21        
 Male  56.2 ± 3.7  54.3 ± 3.3  54.7 ± 5.2  54.0 ± 5.1
 Female  53.8 ± 3.5  52.8 ± 2.8  53.9 ± 5.1  51.1 ± 5.7
 Week 7        
 Male  231 ± 26  218 ± 31  230 ± 27  224 ± 18
 Female  177 ± 16  171 ± 14  178 ± 20  171 ± 13

a: Expressed as mean ± SD

b: (No. of live newborns at birth/no. of implantation remnants) X 100.

c (No. of live offspring/ no. of newborns after adjustment of litter size at birth) X 100.

Applicant's summary and conclusion