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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: GLP and OECD Guideline study (TG 421), acceptable documented (abstract and result tables in English, publication in Japanese)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction/Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity: 98.2%, produced by Sumitomo Chemical, Lot No: 710140

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
Weight at study initiation: (P) Males: 332-383 g; Females: 206-238 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: in 5% gum arabic
Details on mating procedure:
Male/female per cage: 171, length of cohabitation: at the most 14 d, until proof of pregnancy (formation of vaginal closing or sperm detection in vagina)
Duration of treatment / exposure:
male: 50-52 d, female: 40-48 d (from 14 days before mating to the day 3 of lactation)
Frequency of treatment:
daily
Duration of test:
male: 50-52 d, female: 40-48 d (from 14 days before mating to the day 3 of lactation)
No. of animals per sex per dose:
12/per dose group/sex
Control animals:
yes, concurrent vehicle
Details on study design:
clinical observations: general appearance twice a day, organ weights: testis, epididymis, cauda epididymis, ovary, microscopic evalauations:( control and all teatment groups): testis, caput epididymis, (control and 800 mg/kg group): seminal vesicle, ovary

Examinations

Maternal examinations:
BODY WEIGHT: Yes,
DETAILED CLINICAL OBSERVATIONS: Yes
FOOD CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes


Ovaries and uterine content:
lengh of gestation, corporal lutea, implantation scars, implantation index, gestation index, pups born, delivery index, live pups born, sex ratio at birth. birth index,
Fetal examinations:
Dead pups on day 0 of lactation, live birth index, live pups on day 4 of lactation, viability index, external anomalies, body weights of pups
Statistics:
Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
Indices:
live birth index, viability index, implantation index, gestation index, delivery index

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
decrease in body weight gain,

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Pups (200 mg/kg bw): Pup numbers on day 0 and 4 of lactation were decreased
Remarks on result:
other: Pups (200 mg/kg bw): Pup numbers on day 0 and 4 of lactation were decreased

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Dams:

Females (200 mg/kg bw):Suppression of body weight gain during the lactation period, lower food consumption was evident during the pre-mating, pregnancy and lactation periods, decrease in the number of corpora lutea, decrease in number of implantation scars and number of pups born

Females (800 mg/kg bw):Supression of body weight gain was noted during the pregnancy and lactation periods, lower food consumption was noted during the pre-mating, pregnancy and lactation periods; decrease in the number of corpora lutea, decrease in number of implantation scars and number of pups born, 1 dam was unable to deliver pups, and 1 dam lost all their pups during the lactation period

Offspring:

Pups (200 mg/kg bw): Pup numbers on day 0 and 4 of lactation were decreased

Pups (800 mg/kg bw): the number of pups on day 0 and 4 of lactation, live birth index, and body weights of both sexes on day 4 of lactation were decreased, and the number of stillbirths was increased

Organ weight of female rats

 Dose (mg/kg) 12.5  50  200  800 
 number of dams 12  12  12  12  12 
 Body weight (g) 310.4  ± 12.3    312.2 ± 18.9   310.7 ± 17.2   287. 4± 13.3**   281.9 ± 22.9**
 Ovaries (mg)  94.50 ± 12.06  91.43 ± 10.00   89.88 ± 8.77   89.69 ± 16.74   88.78 ± 14.65

significantly different from control (**p<0.01)

Number of estrous cases and reproductive performance

 Dose (mg/kg) 12.5  50  200  800 
 Number of females  12 12  12  12  12 
 Number of estrous cases before mating (14 days)  3.3 ± 0.5   3.5 ± 0.5  3.5 ± 0.5   3.7 ± 0.5   3.2 ± 0.6
 Fertility index (%)  100.0 100.0  100.0  91.7  100.0 
 number of pregnant females with live pups  12  12  12  11  10

Observation of pups

Dose (mg/kg) 12.5  50  200  800 
 Number of dams  12 12  12  12  12 
 Lengh of gestation (days)  22.08 ± 0.29  22.00 ± 0.00 22.33  ± 0.49  22.45 ± 0.52   22.27 ± 0.65
 Corpa lutea  16.4 ± 3.0 16.4 ± 2.6    16.3 ± 1.5  15.1 ± 1.4   14.1 ± 1.6*
 Implantation scars  14.3 ± 3.0  14.7 ± 1.1   15.2 ± 1.3  13.5 ± 1.4   13.1 ± 1.5*
 Implantation index  86.9 ± 14.7  91.0 ± 12.8   93.6 ± 7.4  90.1 ± 8.5   93.1 ± 7.2
 Gestation index (%)  100 100  100  100  83.3 
 Pups born  13.5 ± 3.3  13.5 ± 1.0    14.8 ± 1.3  11.7 ± 1.4**   12.2 ± 1.8*
 Live pups born   13.1 ± 3.2  13.3 ± 0.8   14.3 ± 1.3  11.5 ± 1.0**   11.3 ± 4.1
 Birth index (%)  90.7  ± 9.4 91.2  ± 4.8  94.7 ±  4.4   86.0 ± 9.6   83.8 ± 28.8
 Dead pups on day 0 of lactation  0.4  ± 0.7  0.2 ± 0.4  0.4 ± 0.5  0.2 ± 0.6  0.9 ± 2.7
 Live birth index (%)  97.1  ± 4.6   98.9 ± 2.5  97.2 ± 3.5  98.8 ± 3.9  89.9 ± 30.0
 Live pups on day 4 of lactation   13.1 ± 3.2  13.3 ± 0.8  14.3± 1.4  11.4 ± 1.0**  12.4 ± 1.8
 Viability index (%)  100.0  ± 0.0 100.0 ± 0.0  99.4 ± 2.0  98.5 ± 3.4  100.0 ± 0.0
 External anomalies (%)  0.0 ± 0.0   0.0 ± 0.0  0.0 ± 0.0   0.0 ± 0.0   0.0 ± 0.0 
 Body weight of pups          
 Male Day 0  6.78 ± 0.40   6.81 ± 0.23  6.90 ± 0.50  7.60 ± 0.52**  6.97 ± 0.71
 Male Day 4   11.02 ± 0.83  11.05 ± 0.77  10.58 ± 1.11  11.29 ± 1.14  9.68 ± 1.72*
 Female Day 0   6.43 ± 0.37  6.40 ± 0.17  6.53 ± 0.44  7.25 ± 0.49**  6.61 ± 0.66
 Female Day 4   10.33 ± 0.81  10.36 ± 0.67   10.20 ± 1.15  10.77 ± 1.04   9.30 ± 1.64

Significantly different from control (*p<0.05, **p<0.01)

Applicant's summary and conclusion

Executive summary:

In a reproduction/developmental toxicity screening test (OECD Guideline 421) with rats toxic effects of the test substance Vulcanox BKF were seen. In dams suppression of the body weight gain was noted in the 200 mg/kg bw/day treatment group during the lactation period. In the highest dose group (800 mg/kg bw/day) a suppression of body weight gain was seen during the pregnancy and lactation periods. Lower food consumption was noted in the 200 and 800 mg/kg bw/day groups during pre-mating, pregnancy, and lactating periods. Decreases in the number of corpora lutea, number of implantation scars, and number of pups born were noted at 200 and 800 mg/kg bw/day. In addition, 1 dam was unable to deliver pups, and 1 dam lost all their pups during the lactation period at 800 mg/kg bw/day. No external anomalies were found in any of the pups evaluated

The maternal NOAEL for developmental toxicity was assessed to be 50 mg/kg bw/ day and the NOAEL for pup development is considered to be 50 mg/kg bw/day (MHWJ 1999).