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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tercarol 5903
- Molecular weight: Mn = 340 g/mole
- Physical state: liquid (red viscous)
- Content: > 99%
- Storage : room temperature under light protection

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at delivery: about 11-13 weeks
- Weight at study initiation: males : 329 (298-354)g, females: 221 (195-239)g
- Housing: individual
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ± 5%
- Air changes (per hr): = 10 passages/hour
- Photoperiod (hrs dark / hrs light): 12 hours rhythm


IN-LIFE DATES: From: May 19, 2008 To: July 8, 2008

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: ethanol/solutol HS 15/demineralized water, 1/4/5 (w/w/v)
Details on exposure:
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The content of the test item was assumed to be nominally 100% for calculation.
Before the start of the study formulations containing the test item in concentrations
of 1 mg/mI and 100 mg/ml were analyzed to determine stability of the test
item in the vehicle. Stability was analytically verified for a period of 7 days. No tests on homogeneity were done because the formulations were clear solutions. The test item content (all concentrations including vehicle control formulation) were checked at begin and near termination of the study.
Duration of treatment / exposure:
males: 4 weeks at a minimum
females: approximately 54 days, [at least 14 days premating, (up to) 14 days mating, 22 days gestation, 4 days lactation].
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
160 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: dose selection was based on the results of a subacute toxicity study, where rats received 0, 40, 160, 640 mg/kg bw. The NOAEL was established at 40 mg/kg bw for both sexes. (for further details see chapter 7.5.1 of this IUCLID).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The experimental animals were inspected twice a day for morbidity and mortality (once on weekends and public holidays). General clinical examinations (in the home cage) were made daily with special care during littering e.g. for evidence of prolonged parturition, etc.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
F0-Females: Prior to the treatment and then weekly during premating and mating
period. Additionally, during pregnancy and lactation period daily.
BODY WEIGHT: Yes
- Time schedule for examinations: The individual body weights of all parental animals were determined just prior before the first treatment of animals and then daily thereafter.
Fetal examinations:
-The numbers of live and dead pups as well as the sex of the pups (including those of dead pups, if possible) were determined shortly after birth (on postpartum day 0) and on day 4 p.p. At these time points individual body weights and clinical signs were recorded as well. Note was taken of any apparent malformations.

-When pups were 4-6 days old they were killed under carbon dioxide anesthesia and were examined for macroscopical alterations. After opening the body cavities, particular attention was given to examining the organs of reproduction. All pups were also examined for visible skeletal abnormalities.
Statistics:
Analysis of Variance (ANOVA) and in case of significant results Dunnett test as post hoc test
2*N CHi2 test; in case of significant differences Fisher's exact test with Bonferroni correction
CHi2 test and Fisher’s Exact test
Indices:
Repro indices
mating performance
insemination index
fertility index
gestation index

offspring viability indices
live birth index
viability index

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related

Maternal developmental toxicity

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
No mortalities occurred in any treatment group, a single male rat in the 160 mg/kg/ bw group showed poor general condition.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute and relative liver weights were increased at 160 mg/kg bw in both sexes

GROSS PATHOLOGY (PARENTAL ANIMALS)
At 160 mg/kg bw, distinct lobulation of the liver in 10/12 males.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Liver effects included hepatocellular hypertrophy (both sexes, 40 mg/kg and above) increased hepatocellular lipid content (males, 40 mg/kg and above, the effect was border line in the 40 mg/kg bw group with only 1/10 male exhibiting grading 3 compared to 7/12 males in the 160 mg/kg bw treatment group), increased glycogen content (females 160 mg/kg), prominent bile ducts (160 mg/kg, both sexes).

Thyroid follicular cell hypertrophy was seen in both sexes at doses of 40 mg/kg bw and above, this change was regarded as being secondary to the liver changes. The mode of action responsible for the thyroid changes is regarded to be probably of no relevance to humans.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day
Basis for effect level:
other: liver and thyroid histopathology

Results (fetuses)

Details on embryotoxic / teratogenic effects:
CLINICAL SIGNS (OFFSPRING)
No clinical signs with a dose-dependent distribution were observed in F1 pups during the five days lactation period at levels up to and including 40 mg/kg. At 160 mg/kg few thin or small pups were born.

There are no toxicologically relevant changes in the parameters: total numbers of pups born, stillborn pups, the live birth index, percentage of males born, the litter size at birth and the viability index up to and including 160 mg/kg.

Data On PUPS (F1):
dose mg/kg: 0 / 10 /40 / 160
Live birth index %: 99.4 / 98.4 / 100.0 / 99.4
Viability index %: 81.12 / 98.98 / 90.91 / 99.35
- Males %: 55.14 / 50.85 / 48.26 /54.54
Mean litter size n: 11.55/11.57/12.09/11.55
No clinical signs with a dose-dependent distribution were observed during the five days lactation period up to and including 40 mg/kg. At 160 mg/kg few thin or small pups were born.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no adverse effects up to highest dose

Overall developmental toxicity

Developmental effects observed:
no
Lowest effective dose / conc.:
160 mg/kg diet
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
Treatment with Diaminotoluene, propoxylated is not a developmental toxicant at doses producing parental toxicity. The NOEL for developmental toxicity is 160 mg/kg bw.
Executive summary:

The developmental toxicity of Diaminotoluene, propoxylated has been investigated in a reproductive and developmental toxicity screening test in rats [OECD TG 421]. In this study, Diaminotoluene, propoxylated was administered via gavage to 12 rats/sex/dose at 0, 10, 40 and 160 mg/kg bw/day. The study did not reveal substance related impairment or adverse effects on reproduction at all dose levels examined including the highest treatment of 160 mg/kg bw which produced both hepatic and thyroid changes in male and female parental animals. The histopathological change seen in the thyroid (i.e. follicular cell hypertrophy), was interpreted as being secondary to the liver changes and probably of little relevance for human health.

No effects were observed on mating behaviour, fertility, insemination and live birth indices, gestation parameters, number of implantation sites or prenatal loss, litter size, number of pups born, viability of pups and pup weight up to the 160 mg/kg dose group. There were no remarkable clinical or necropsy findings in pups and no adverse effects on the course of birth or lactation behaviour of the dams in these groups. In conclusion, treatment with Diaminotoluene, propoxylated is not a developmental toxicant at doses producing parental toxicity. The NOEL for developmental toxicity is 160 mg/kg bw.