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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: Study conducted to OECD guidelines to to GLP, and therefore meets the requirements for Klimisch code 1. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD 415
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test article (CAS 115733-09-0) is from the chemical group of alkaryl sulfonates.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS: Sprague-Dawley Crl: CD®(SD) IGS BR rats,
- Source: Charles River Laboratories
- Age at study initiation: (P) males 5 wks, females 7 weeks; (F1) x wks
Males approximately 7 weeks of age at initiation of treatment. Females approximately 8 weeks of age at initiation of treatment.
- Weight at study initiation: (P) Males: 154-197 g; Females: 139-184 g; (F1) Males: x-x g; Females: x-x g
- Housing: Suspended wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Corn oil was added to the test substance to achieve the desired volume and then stirred for 30 minutes.
VEHICLE: Justification for use and choice of vehicle (if other than water): Corn oil
The test article was administered orally via gastric intubation
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical confirmation of concentration: Homogeneity, stability and weekly dose concentration confirmation.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually
Duration of treatment / exposure:
F0 males - 70 days premating; mating period through completion of parturition
F0 females - 14 days premating; mating; 25 days of gestation and 20 days of lactation.
F1 pups - gestation through day 20 of lactation
Frequency of treatment:
once daily
Duration of test:
96 d (males)
min. 60 (females)
No. of animals per sex per dose:
28 F0 rats/sex/group in control, low, mid and high dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of a 28 day oral gavage study (according to OECD 407).
- Control and treatment groups: 28 F0 rats/sex/group in the control, low, mid and high dose groups.
- Mating: 1 male mated to 1 female from the same group until evidence of mating (presence of copulatory plug or sperm) was observed. If evidence of mating was not observed mating was discontinued after three weeks.

Examinations

Maternal examinations:
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly and daily for females during gestation

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and on the day on euthanasia for males. After evidence of mating, females were weighed on gestational days 0, 7, 14 and 21 and on lactation days 1, 4, 7, 14 and 21.
gross necropsy on death, organ weights and microscopic examination on termination
SACRIFICE
- Male animals: All surviving animals after completion of female parturition.
- Maternal animals: All surviving animals that delivered on lactation day 21; females that failed to deliver were sacrificed on gestation day 25.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
Ovaries and uterine content:
Parameters examined in P male parental generations:
testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology.
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.

SACRIFICE - These animals were subjected to maroscopic postmortem examinations
GROSS NECROPSY - Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.



Statistics:
ANOVA for body weights, changes, food consumption semen parameters, organ weights.

Body weights, body weight changes, food consumption, semen parameters, organ weights, number of days to mating, gestation length, pup viability data, total pups delivered, pup body weights and mean live litter size were analysed by ANOVA followed, as needed, by Dunnett’s test. Count data were analysed by Chi-Square test followed by Fisher’s Exact Test for copulation and fertility indices, pup sex ratios, number of live and dead pups/group and pup survival. All analysis were two-tailed with a minimum significance level of 5%..
Indices:
Reproduktive indices: YES
Offspring viability indices: YES

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Clinical signs (parental animals): no effects
Body weight and food consumption (parental animals): no effects
Test substance intake (parental animals): no data
Reproductive function: estrous cycle (parental animals): not examined
Reproductive function: sperm measures (parental animals): no effects
Reproductive performance (parental animals): no effects
Organ weights (parental animals): no effects
Gross pathology (parental animals): no effects
Histopathology (parental animals): yes
Details on results (parental animals): There were no remarkable findings in F0 males, with the exception of post dosing salivation.
In F0 females there were no remarkable findings with the exception of negative ammonium sulphide staining in two high dose and one mid dose animal.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
> 500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
> 500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Viability (offspring): no effects
Clinical signs (offspring): no effects
Body weight (offspring): no effects
Sexual maturation (offspring): not examined
Organ weights (offspring): no effects
Gross pathology (offspring): no effects
Histopathology (offspring): no effects
Details on results (offspring): There were no remarkable observations in F1 animals.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
changes in postnatal survival
external malformations
skeletal malformations
other: sexual maturation, histopathology, gross pathology, organ weights

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Results of the homogeneity analysis indicate that the test article was homogeneous in the vehicle and stable for ten days when stored under ambient conditions. Concentration analysis confirmed that the test article was at the appropriate concentration in the dosing solutions.

Results

F0 Generation:

F0 males exhibited a dose related increase in post dosing salivation and dark material around the nose in the mid and high dose groups The remaining F0 male parameters were unremarkable including: mean body weight and food consumption, mating and fertility indicies, absolute and relative organ weights, sperm evaluation parameters and macro and microscopic pathology.

The clinical signs of the Fo females were generally unremarkable. There were no toxicologically meaningful differences between the control low, mid and high dose groups with respect to F0 female mean body weights, body weight change, food consumption, mating and fertility indicies, precoital intervals or gestation length. A macroscopic finding observed in two high dose and one mid female sacrificed on post mating day 25 was a finding of negative ammonium sulfide staining in animals that failed to deliver and were euthanized on gestation day 25.

No other remarkable findings were noted in the F0 females at necropsy and no meaningful microscopic lesions were observed in any of the treated F0 females.

F1 Generation:

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21.)

Applicant's summary and conclusion

Conclusions:
Adverse effects did not occur in parental animals or offsprings at doses up to 500 mg/kg bw/day, therefore a NOAEL of 500 mg/kg bw was identified in this study.
Executive summary:

In a 1-generation reproduction study, benzenesulfonic acid, C14-C24 branched and linear alkyl derivatives (CAS 115733 -09 -0) was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004, according to OECD 415). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for 14 days prior to mating, mating (maximum 3 weeks), 25 days of gestation and through day 20 of lactation. The offspring (F1) were potentially exposed to the test substance in utero (during gestation) and through nursing during lactation days 1-21 until euthanization on post-natal day 21. On lactation day 4 each litter was randomly culled to a maximum of eight pups, 4/sex/litter, when possible. Detailed pup examinations were performed on lactation days 0, 4, 7, 14 and 21. Pup sex was determined on lactation day 0 and verified on lactation days 4, 7, 14 and 21. Individual pup weights were determined on lactation days 1, 4, 7 14 and 21. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All surviving pups were euthanized on lactation day 21 and examined macroscopically. All internal gross lesions were preserved for possible future microscopic examination.

The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities. Moreover a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death fro pups born or found dead was evaluated.

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). As no effects occurred at the highest dose, the NOAEL for developmental toxicity is greater than 500 mg/kg bw/day.