Addition reaction products of conjugated sunflower-oil fatty acids and tall-oil fatty acids with maleic anhydride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented and reported study fully adequate for assessment. The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a recognized contract research organization.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: Wistar Crl:WI rats
- Source:Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: 11 weeks
- Weight at study initiation: males: Males: 350 g – 382 g, Females: 183 g - 218 g
- Fasting period before study: overnight prior to treatment
- Housing: 5 animals of the same sex and group/cage with the exception of the mating and gestation/delivery period, when they
were paired or individually housed, respectively. (cage: Type II and/or III polycarbonate)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20,1-25
- Humidity (%): 36-70
- Air changes (per hr):15-20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on exposure:

VEHICLE
- Concentration in vehicle: 20, 60, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw

The test material and the vehicle was warmed up on a water bath to 50 C for approximately 10 minutes separately and mixed up on a hot stirrer plate. Once a suitable formulation was obtained, the container was removed from the plate. Pending administration to the animals, the dose formulations were stirred on a magnetic stirrer at room temperature and were protected from light.

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: until copulation occurred, for up to 7 days.
- Proof of pregnancy: Vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged individually.
- Mating of siblings was avoided.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis of WS400104 formulations for concentration and homogeneity was performed using validated HPLC method (CiToxLAB study code 11/352-316AN). The concentration analysis was performed on 3 occasions, during the first, fourth and last weeks of the treatment period. Recovery of WS400104 from propylene glycol ranged between 92% and 106%.

Duration of treatment / exposure:

Main males: 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week)
Main females: ca. 47 days (14 days pre-mating, for up to 7 days mating period, through gestation til PPD 4)
Satellite females (nulliparous and nonpregnant): 35 days

Frequency of treatment:

daily, 7 days/week

Details on study schedule:

- Age at mating of the mated animals in the study: 13 weeks

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

12 animals/sex/dose
(Satellite female group: 5 animals/dose for Repeated Dose Toxicity Testing according to OECD 407)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The dose finding toxicity study with WS400104 (administered via oral gavage to Wistar rats for 7 consecutive days at dose levels of 100, 300 and 1000 mg/kg bw) showed no overt adverse effects related to the test material (7.5.1 Dose Range Finding Study 7 days_WS400104).
Based on these results, the dose levels selected for the main study were 0, 100, 300 and 1000 mg/kg bw/day.

This study (OECD Guideline 422) was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study . Therefore, animals initially entering the study were divided into toxicity subgroup animals (Satellite females) and reproductive subgroup animals (Main females and males), whereby 5 of the 12 Main males (used for pairing) per dose group formed the toxicity male Subgroup A.

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
All animals were monitored for pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity including mortality.
Delivery process was observed as carefully as possible. Dams were observed to record whether they form a nest from the bedding material and cover their new-borns or not.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least weekly (observations in a standard arena)

BODY WEIGHT: Yes
- Time schedule: Parent females were weighed on gestation Days GD 0, 7, 14 and 20 and on postpartal Days PPD0 (within 24 hours after parturition), and PPD5 (before termination).
Parent males were weighed on Day 0 and at least weekly.

Sperm parameters (parental animals):

Parameters examined in male parental generations, all males (12/dose):
testes, epididymides (total and cauda), prostate, seminal vesicles with coagulating glands.
Detailed qualitative histopathology examination of the testes taking into account the tubular stages of the spermatogenic cycle. This was to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells in the lumen. Any cell- or stage-specificity of testicular findings was noted.

Litter observations:

STANDARDISATION OF LITTERS Not performed. The study ended on Lactation Day 4.

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 (PPD0-PPD4), physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes; for external abnormalities, any pups showing abnormalities in structure or behaviour were subjected to necropsy with macroscopic examination.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on Day 35.
- Maternal animals: All surviving animals on Day 5 of lactation (PND5).

GROSS NECROPSY
- Gross necropsy consisted of external examinations including the cervical, thoracic, and abdominal viscera.
- Special attention was paid to the organs of the reproductive system. The number of implantation sites and of corpora lutea were recorded in the Main females as applicable.

ORGAN WEIGHTS
Weight of the following organs of all adult animals were determined:
- With a precision of 0.01 g: uterus (with and without cervix), vagina, testes, epididymides (total and cauda), prostate, seminal vesicles with coagulating glands, brain
- With a precision of 0.001 g: ovaries, pituitary

HISTOPATHOLOGY :
Detailed histological examinations was performed in all main adults of control and high dose groups.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring on Day 4:
Pups were carefully examined at least externally for gross abnormalities. Any pups showing abnormalities in structure or behaviour were subjected to necropsy with macroscopic examination. The probable cause of death of dead pups were recorded if it can be identified, e.g. cannabilism.

Macroscopic examination included assessment of the presence of milk in the stomach, where possible.

Statistics:

Performance with the statistical program package SPSS PC+4.0.
The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant, Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test,the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed as feasible.

Reproductive indices:

Formulas for Calculation of Mating and Fertility Indices
Male Mating Index: Number of males with confirmed mating : Total Number of males cohabited x 100
Female Mating Index: Number of sperm-positive females : Total Number of females cohabited x 100
Male Fertility Index: Number of males impregnating a female : Total Number of males cohabited x 100
Female Fertility Index: Number of pregnant females : Number of sperm-positive females x 100
Gestation Index: Number of females with live born pups : Number of pregnant females x 100

Offspring viability indices:

Formulas for Calculation of Pups’ Mortality and Sex Ratio Indices
Survival Index: Number of live pups (at designated time) : Number of pups born x 100
Pre-implantation mortality: (Number of Corpora lutea − Number of Implantations) : Number of Corpora lutea x 100
Intrauterine mortality: (Number of implantations - Number of liveborns) : Number of implantations x 100
Total mortality: (Number of implantations - Number of viable pups (d4)) : Number of implantations x 100
Post-natal mortality: (Number of viable pups (d0) - Number of viable pups (d4)) : Number of viable pups (d0) x 100
Sex ratio: (Number of pups exa min ed − Number of males) : Number of pups examined x 100

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Variant findings were not considered toxicologically significant.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Variant findings were not considered toxicologically significant.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Observations in high dose groups (1000 mg/kg bw/day).

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There was no mortality during the study and there were no clinical signs related to treatment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There was no adverse effect of test material on body weight or body weight gain.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Compared to control, differences attaining statistical significance (p<0.05) were noted for males and females at 300 mg/kg (Mid dose) during mating period (lower values), and for males at 300 mg/kg (Mid dose) following the mating period on Weeks 3 and 4 (higher values). The individual values remained within the normal ranges and the finding was not considered toxicologically significant or to reflect an adverse effect of WS400104.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect of treatment on the oestrus cycle or reproductive parameters.
There was no effect of treatment noted during gestation, parturition or the post-partal period.
The mean duration of pregnancy was similar in the control and test item treated groups and varied from 22.8 days (control), 22.7 days (100 mg/kg, Low dose), 22.6 days (300 mg/kg, Mid dose), to 22.8 days (1000 mg/kg, High dose group). All the parturitions were normal.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Compared to controls, the absolute and body weight relative weights of testes were slightly increased at 100 mg/kg bw/day (Low dose). The differences were in the range of 7% and were statistically significant for absolute values (p<0.05). The values were within physiological range, and were not considered to reflect an adverse effect.
For main study females, slightly higher weights of uterus were recorded at 1000 mg/kg bw/day (High dose), when compared to controls. The differences were no more than 10% for absolute and for brain related mean values and were not statistically significant.
In the satellite group of females, no significant differences in organ weights were recorded.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Test material related microscopic findings were found at 1000 mg/kg bw/day (High dose) in stomach, in the form of hyper/paraceratosis of the nonglandular gastric mucosa. This minimal to mild multifocal change occurred in 4 of 5 males and 2 of 5 females.

There was no evidence of test item-related histological findings in the reproductive organs. Histopathological evaluation of the male gonads as well as testicular interstitial cell structure, the spermatogenic cells representing different phases of the development and differentiation of the spermatozoons were revealed normal histological pictures. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma were similar histological structure in both Control and High Dose females.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

VIABILITY (OFFSPRING) / CLINICAL SIGNS (OFFSPRING)
There was/were no mortality or any adverse effects considered related to treatment or toxicologically significant in the F1 generation. No abnormal behaviour of the pups was noted. No external abnormalities ascribed to treatment were detected at the clinical or external macroscopic examinations of the pups. In single pups at 100, 300 and 1000 mg/kg haemorrhage was observed on PND0.
The sex ratios were similar in the Control and treated groups.

BODY WEIGHT (OFFSPRING)
There was no effect of treatment on the offspring body weight or body weight gain.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 1000 mg/kg bw/day was the highest dose tested. Offspring development up to Day 4 of age.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

For the reproduction toxicity endpoints the NOAEL was considered to be 1000 mg/kg day. Dose levels of 1000 mg/kg body weight to Wistar rats for 35 consecutive days caused a minimal/mild hyper/paraceratosis of the nonglandular gastric mucosa in stomach in 4 of 5 males and 2 of 5 females. This finding is considered to be indicative of local irritation in a structure of the stomach that does not exist in man. Systemic effects were not observed.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the 90 day oral toxicity after 10 weeks of dosing, no effects were observed on the oestrous cycle of females and after 13 weeks of dosing no effects were observed on sperm parameters of male rats of the high dose group.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May - Nov 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Ltd
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age at study initiation: 78-84 days
- Weight at study initiation: females 167-217 g
- Fasting period before study: no
- Housing: 4 females per cage during acclimatisation, 1 male and 1 female per cage during pairing ,1 female per cage during gestation
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

DETAILS OF FOOD AND WATER QUALITY: SDS VRF1 certified pelleted diet; potable water from public supply

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The required amounts of test material were weighed, warmed in a water bath to 50°C and mixed on a hoit stirrer plate.

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 20, 60, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required):
- Purity:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations of dose formulations were analysed by HPLC with UV detector. Mean concentrations were within 5% of the nominal concentrations.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1 : 1
- Length of cohabitation: until evidence of mating
- Verification of same strain and source of both sexes: yes, a colony of stud males was maintained
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

from day 6 till day 19 of gestation

Frequency of treatment:

daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

20 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: In an OECD422 study in Charles River Wistar rat, oral administration of WS400104 at dose levels of 100, 300 and 1000 mg/kg/day was well tolerated. At 1000 mg/kg/d there was minimal or mild hyperkeratosis/parakeratosis of the non-glandular stomach in 4/5 males and 2/5 females. No effects were observed at lower doses.

No adverse effect was found on reproduction/developmental parameters at 1000 mg/kg/day. No adverse effects or test item related histopathological findings were observed at 100 or 300 mg/kg/day. In conclusion, for the toxicology endpoints, the NOAEL was considered to be 300 mg/kg/day, while for the reproduction/developmental toxicity the NOAEL was considered to be 1000 mg/kg/day.

Therefore, a high dose for this embryo-fetal study was selected at 1000 mg/kg/day. The low and intermediate dose levels of 300 and 100 were selected to allow evaluation of a dose response.
The Han Wistar rat is the strain of choice at Envigo for which there is a greater extent of historical control data. This change of strain was not considered to result in a different toxicological profile to that seen in the OECD 422 study.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations : visual inspection for ill-health or reaction to treatment

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: days 0, 5, 12, 18, and 20

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 3, and daily from 6-20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: full macroscopic examination of tissues

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of fetuses (live and dead)

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter

Statistics:

The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, live young, fetal, placental and litter weight data:
A parametric analysis was performed if Bartlett's test for variance homogeneity (Bartlett 1937) was not significant at the 1% level. For pretreatment data, analysis of variance was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using t-tests, with the error mean square from the one-way analysis of variance, were made. For all other comparisons t/The F1 approximate test was applied. This test is designed to detect significant departure from monotonicity of means when the main test for the comparison of the means is a parametric monotonic trend test, such as Williams’ test (Williams 1971, 1972). The test statistic compares the mean square, NMS, for the deviations of the observed means from the maximum likelihood means, calculated under a constraint of monotonicity with the usual error mean square, EMS. The null hypothesis is that the true means are monotonically ordered. The test statistic is F1 = NMS/EMS which can be compared with standard tables of the F-distribution with 1 and error degrees of freedom. If the F1 approximate test for monotonicity of dose-response was not significant at the 1% level, Williams' test for a monotonic trend was applied. If the F1 approximate test was significant, suggesting that the dose response was not monotone, Dunnett's test (Dunnett 1955, 1964) was performed instead.

A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. For pretreatment data, Kruskal-Wallis’ test (Kruskal and Wallis 1952, 1953) was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using Wilcoxon rank sum tests (Wilcoxon 1945) were made.

Indices:

Prenatal losses were separated into pre- and post-implantation phases. Pre-implantation loss was considered to reflect losses due to non-fertilization of ova and failure to implant. It was calculated from the formula:
Pre-implantation loss (%) = (Number of corpora lutea – Number of implantations) x 100 / Number of corpora lutea

Where the number of implantations exceeded the number of corpora lutea observed, pre implantation loss was assumed to be zero (i.e. no pre-implantation loss was considered to have occurred).
Post-implantation loss was calculated from the formula:
Post-implantation loss (%) = (Number of implantations – Number of live fetuses) x 100 / Number of implantations

All group values and SD (as appropriate) were calculated from the individual litter values

Historical control data:

Historical control data from 11 studies performed during 2016 with the same rat strain are provided in the report.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Figure Body weight of dams

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter data

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter data

Early or late resorptions:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter data

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter and fetal weights

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter data

Changes in sex ratio:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter data

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Litter and fetal weights

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Fetal major abnormality findings

Skeletal malformations:

no effects observed

Description (incidence and severity):

see Table Fetal minor skeletal abnormality findings

Visceral malformations:

no effects observed

Description (incidence and severity):

see "overall remarks, attachments" : Table Fetal minor visceral abnormality findings

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

There were no findings or adverse effects in the Combined Repeated Dose Oral (Gavage) Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) and in the prenatal developmental toxicity study warranting the classification of WS400104 regarding reproductive or developmental toxicity according to European classification rules [ REGULATION (EC) 1272/2008].