Thiram

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 Jul 1989 - 2 Dec 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Version / remarks:

adopted in 2001

Deviations:

yes

Remarks:

methodological limitations (missing examinations like anogenital distance, data on physical landmarks in pups and other postnatal developmental data, limited organ weights, and the oestrus cycle)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPP 83-4 (Reproduction and Fertility Effects)

Deviations:

yes

Remarks:

Food intake dring mating period was not measured

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Thiram

EC Number:

205-286-2

EC Name:

Thiram

Cas Number:

137-26-8

Molecular formula:

C6H12N2S4

IUPAC Name:

thiram

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD® VAF/Plus®

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: (P) 49 days; (F1) x wks
- Weight at study initiation: ♂: 268-310 g; ♀: 176-205 g
- Fasting period before study: not applicable
- Housing: individually in stainless steel, wire-mesh cages, except during mating, gestation and lactation. Females were housed individually in plastic cages containing wood chip bedding during periods of gestation and lactation.
- Diet: Certified Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7 - 26.7
- Humidity (%): 26 - 76
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 Jul 1989 To: 2 Dec 1990

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet: weekly
- Mixing appropriate amounts with (basal diet): A pre-mix was prepared in a Hobart blender and then this pre-mix was added to appropriate amounts of the basal diet.
- Storage temperature of food: frozen until dispensed in daily aliquots

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 21 days
- Proof of pregnancy: daily check, copulatory plug referred to as day 1 of pregnancy
- Due to poor conception rates in the F1b litter, the F0 parents were mated altogether three times. F1c litter was used to select the F1 parents, which were mated twice to produce the F2a and F2b litters.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability of the test material was analyzed prior to initiation of treatment and after termination of the study and was found to be 97.6 and 97.84%, respectively.

Homogeneity of the test material was also evaluated before initiation of dosing and at study Week 20. Homogeneity was 79 – 84%, 86 – 95% and 89 – 172% of the target dietary concentration for 30, 60 and 180 ppm, respectively. The homogeneity was considered to be sufficient.

Stability of the test material in the diet was investigated for all dietary levels at the time of homogeneity testing. Samples were a) tested immediately, b) held at room temperature for 12 h before extraction, c) frozen for 7 days and then held at room temperature for 12 h before extraction or d) frozen for 12 days and then held at room temperature for 12 h before extraction. Concentration of the test substance in the diet decreased by up to 32% after 12 h at room temperature. However in most test, the test material dietary concentration decreased only by 9-18% after 12 h at room temperature. Freezing did not affect test item concentration in the diet.

Determination of test article concentration in the diet was analyzed from test article containing diets in Week 1 - 4 and every 4 weeks thereafter. The mean percent of target ppm found in all analyzed and administered diets was 93 ± 6.3%, 94 ± 6.6% and 98 ± 5.2% of the target dietary concentration for 30, 60 and 180 ppm, respectively.

Duration of treatment / exposure:

Duration of exposure before mating: F0 / F1 parents: 81/84 days
Duration of exposure in general F0, F1, F2 males, females: Continuously throughout the study

Frequency of treatment:

continously via the diet

Details on study schedule:

Study schedule:

F0 parents received the test diet for 81 days prior to initiation of mating (F1a).

Selection of parents from F1 generation when pups were 21 days of age. F1 parents received the test diet from weaning on for 81 days prior to initiation of mating (F2a). The F1c litters were used for mating F2 litters.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

30 ppm

Remarks:

corresponding to an actual ingested dose of 1.52 mg/kg bw/day (F0 males), 2.27 mg/kg bw/day (F0 females), 1.83 mg/kg bw/day (F1 males) and 2.39 mg/kg bw/day (F1 females)

Doses / concentrations 2

Dose / conc.:

60 ppm

Remarks:

corresponding to an actual ingested dose of 2.94 mg/kg bw/day (F0 males), 4.61 mg/kg bw/day (F0 females), 3.82 mg/kg bw/day (F1 males) and 5.12 mg/kg bw/day (F1 females)

Doses / concentrations 3

Dose / conc.:

180 ppm

Remarks:

corresponding to an actual ingested dose of 8.88 mg/kg bw/day (F0 males), 13.89 mg/kg bw/day (F0 females), 11.37 mg/kg bw/day (F1 males) and 16.21 mg/kg bw/day (F1 females)

No. of animals per sex per dose:

26

Control animals:

yes, concurrent no treatment

Positive control:

No

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to treatment (F1)/selection (F2), weekly throughout the pre-mating period. Body weights of female rats were determined on Days 0, 7, 14 and 20 of gestation and on Days 0, 4, 7, 14 and 21 of lactation, respectively.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Food consumption was recorded daily throughout the study except during the mating period.

WATER CONSUMPTION: No

Oestrous cyclicity (parental animals):

No

Sperm parameters (parental animals):

Parameters examined in all male parental generations:
testis weight, sperm count in epididymides

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Litter size was reduced by random selection to 8 pups of equal sex distribution on lactation day 4. An exception was made for the F1c litter due to too few pups.

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring: litter size, stillbirths, live births and gross anomalies. Pups were observed for survival, behavioural abnormalities and dead pups at least twice daily. Such pups were subjected to a gross post mortem examination. Any abnormalities were recorded in pups killed or found dead before discarding.
Body weights of pups were recorded on lactation day 0, 4, 7, 14 and 21.


GROSS EXAMINATION OF DEAD PUPS:
Yes, for external and internal abnormalities

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals , F0 generation: three weeks after the completion of the F1c mating period, F1 generation: three weeks after the completion of the F2b mating period.
- Maternal animals: All surviving animals, F0 generation: prior to the date on which it was decided to mate the F0 females a third time, 5, 7, 9 and 5 females of the control, low- mid and high-dose groups, respectively, where sacrificed as they did not produce litter. All other F0 females were euthanized after the selection of the F1 parents. F1 generation: sacrificed and necropsied after F2b litters were weaned.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weights: testes
- Tissues: Coagulating gland, ovary, pituitary, prostate, seminal vesicle, testis with epididymis, uterus, cervix, vagina, gross lesions, tissue masses.
- How many animals: All animals from control and high-dose group (gross lesions also from low- and mid-dose group).

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age (following weaning).
- These animals were subjected to postmortem examinations as follows: culled pups for litter adjustment were examined externally and discarded. Any intact pups dying during lactation were necropsied, examined for abnormalities and preserved (10% neutral buffered formalin).

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues of gross abnormalities were prepared for microscopic examination and weighed, respectively. No other histopathology was performed.

Statistics:

All statistical analysis was performed to compare the test groups with the control group. Levels of significance were p < 0.05 and p < 0.01. All means were accompanied by standard deviation.

Statistical tests performed were the one-way analysis of variance (ANOVA), Bartlett's test for homogeneity of variance and the appropriate t-test with Dunnett's multiple comparison tables or Bonferroni correction, the chi-square test, Fisher's exact probability test and the Mann-Whitney U-test.

Reproductive indices:

Male and female viability indices were calculated.

Offspring viability indices:

Pup survival indices were calculated.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Treated F0 females showed an increased incidence of hair loss in a non-dose-related pattern.

Summarized results can be found in Attachment 1 in the attached background material.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Two deaths occurred in the F0 generation but were not regarded as treatment-related.

Summarized results can be found in Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant and treatment-related reductions in body weight in F0 females were observed during the F1a gestation period in the mid- and high-dose group. During the F1b and F1c gestation periods, reductions in body weight were observed in the high-dose group only.

Summarized results can be found in Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reductions were noted for the F0 males at the high-dose level for three weeks and at the mid-dose level for two weeks. Food consumption of F0 females in the mid-dose group was reduced for one week and for several weeks in the high-dose group.
Dose-related reductions were additionally noted for F0 females in the mid- and high-dose group throughout the F1a gestation period. This treatment-related reduction continued throughout the F1b and, without reaching statistically significance, in the F1c gestation period in the high-dose group.

Summarized results can be found in Attachment 1 in the attached background material.

Food efficiency:

not examined

Description (incidence and severity):

not applicable

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

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not examined

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Endocrine findings:

not specified

Description (incidence and severity):

The following ED-related parameters were investigated in the study: histopathology of cervix, coagulating gland, epididymis, prostate, seminal vesicles, testis, thyroid, pituitary, uterus and vagina, organ weights were recorded for liver, coagulating gland, epididymis, prostate, seminal vesicles, uterus, testis and brain. Gestation length, litter size, viability, weight and number of implantation sites and live births were investigated as well as pre- and post-implantation loss, presence of anomalities, pup development and sex ratio. For details, please refer to the respective result fields and the endpoint summary.

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

not applicable

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

All microscopic changes seen in the rats were considered to be spontaneous or agonal.

Summarized results can be found in Attachment 1 in the attached background material.

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

not applicable

Other effects:

not examined

Description (incidence and severity):

not applicable

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

not applicable

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Sperm were present, motile and morphologically normal.

Summarized results can be found in Attachment 1 in the attached background material.

Reproductive performance:

no effects observed

Description (incidence and severity):

No treatment-related differences in the male and female copulatory and fertility indices, the gestation index, the mean copulatory interval or the mean gestation length were observed.

Summarized results can be found in Attachment 1 in the attached background material.

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Remarks:

parental general toxicity

Effect level:

30 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effect was observed at this dose level.

Remarks on result:

other: corresponding to an actual ingested dose of approx. 1.5 mg/kg bw/day.

2

Key result

Dose descriptor:

LOAEL

Remarks:

parental general toxicity

Effect level:

60 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: corresponding to an actual ingested dose of aprrox. 3 mg/kg bw/day

3

Key result

Dose descriptor:

NOAEL

Remarks:

reprotoxicity

Effect level:

180 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed up to and including the highest dose level.

Remarks on result:

other: corresponding to an actual ingested dose of approx. 9 mg/kg bw/day.

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:

no effects observed

Description (incidence and severity):

In F1 animals no clinical signs of toxicity were observed.

Summarized results can be found in Attachment 1 in the attached background material.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Two deaths occurred in the F1 generation but were not regarded as treatment-related.

Summarized results can be found in Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreases in the mean weekly body weight were observed in the F1 generation at the high dose level during the initial 10 weeks (males) or 13 weeks (females). These decreases were consistent with a reduced growth observed in these animals.
Statistically significant reductions were additionally noted for high-dose females during the F2a and F2b gestation period.

Summarized results can be found in Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

During the F2a and F2b gestation and lactation period food consumption was significantly and treatment-related reduced in the high-dose group.

Summarized results can be found in Attachment 1 in the attached background material.

Food efficiency:

not examined

Description (incidence and severity):

not applicable

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

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not examined

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Endocrine findings:

not examined

Description (incidence and severity):

not applicable

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Immunological findings:

not examined

Description (incidence and severity):

not applicable

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

There was no treatment-related effect on testes weight in the F1 generation males.

Summarized results can be found in Attachment 1 in the attached background material.

Gross pathological findings:

no effects observed

Description (incidence and severity):

All macroscopic changes seen in the rats were considered to be spontaneous or agonal.

Summarized results can be found in Attachment 1 in the attached background material.

Neuropathological findings:

not examined

Description (incidence and severity):

not applicable

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

All microscopic changes seen in the rats were considered to be spontaneous or agonal.

Summarized results can be found in Attachment 1 in the attached background material.

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

not applicable

Other effects:

not examined

Description (incidence and severity):

not applicable

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

not applicable

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Sperm were present, motile and morphologically normal.

Summarized results can be found in Attachment 1 in the attached background material.

Reproductive performance:

no effects observed

Description (incidence and severity):

No treatment-related differences in the male and female copulatory and fertility indices, the gestation index, the mean copulatory interval or the mean gestation length were observed.

Summarized results can be found in Attachment 1 in the attached background material.

Effect levels (P1)

1

Key result

Dose descriptor:

NOAEL

Remarks:

parental general toxicity

Effect level:

60 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed at this dose level.

Remarks on result:

other: corresponding to an actual ingested dose of approx. 3 mg/kg bw/day

2

Key result

Dose descriptor:

LOAEL

Remarks:

parental systemic toxicity

Effect level:

180 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: corresponding to an actual ingested dose of approx. 9 mg/kg bw/day

3

Key result

Dose descriptor:

NOAEL

Remarks:

reprotoxicity

Effect level:

180 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed up to and including the highest dose level.

Remarks on result:

other: corresponding to an actual ingested dose of approx. 9 mg/kg bw/day

Target system / organ toxicity (P1)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Description (incidence and severity):

No dose-related trends were observed in the type and incidence of clinical observations in treated F1 offspring when compared to the untreated controls.

Summarized results can be found in Attachment 1 in the attached background material.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The mean number of stillborn and live pups in the treated groups was comparable with the one of the control litters at all dose levels.

Summarized results can be found in Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean offspring body weights were consistently reduced to a significant degree in all litters at the 180 ppm level.

Summarized results can be found in Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

not applicable

Food efficiency:

not examined

Description (incidence and severity):

not applicable

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

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not examined

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Sexual maturation:

not examined

Description (incidence and severity):

not applicable

Anogenital distance (AGD):

not examined

Description (incidence and severity):

not applicable

Nipple retention in male pups:

not examined

Description (incidence and severity):

not applicable

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

not applicable

Gross pathological findings:

no effects observed

Description (incidence and severity):

No dose-related trends were observed in the type and incidence of clinical observations in treated F1 offspring when compared to the untreated controls.

Summarized results can be found in Attachment 1 in the attached background material.

Histopathological findings:

not examined

Description (incidence and severity):

not applicable

Other effects:

not examined

Description (incidence and severity):

not applicable

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Description (incidence and severity):

not applicable

Effect levels (F1)

1

Key result

Dose descriptor:

NOAEL

Remarks:

neonatal toxicity

Generation:

F1

Effect level:

60 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed at this dose level.

Remarks on result:

other: corresponding to an actual digested dose of approx. 3 mg/kg bw/day.

2

Key result

Dose descriptor:

LOAEL

Remarks:

neonatal toxicity

Generation:

F1

Effect level:

180 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other: corresponding to an actual digested dose of approx. 9 mg/kg bw/day.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Results: F2 generation

General toxicity (F2)

Clinical signs:

no effects observed

Description (incidence and severity):

No dose-related trends were observed in the type and incidence of clinical observations in treated F2 offspring when compared to the untreated controls.

Summarized results can be found in Attachment 1 in the attached background material.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

not applicable

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The mean number of stillborn and live pups in the treated groups was comparable with the one of the control litters at all dose levels.

Summarized results can be found in Attachment 1 in the attached background material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean offspring body weights were consistently reduced to a significant degree in all litters at the 180 ppm level.

Summarized results can be found in Attachment 1 in the attached background material.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

not applicable

Food efficiency:

not examined

Description (incidence and severity):

not applicable

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

not examined

Description (incidence and severity):

not applicable

Ophthalmological findings:

not examined

Description (incidence and severity):

not applicable

Haematological findings:

not examined

Description (incidence and severity):

not applicable

Clinical biochemistry findings:

not examined

Description (incidence and severity):

not applicable

Urinalysis findings:

not examined

Description (incidence and severity):

not applicable

Sexual maturation:

not examined

Description (incidence and severity):

not applicable

Anogenital distance (AGD):

not examined

Description (incidence and severity):

not applicable

Nipple retention in male pups:

no effects observed

Description (incidence and severity):

not applicable

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

not applicable

Gross pathological findings:

no effects observed

Description (incidence and severity):

No dose-related trends were observed in the type and incidence of clinical observations in treated F1 offspring when compared to the untreated controls.

Summarized results can be found in Attachment 1 in the attached background material.

Histopathological findings:

not examined

Description (incidence and severity):

not applicable

Other effects:

not examined

Description (incidence and severity):

not applicable

Developmental neurotoxicity (F2)

Behaviour (functional findings):

not examined

Description (incidence and severity):

not applicable

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not examined

Description (incidence and severity):

not applicable

Effect levels (F2)

1

Key result

Dose descriptor:

NOAEL

Remarks:

neonatal toxicity

Generation:

F2

Effect level:

60 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed at this dose level.

Remarks on result:

other: corresponding to an actual digested dose of approx. 3 mg/kg bw/day.

2

Key result

Dose descriptor:

LOAEL

Remarks:

neonatal toxicity

Generation:

F2

Effect level:

180 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other: corresponding to an actual digested dose of approx. 9 mg/kg bw/day.

Target system / organ toxicity (F2)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

The study was conducted similar to OECD guideline 416 and under GLP conditions. Several examinations are missing when the study protocol is compared to the current guideline, but the study was considered valid.

In conclusion, parental toxicity in the F0 and F1 generations was exhibited at a concentration of 60 and 180 ppm, respectively, by inhibition of body weight gain and reduced food consumption. No parental systemic toxicity was observed at concentrations of 30 ppm in the Fo or at 60 ppm in the F1 generation.
Reproductive performance was unaffected by test article administration at the 30, 60 and 180 ppm. Neonatal toxicity was expressed at a concentration of 180 ppm by reduced pup body weights (F1 and F2). No neonatal toxicity was observed at concentrations of 30 and 60 ppm. Based on the results of this study, in the P0 generation, a concentration of 30 ppm was considered to be the NOAEL (no observable adverse effect level) for parental systemic toxicity (corresponding to approx. 1.5 mg/kg bw/day), 60 ppm was considered to be the NOAEL for systemic toxicity in the P1 generation and for neonatal toxicity (corresponding to approx. 3 mg/kg bw/day) and 180 ppm was considered to be the NOAEL for reproductive and developmental neurotoxicity (corresponding to approx. 9 mg/kg bw/day).