Sodium dimethyldithiocarbamate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP guideline study; According to the ECHA guidance document “Practical guide 6, V2: How to report read-across and categories” (Dec 2012), the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

- Not all required organ weights were determined. - Sperm parameters were not assessed for all animals.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 144-218 g, ♀: 117-174

Route of administration:

oral: feed

Vehicle:

other: diet

Details on mating procedure:

- M/F ratio: 1:1
- Length of cohabitation: Up to 15 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of gestation
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Any other deviations from standard protocol: Litters were culled to 8 pups/litter on lactation day 4.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

F0 parents: from study initiation until scheduled sacrifice
F1 parents: from weaning (day 22) until scheduled sacrifice
F2 pups: from weaning (day 22) until scheduled sacrifice

Duration of exposure before mating (F0 / F1 parents): 10 weeks

Frequency of treatment:

Ad libitum

Remarks:

Doses / Concentrations:
0, 60*, 180#, 540 ppm (Concentration was increased to 72 ppm (*)/ 207 ppm (#) to compensate losses during storage)
Basis:
nominal in diet

No. of animals per sex per dose:

30

Control animals:

yes, plain diet

Details on study design:

- Actual doses
F0 ♂:
5, 15, 37 mg/kg/day (prior to breeding)
3, 10, 25 mg/kg/day (after breeding)

F0 ♀: 6, 17, 43 mg/kg/day (prior to breeding)
5, 13, 33 mg/kg/day (gestation)
12, 33, 85 mg/kg/day (lactation)
5, 15, 37 mg/kg/day (after weaning)

F1 ♂:
6, 18, 46 mg/kg/day (prior to breeding)
3, 10, 26 mg/kg/day (after breeding)

F1 ♀:
7, 20, 51 mg/kg/day (prior to breeding)
5, 13, 32 mg/kg/day (gestation)
11, 30, 79 mg/kg/day (lactation)
5, 14, 34 mg/kg/day (after weaning)

Positive control:

none

Parental animals: Observations and examinations:

MORTALITY
- Twice daily

CLINICAL SIGNS
- Twice daily

BODY WEIGHT
- Weekly during treatment and prior to terminal sacrifice for males.
- Confirmed mated ♀ were weighed on presumed gestation Days 0, 7, 10, 14, and 20. Nursing dams were weighed on Days 1, 4, 7, 14, and 21 post partum. After weaning (day 22) once weekly until scheduled sacrifice.

FOOD CONSUMPTION
- Daily until pairing for all animals.
- Male food consumption was measured after mating again daily until scheduled sacrifice.
- Female food consumption was measured daily throughout gestation and lactation period.
- No food consumption data was obtained during the mating period.

Oestrous cyclicity (parental animals):

- Daily during mating.

Sperm parameters (parental animals):

- Only performed on males which were paired, but failed to sire a litter.

Litter observations:

- Sex-determination, pup viability, body weight gain, clinical signs, necropsy on dead pups, behavioural testing (F2)

Postmortem examinations (parental animals):

ORGAN WEIGHTS
- Yes
- Organs: testes + epididymides/ovaries, brain, pituitary gland, kidneys, liver

HISTOPATHOLOGY
- All animals from control and high-dose group.
- Tissues: Cervix, coagulating gland, epididymides, kidneys, liver, ovaries, pituitary gland, prostate, seminal vesicles, testes, uterus, vagina, vas deferens, all internal gross lesions

Postmortem examinations (offspring):

- neuropathological examination (F2)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

F0 (♂+♀):
- Mean body weights and body weight gains in the 540 ppm group males were reduced early in the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.

Key result

Dose descriptor:

NOAEL

Remarks:

maternal

Effect level:

ca. 10 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: (post-breeding intake ) = 9.4 mg SDDC (a.s.)/kg bw/day = 22.6 mg SDDC (41.44%)/kg bw/day

Key result

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

ca. 25 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (post-breeding intake) = 23.4 mg SDDC (a.s.)/kg bw/day = 56.5 mg SDDC (41.44%)/kg bw/day

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

F1 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation. Mean body weights and body weight gains in the 540 ppm group males were reduced throughout the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.
F2 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation and throughout the remainder of the study until the postnatal day 70 neuropathology evaluation.

Key result

Dose descriptor:

NOAEL

Remarks:

foetal

Generation:

F1

Effect level:

ca. 10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (post-breeding intake ) = 9.4 mg SDDC (a.s.)/kg bw/day = 22.6 mg SDDC (41.44%)/kg bw/day

Reproductive effects observed:

not specified

Table 7.8.1-A1        Body weight changes in reproductive toxicity study
Parameter	Genera­tion	Controls		60 ppm		180 ppm		540 ppm		Dose-response +/–
		♂	♀	♂	♀	♂	♀	♂	♀	♂	♀
Body weight [g]
average weight on gestation Day 14	F0 dams	/	348.4	/	338.6	/	356.0	/	343.8	/	−
	F1 dams	/	357.1	/	339.1	/	344.7	/	316.7*	/	−
average pup weight on lactation Day 21	F1 pups	44.8	42.8	44.6	41.8	46.3	43.5	40.2*	37.7*	−	−
	F2 pups	40.7	39.5	41.0	39.3	44.1	41.2	38.5	36.9	−	−
* statistically significant different from control p </= 0.05

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

56.5 mg/kg bw/day

Study duration:

subchronic

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

According to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, substances may be considered as analogues provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The target (SDDC) and source substance (ziram) are considered to apply to these general rules. The assumed similarity is justified on basis that both, SDDC and ziram, represent salts of dimethyl dithiocarbamic acid (DDC) which have similar physico-chemical properties, exhibit a similar environmental fate and ecotoxicity profile, similar metabolic pathways in mammals and comparable systemic effects in mammals. There is convincing evidence that these chemicals lie in the overall common profile with respect to the present analogue approach. For a detailed discussion please refer to the analogue justification.T

Two-generation reproduction toxicity study in the rat with ziram (Nemec, 1996):

Based on reduced body weight and food consumption in F0 and F1 dams, the NOAEL for maternal systemic toxicity was determined to be 180 ppm (10 mg ziram/kg bw/day). Reproductive parameters such as fertility, mating, days between pairing and coitus, gestation and parturition were not adversely affected by ziram administration. The NOAEL for reproductive toxicity is therefore considered to be 540 ppm (25 mg ziram/kg bw/day).

In the examination of post-natal development in rats, the primary findings were a slight decrease in mean pup body weight in the F1 generation at the mid dose of 180 ppm during lactation. A similar effect was observed for F2 offspring and throughout the remainder of the study until the postnatal day 70 neuropathology evaluation. Thus, the foetal and post-natal NOAEL for this study was determined to be 180 ppm (10 mg ziram/kg bw/day) for ziram administered in the diet.

These values can be adapted to technical SDDC by correcting for the difference in molecular weight, DDC-release and concentration:

NOAEL (maternal)= 10 mg ziram/kg bw/day × 2.26= 22.6 mg SDDC/kg bw/day,

NOAEL (repro)= 25 mg ziram/kg bw/day × 2.26= 56.5 mg SDDC/kg bw/day,

NOAEL (foetal)= 10 mg/kg bw/day × 2.26= 22.6 mgSDDC/kg bw/day.

Data for thiram were submitted in the initial registration dossier. However, as detailed in the analogue justification, ziram is the more relevant source substance. The data on thiram are provided for sake of completeness.

Short description of key information:
A two-generation toxicity study (OECD 416) with the source substance ziram revealed no indication for effects on fertility.
NOAEL (maternal) = 22.6 mg SDDC/kg bw/day
NOAEL (repro) = 56.5 mg SDDC/kg bw/day
NOAEL (foetal) = 22.6 mg SDDC/kg bw/day
(NOAELs are corrected for differences in molecular weight and for the differences in the concentration of ziram tested and SDDC (41.44%))

Justification for selection of Effect on fertility via oral route:
The study performed with the relevant source substance was chosen.

Effects on developmental toxicity

Description of key information

No indication for specific effects on pre-natal development in a developmental toxicity study (OECD 414) with SDDC.
NOAEL (maternal), rat = 5 mg/kg bw/day
NOAEL (foetal), rat = 500 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 Sep 1986 - 03 Feb 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: 190 - 290 g (females); 270 - 470 g (males)
- Housing: Animals were individually housed in suspended stainless steel cages except during acclimation and during mating period.
- Diet: certified rodent chow (mash, by Ralston Purina Company), ad libitum
- Water: tap water
- Acclimation period: at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.4
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 30 Sep 1986 To: 03 Feb 1987

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared immediately prior to dosing on each day by dissolving the test material in distilled water yielding a final concentration of 1, 10 and 100 mg/mL dosing solution, respectively.

VEHICLE
- Amount of vehicle: 5 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability of the samples, and the concentration of the dosing solutions were investigated using High Pressure Liquid Chromotagraphy (HLPC). Homogeneity analysis was performed prior to initiation of the definitive study on 2 and 200 mg/mL solutions of the test material in water. The results were found to be homogenous. Stability analysis was performed on 2 and 200 mg/mL solutions of the test material in water at 0, 0.5 and 1 h after vehicle addition prior to initiation of the definitive study. There was no significant decrease in test material concentration over the 1 h interval. Once per week during dosing, the dose solutions from all groups for that day were analyzed for test material concentration. The actual mean values for test material concentrations were 0.79 mg/mL for the low-dose group, 11.38 mg/mL for the mid-dose group and 120.14 mg/mL for the high-dose group resulting in dose levels of 3.95, 56.9 and 601 mg/kg bw/day, respectively. The nominal concentration of the dosing solutions were 1, 10 and 100 mg/mL (corresponding to 5, 50 and 500 mg/kg bw/day (nominal)), respectively.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug or sperm in vaginal rinse referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 6 - 15 of gestation

Frequency of treatment:

daily

Duration of test:

Day 6 - 20 of gestation

Dose / conc.:

5 mg/kg bw/day (nominal)

Dose / conc.:

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

Remarks:

based on the results of the dose formulation analysis

Dose / conc.:

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

Remarks:

Doses in maternal animals are based on maternal body weight determined on gestation day 6. However, the pregnant animals gain weight rapidly during the study and are approximately 20% (50 g) heavier at the end of dosing (day 15/16) than on day 6. Therefore, applying a conservative approach, the actual dose level of 3.95 mg/kg bw/day was converted to maternal body weights on gestation day 16, resulting in a body weight-corrected and actually received dose level of 3.33 mg/kg bw/day.

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

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

Remarks:

based on the results of the dose formulation analysis

Dose / conc.:

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

Remarks:

Doses in maternal animals are based on maternal body weight determined on gestation day 6. However, the pregnant animals gain weight rapidly during the study and are approximately 20% (50 g) heavier at the end of dosing (day 15/16) than on day 6. Therefore, applying a conservative approach, the actual dose level of 56.9 mg/kg bw/day was converted to maternal body weights on gestation day 16, resulting in a body weight-corrected and actually received dose level of 48.69 mg/kg bw/day.

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

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

Remarks:

based on the results of the dose formulation analysis

Dose / conc.:

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

Remarks:

quivalent to 601 mg/kg bw/day based on the results of the dose formulation analysis. Moreover, dDetermined on gestation day 6. However, the pregnant animals gain weight rapidly during the study and are approximately 20% (50 g) heavier at the end of dosing (day 15/16) than on day 6. Therefore, applying a conservative approach, the actual dose level of 601 mg/kg bw/day was converted to maternal body weights on gestation day 16, resulting in a body weight-corrected and actually received dose level of 540 mg/kg bw/day.

No. of animals per sex per dose:

22 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Confirmed mated females were assigned to groups randomly using a random numbers table.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined for viability once in the morning, once in the afternoon and at times of dosing.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A physical examination was schedulded to be performed prior to treatment and on days 6, 9, 12, 16 and 20 of gestation.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded prior to treatment and on days 6, 9, 12, 16 and 20 of gestation.

FOOD CONSUMPTION: Yes
- Food consumption of mated females was calculated for days 0 - 6 of gestation, days 6 - 9 of gestation, days 9 - 12 of gestation, days 12 -16 of gestation and days 16 - 20 of gestation based on feed jar weights measured on corresponding days.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20: Mated females were sacrificed by CO2 inhalation on day 20 of gestation.
- Organs examined: A gross necropsy was performed on mated females, and abnormal tissues were stored in 10% neutral buffered formalin but were not examined histopathologically.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes, uterus with ovaries attached were weighes.
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes, late resorptions were examined grossly for external malformations. All live and dead fetuses were examined externally and weighed.
- Soft tissue examinations: Yes, approximately one half of the fetuses of each litter. The viscera of all decapitated fetuses was examined by the Staples technique.
- Skeletal examinations: Yes, all fetuses were processed for skeletal staining with Alizarin red. Examination of the skeletons for malformation and ossification variation was made on the fetuses that were not decapitated.
- Head examinations: Yes, approximately one half of the fetuses of each litter were decapitated and the heads were examined by the Wilson`s technique.
- Other: The sex of each fetus was determined by external and internal examination.

Statistics:

Please refer to "any other information on materials and methods incl. tables".

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

50 mg/kg bw/day: 1/22 females showed chromodacryorrhea.
500 mg/kg bw/day: Excess salivation before and after dosing was observed in 6/22 females. 1/22 females showed chromodacryorrhea and 1/22 females had dry red material around the eye.

Alopecia was noted in animals of each experimental group and was not judged to be treatment related.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

5 mg/kg bw/day: The body weight gain was significantly reduced during days 6 - 20 (75%), when compared with the body weight gain of the control group. Absolute body weights were not affected.
50 mg/kg bw/day: Body weight gain was significantly reduced during gestation intervals on days 6 - 9 (44%) and on days 0 - 20 (73%), respectively, when compared with the body weight gain of the control group. The absolute body weights on gestation days 16 (95%) and 20 (94%) were also significantly reduced when compared with the control group.
500 mg/kg bw/day: Significantly reduced absolute body weights on gestation days 9 (90%), 12 (92%), 16 (90%) and 20 (90%), and significant decreased body weight gain during gestation intervals (gestation days 6 - 9, 9 - 12, 12 - 16 and 0 - 20, respectively) were calculated when compared with the control group, respectively.

The gestation day 20 maternal body weight corrected for uterus weight (day 20C) was significantly reduced for the 50 mg/kg bw/day (94%) and 500 mg/kg bw/day (91%) groups with a dose related trend evident. This variable (day 6-20C) was significantly decreased (75, 73 and 50%) for the low-, mid- and high-dose females, respectively, and was linearly related to dose. However, the effect in the low-dose group was not considered to be toxicologically relevant, since the absolute body weights and the corrected body weight gains during the other intervals (day 0-6, day 6-9, day 9-12, day 12-16, day 16-20 and day 0-20) were not affected by the treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption by pregnant rats was significantly reduced on days 6 - 9 of gestation for the 50 mg/kg bw/day and the 500 mg/kg bw/day group, respectively. In the 500 mg/kg bw/day group reduced food consumption was noted during days 9 - 12 of gestation and days 12 - 16 of gestation. Dose related trends of decreased food consumption were evident for the intervals of days 6 - 9, 9 - 12 and 12 - 16 of gestation, respectively. Food consumption was not significantly reduced for the 5 mg/kg bw/day group.

Food efficiency:

not examined

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

not examined

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:

no effects observed

Description (incidence and severity):

Gravid uterus weight, measured on gestation day 20, was not significantly different among the experimental groups.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Control group: 1/22 females showed an apparent diverticulum of the colon.
5 mg/kg bw/day: In 1/22 females a moderately dilated renal pelvis was noted.
500 mg/kg bw/day: A renal pelvis moderately distended, filled with a white suspension and a pale renal medulla were observed in 1/22 females.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

not examined

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

5 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: The only effect observed at the lowest dose level was the reduced body weight gain during days 6 - 20 (corrected for gravid uterus weight), which was not considered to be adverse, since the absolute body weights were not affected.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

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

Based on:

test mat.

Remarks:

body weight-corrected dose level

Basis for effect level:

other: The only effect observed at the lowest dose level was the reduced body weight gain during days 6 - 20 (corrected for gravid uterus weight), which was not considered to be adverse, since the absolute body weights were not affected.

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Anal atresia was noted in 1 fetus of the control group and 1 fetus of the 500 mg/kg bw/day group. Other malformations were unique to individual fetuses.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Several variations in the extent of skeletal ossification (e.g. parietals, zygomatic arch, hyoid, sacral vertebrae, hindpaw phalanges) were decreased in incidence for the test material treated groups, although these findings were isolated and do not appear biologically significant. The overall incidence of fetal variations was not statistically different among the experimental groups.
Incidences of individual types of malformation were not statistically significantly different among the experimental groups based on either the litter or fetus as the experimental unit. The most commonly observed malformation was an abnormality of the thoracic ribs (angular, knobby, or wavy) noted in 4 fetuses (3 litters) of the control group and 1 fetus of the 5 mg/kg bw/day group. Missing lumbar vertebrae was seen in 1 fetus of the control group, 1 fetus of the 50 mg/kg bw/day group, and 2 fetuses (2 litters) of the 500 mg/kg bw/day group. Missing lumbar vertebrae with pelvic girdle malformed was observed in 1 fetus of the control group and 1 fetus of the 500 mg/kg bw/day group.
Overall malformation incidences were not statistically significantly different among the experimental groups when tested as total malformed fetuses/total live fetuses, litters with malformed fetuses/total litters, total malformed fetuses/total implantations, or the mean number of malformed fetuses in the litter. There were no statistically significant differences between the experimental groups in the total number of resorptions/total implantations, the total affected implantations/total implantations, litters with at least one resorption/total litters, or litters with at least one affected implantation/total litters.

Visceral malformations:

no effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse and treatment-related effects on developmental parameters were observed.

Key result

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

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

Based on:

test mat.

Remarks:

body weight-corrected dose level

Sex:

male/female

Basis for effect level:

other: No adverse and treatment-related effects on developmental parameters were observed.

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

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A pre-natal developmental toxicity study, conducted similar to OECD 414 and according to GLP, is available for SDDC (Wier, 1987). 22 female Sprague-Dawley rats were treated with dose levels of 5, 50 and 500 mg/kg bw/day (nominal values) via gavage from gestation days 6 to 15. Dose levels in animals were based on maternal body weight determined on gestation day 6. To consider the rapid weight gain during gestation the nominal dose values 5, 50 and 500 mg/kg bw/day were converted to maternal body weights on gestation day 16 and in addition to the results of the analytical verification, resulting in corrected dose level of 3.3, 48.7 and 540 mg/kg bw/day, respectively. All animals were examined for viability once in the morning, once in the afternoon and at times of dosing. A physical examination was schedulded to be performed prior to treatment and on days 6, 9, 12, 16 and 20 of gestation. Body weight and food consumption were measured prior to treatment and on days 6, 9, 12, 16 and 20 of gestation. A gross necropsy was performed on all mated females on gestation day 20. Intact uteri with ovaries attached were weighed and Corpora lutea were counted. Uterine contents were examined for the number of implantation sites, early and late resorptions, live and dead fetuses. Fetuses were examined for external abnormalities, and fetus weight was measured. The heads of approximately one half of fetuses from each litter were preserved and sections were examined by the Wilson technique, and the viscera of these fetuses were examined for abnormalities by the Staples technique. Remaining fetuses were eviscerated and processed for skeletal staining with Alizarin Red stain for assessment of skeletal malformations and ossification variations. No maternal morbidity or mortality was observed. 1/22 females showed chromodacryorrhea at 50 mg/kg bw/day. At the highest dose level of 500 mg/kg bw/day, excess salivation before and after dosing was observed in 6/22 females. In addition, 1/22 females showed chromodacryorrhea and 1/22 females had dry red material around the eye. Maternal body weight gain and food consumption were significantly lower throughout the treatment period for the 500 mg/kg bw/day group and during treatment days 6-9 for the 50 mg/kg bw/day group. At 50 mg/kg bw/day, body weight gain was significantly reduced during gestation intervals on days 6 - 9 (44%) and on days 0 - 20 (73%), respectively, when compared with the body weight gain of the control group. The absolute body weights on gestation days 16 (95%) and 20 (94%) were also significantly reduced when compared with the control group. At 500 mg/kg bw/day, significantly reduced absolute body weights on gestation days 9 (90%), 12 (92%), 16 (90%) and 20 (90%), and significant decreased body weight gain during gestation intervals (gestation days 6 - 9, 9 - 12, 12 - 16 and 0 - 20, respectively) were calculated when compared with the control group, respectively. The gestation day 20 maternal body weight corrected for uterus weight (day 20C) was significantly reduced for the 50 mg/kg bw/day (94%) and 500 mg/kg bw/day (91%) groups with a dose related trend evident. This variable (day 6-20C) was significantly decreased (75, 73 and 50%) for the low-, mid- and high-dose females, respectively, and was linearly related to dose. However, the effect in the low-dose group was not considered to be toxicologically relevant, since the absolute body weights and the corrected body weight gains during the other intervals (day 0-6, day 6-9, day 9-12, day 12-16, day 16-20 and day 0-20) were not affected by the treatment at the low dose level. Females within all experimental groups had comparable numbers of implantation sites and live fetuses. Nor fetal weight, malformation incidences neither incidences in variations of structure or extent of skeletal ossification appear biologically significant. Under the condition of this study, no developmental toxicity in rats was observed. The NOAEL for maternal toxicity was set at 5 mg/kg bw/day (equivalent to 3.95 mg/kg bw/day actually dose received) and the NOAEL for developmental toxicity was set at 500 mg/kg bw/day (equivalent to 540 mg/kg bw/day actually dose received).

Justification for classification or non-classification

The available data do not require a classification regarding reproductive toxicity.