Registration Dossier

Administrative data

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:
experimental study
Adequacy of study:
key study
Study period:
26 September 1989 - 5 October 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study compliant with test guidelines of the time. However, current guidelines for two-generation reproduction toxicity studies require additional endpoints. Available as unpublished report, fully adequate for assessment.
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
1983 (current guideline adopted 2001)
Deviations:
yes
Remarks:
(does not meet current guideline specification)
Qualifier:
according to
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Version / remarks:
1982 (current guideline adopted 1998)
Deviations:
yes
Remarks:
(does not meet current guideline specification)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Spraque-Dawley rats, strain Crl:CD (SD)BR
- Age at study initiation: P generation - approx. 6 weeks old
- Weight at study initiation: P generation - males 162-226 g, females 134-181 g
- Housing: individual in solid floor macrolone cages with stainless steel lids except during mating (one male with one female) and during lactation (one female with litter). Autoclaved sawdust bedding.
- Diet: powdered Ssniff R 10 ad libitum
- Water: tap water in plastic bottles ad libitum
- Acclimation period: P generation 18 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25°C
- Humidity: 30-70%
- Photoperiod: 12 hrs dark / 12 hrs light

Route of administration:
oral: feed
Vehicle:
other: diet
Details on exposure:
DIET PREPARATION
- The test substance was milled to a standardised particle size and admixed to the powdered diet. Fresh preparations were made monthly


Details on mating procedure:
One male was housed with one female from the same group for up to three weeks. After 2 weeks, females with no evidence of mating were paired with a proven male from the same group. Mating was confirmed by the presence of sperm in a vaginal smear or a vaginal plug and designated day 0 of gestation. After successful mating, females and males were caged individually. Sibling pairing was avoided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
All batches of test diet made were analysed for achieved concentration and homogeneity. Stability was confirmed for the period of use and storage conditions. Satisfactory results were obtained. Analysis was by HPLC.
Duration of treatment / exposure:
From the start of the P generation through to necropsy of individual animals - F1 and F2a.
Frequency of treatment:
Continuous
Details on study schedule:
- Pre-mating period P Generation: 100 days
- Selection of F parents from F1 generation at 21 days of age
- F1 parental animals not mated until 100 days after weaning
Remarks:
Doses / Concentrations:
0, 50, 500, 5000 and 10000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: on basis of preliminary study
- Rationale for animal assignment: P generation by stratified randomisation based on body weight and the use randomisation tables; F1 generation selected by stratified use of randomly drawn cards
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly for males and females during the pre-mating and mating periods; for females on days 0, 7, 14 and 20 post coitum and days 1, 4, 7, 14 and 21 post partum

FOOD CONSUMPTION:
- Time schedule for examinations: twice weekly for males and females during the pre-mating period; for females on days 0-3, 3-7, 7-10, 10-14, 14-20 post coitum and days 1-4, 4-7, 7-10, 10-12, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20, 20-21 post partum. Food consumption was calculated as mean daily food consumption per measuring period
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OTHER:
- Date of mating
- Date of parturition
- Duration of gestation
- Abnormalities of nesting or nursing behaviour

Oestrous cyclicity (parental animals):
Not recorded
Sperm parameters (parental animals):
Not recorded
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes to 8 pups (4 males and 4 females where possible)

PARAMETERS EXAMINED
- F1 and F2 offspring: number and sex of pups, live births, postnatal mortality, clinical condition, body weight, pinna unfolding, tooth eruption, eye opening, pupillary reflex and auditory response

GROSS EXAMINATION OF DEAD PUPS:
- yes, for external and visceral abnormalities
Postmortem examinations (parental animals):
Parental males were necropsied after mating, females after weaning. Successfully mated females which failed to produce a litter were necropsied on day 26 post coitum. All parental animals were examined for gross pathological changes. Uteri were immersed in 10% ammonium sulfide to reveal evidence of implantation. The number of implantations was recorded.
The following tissues were sampled and fixed from all F0 and F1 adult animals: bladder, cervix, coagulating gland, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, testes, uterus, vagina and macroscopically altered organs. Histopathology was conducted in controls and top dose group animals. Epididymides, kidneys, liver and testes were weighed before fixation. In addition, the kidneys of group 4 animals were examined histologically.
Postmortem examinations (offspring):
Non-selected pups from F1 and F2 litters were necropsied after weaning.
Statistics:
Statistical analyses used the SAS software package release 6.03.
Analysis of variance with one factor treatment followed by the Student-Newman-Keuls test for multiple group comparisons: body weight, body weight gain, litter weight, organ weights, food consumption.
Analysis of variance with one factor treatment based on taking the ranks of the variables and followed by the Student-Newman-Keuls test for multiple group comparisons: mating performance, duration of gestation, mean pup weight, pup number, live birth index, viability indices, weaning index, pinna unfolding, hair growth, incisor eruption, eye opening.
Reproductive indices:
For both generations the parental reproductive performance was assessed and the following calculated: mating performance, insemination index, fecundity index, fertility index, gestation index
Offspring viability indices:
Live birth index, pup viability index, weaning index and sex ratio
Clinical signs:
effects observed, treatment-related
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
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: Table 1
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Mortality: No effects in P animals; four F1 males given 10000 ppm and found dead were considered treatment-related
Clinical signs: Five P females with fur staining considered treatment-related but finding not seen in F1 generation

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight: The males and females of the P and F1 generations given 10000 ppm had slightly lower body weights during the premating period.
Food consumption: No effect in P generation; slightly lower food consumption in F1 generation males and females.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS):
Dietary concentrations of 50, 500, 5000 and 10000 ppm are calculated to be equivalent to 4, 40, 420 and 830 mg/kg bw/day respectively based on food intake and body weight during the pre-mating periods.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment-related findings in P generation males or females. Changes in the kidneys and urinary bladder in particular were considered to be related to treatment with 10000ppm in F1 males and females. Groups given 50, 500 or 5000 ppm were unaffected.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment-related findings in P generation males or females. Changes in the kidneys and urinary bladder were considered to be related to treatment with 10000ppm in F1 males and females. There were a variety of inflammatory changes mainly moderate to marked subacute to chronic interstitial pyelonephritis associated with changes such as hyaline casts, tubular and pelvis dilatation associated with parenchymal atrophy, pelvis lithiasis and signs of hyperplastic response such as proliferation and metaplasia of the urothelium. Groups given 50, 500 or 5000 ppm were unaffected.

Dose descriptor:
NOAEL
Remarks:
fertility and reproductive performance
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested equivalent to 830 mg/kg bw/day
Dose descriptor:
NOAEL
Remarks:
toxicity
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Equivalent to 420 mg/kg bw/day. 10000ppm: reduced body weight, renal pelvis dilatation in pups.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Table 2
Sexual maturation:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Table 3
Histopathological findings:
not examined
BODY WEIGHT (OFFSPRING)
The mean pup weight of the F1a and F2a pups was significantly reduced at weaning on day 21 post partum.

PHYSICAL DEVELOPMENT (OFFSPRING)
There were no treatment-related effects on the physical development (incisor eruption, pinna unfolding, eye opening) of the F1a of F2a pups or on the outcome of the functional tests (pupillary reflex, auditory response) on either generation.

GROSS PATHOLOGY (OFFSPRING)
Macroscopic examination revealed a high incidence of changes in the kidneys, particularly dilatation of the renal pelvis, in the F1a pups; groups treated at 50, 500 and 5000 ppm remained unaffected. A low incidence of F2a pups had dilatation of the renal pelvis not clearly treatment-related.


Dose descriptor:
NOAEL
Remarks:
fertility and general reproductive performance
Generation:
F1
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested equivalent to 830 mg/kg bw/day
Dose descriptor:
NOAEL
Remarks:
toxicity
Generation:
F1
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Equivalent to 420 mg/kg bw/day. 10000 ppm: reduced body weight and histological changes in the kidneys of adults.
Reproductive effects observed:
not specified

Table 1 Test Substance Intake During The Pre-Mating Period (corrected means – mg/kg/day)

 

Males

Dietary concentration (ppm)

Females

Dietary concentration (ppm)

P Generation

50

500

5000

10000

P Generation

50

500

5000

10000

Week 1

5.2

51.2

555.4

1066.9

Week 1

5.1

49.7

548.8

1086.0

Week 14

2.8

28.0

277.9

565.9

Week 14

3.7

35.9

369.9

732.4

Mean intake

3.5

35.3

370.7

721.6

Mean intake

4.2

40.7

422.8

846.9

Overall mean intake for males and females

3.9

38.0

396.8

784.3

F1 Generation

F1 Generation

Week 1

6.2

66.6

627.1

1212.1

Week 1

6.6

69.1

673.0

1274.9

Week 14

2.9

30.7

300.9

613.3

Week 14

3.7

38.4

372.2

735.4

Mean intake

4.0

41.1

408.7

819.5

Mean intake

4.6

48.3

487.3

945.6

Overall mean intake for males and females

4.3

44.7

448.0

882.6

Overall mean intake for males and females

P + F1 generations

4.1

41

422

833

 

Table 2 Group Mean Pup Body Weight (g)

 

F1a pup

Weight (g)

Dietary concentration (ppm)

F2a pup

Weight (g)

Dietary concentration (ppm)

0

50

500

5000

10000

0

50

500

5000

10000

Day 1

6.1

5.9

6.1

6.1

6.2

Day 1

6.2

6.0

5.9

6.1

6.3

Day 4

7.5

7.1

7.3

7.6

7.6

Day 4

8.0

7.6

7.3

7.6

7.9

Day 7

11.4

10.3

10.8

11.4

10.9

Day 7

11.6

11.4

10.3

10.6

11.2

Day 14

24.5

21.6

22.9

25.2

21.8

Day 14

24.3

24.6

22.9

24.7

23.8

Day 21

41.0

36.6

38.3

39.6

34.9*

Day 21

41.8

41.0

40.3

40.0

37.7*

 P<0.05 * statistically significant difference from control

Table 3 Incidence of pups with renal pelvic dilatation

 

F1a pups

Dietary concentration (ppm)

F2a pups

Dietary concentration (ppm)

0

50

500

5000

10000

0

50

500

5000

10000

No. Examined

228

253

232

237

206

No. Examined

197

217

185

231

213

Unilateral

1

0

2

0

10

Unilateral

1

1

1

2

1

Bilateral

1

1

3

0

20

Bilateral

0

0

1

3

2

 

Conclusions:
Dietary administration of 10000 ppm CGA185072 over two generations resulted in lower body weights of the adult animals and the pups from weaning together with microscopic renal and urinary bladder alterations in adults and pelvic dilatation in pups (essentially F1a). There was no effect of CGA185072 on fertility or reproductive performance in either generation and no effect on the number and viability of the pups born. The NOAEL for toxicity was 5000 ppm, corresponding to a mean daily intake of 350 mg/kg bw/day.
Executive summary:

Groups of 25 male and 25 female Sprague-Dawley rats were given CGA185072 tech. in the diet at nominal concentrations of 0, 50, 500, 5000 and 10000 ppm continuously from the start of treatment until necropsy.

After a pre-mating period, the P parental animals were mated and allowed to litter and to rear the F1a pups to weaning. After a 100 day post weaning maturation period the selected F1 parental animals were mated and allowed to litter and to rear the F2a pups to weaning.

At 10000 ppm, effects in the P and Fl parental animals included reduced body weight and food consumption, the death of four Fl males and histological changes in the kidney and urinary bladder of the Fl animals. For pups, mean body weight was significantly reduced on day 21 for both F1a and F2a pups and the incidence of renal pelvic dilatation was increased in F1a pups. There were no adverse effects of 50, 500 or 5000 ppm CGA185072 tech.

There was no effect on fertility or general reproductive performance in either of the two generations at any dietary concentration of CGA185072 tech. in this study.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
830 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

The reproductive toxicity of cloquintocet-mexyl has been evaluated in a two-generation (one litter per generation) study in the rat in a key guideline study (OECD 416, 1983) conducted to GLP. This study was supported by a dose range-finding study in which five groups of 7 males and 14 females were fed cloquintocet-mexyl continuously in the diet at concentrations of 0 (control), 40, 400, 4000 or 8000 ppm. After a pre-mating period of 14 days, each male was mated with 2 females and the females were allowed to litter and rear the offspring to weaning. Administration of 8000 ppm revealed slightly toxic effects on parental animals (reductions in body weight gain and food consumption during the premating period) but no toxic effects on the offspring. On the basis of this result, the highest dose level selected for the two-generation study was 10000 ppm.

For the two-generation study, groups of 25 male and 25 female rats were fed cloquintocet-mexyl continuously in the diet at nominal concentrations of 0, 50, 500, 5000 or 10000 ppm. After a 14 week pre-mating period, the P parental animals were mated and allowed to litter and to rear the F1a pups to weaning. After a 14 week post weaning maturation period the selected F1 parental animals were mated and allowed to litter and to rear the F2a pups to weaning.

At 10000 ppm, effects in the P and Fl parental animals included reduced body weight and food consumption, the death of four Fl males and histological changes in the kidney and urinary bladder of the Fl animals. For pups, mean body weight was significantly reduced on day 21 for both F1a and F2a pups and the incidence of renal pelvic dilatation was increased in F1a pups but not in F2a pups. There were no adverse effects of 50, 500 or 5000 ppm cloquintocet-mexyl. The NOAEL for toxicity was 5000 ppm, corresponding to a mean daily intake of 420 mg/kg bw/day.

There was no effect on fertility or general reproductive performance in either of the two generations at any dietary concentration of cloquintocet-mexyl in this study and thus the NOAEL for fertility was 10000ppm corresponding to a mean daily intake of 830 mg/kg bw/day.

The study was not conducted to current guidelines which require evaluation of estrous cyclicity and sperm together with extended histopathology and organ weight information for both parents and offspring. It is however, considered to be robust evaluation with no indication of adverse effects on reproduction hence no further testing is warranted.


Short description of key information:
The fertility and general reproductive performance of cloquintocet-mexyl has been evaluated in a two-generation study (OECD 416, 1983) conducted to GLP. No effect of cloquintocet-mexyl on reproduction was detected at the highest dose level tested, 10000 ppm, equivalent to 830 mg/kg bw/day. At this dose level, parental toxicity was observed and mean pup weight at weaning was decreased. The overall NOAEL for toxicity was 5000 ppm, corresponding to a mean daily intake of 420 mg/kg bw/day. Although the study was not conducted to current guidelines, it is considered to be robust and no further testing is warranted.

Justification for selection of Effect on fertility via oral route:
Only one two-generation study available.

Effects on developmental toxicity

Description of key information
The developmental toxicity of cloquintocet-mexyl has been evaluated in the rat and rabbit, in two key guideline studies (OECD 414, 1981) conducted to GLP and found not to be teratogenic at dose levels that induce maternal toxicity. Developmental toxicity, described as a reduction in mean foetal weight and a slight delay in development, was observed only in the presence of maternal toxicity i.e. at dose levels of 400 and 300 mg/kg bw/day, in the rat and rabbit respectively.  The NOAEL for maternal and developmental toxicity is 100 mg/kg bw/day in the rat and 60 mg/kg bw/day in the rabbit. Although the studies were not conducted to current guidelines, they are considered to be robust and no further testing is warranted.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 August 1987 - 31 December 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP study compliant with test guidelines of the time. However, current guidelines for prenatal developmental toxicity require an extended dosing period - from implantation to termination. Available as unpublished report, fully adequate for assessment.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
1981 (current guideline adopted 2001)
Deviations:
yes
Remarks:
(does not meet current guideline specification)
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Version / remarks:
1982 (current guideline adopted 1998)
Deviations:
yes
Remarks:
(does not meet current guideline specification)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
Chinchilla
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 16 weeks old
- Weight at study initiation: 2.9 - 3.1 kg
- Housing: Individually in Heinkel batteries with wire mesh bottom
- Diet: pelleted, certified standard diet ad libitum (Nafag No. 814)
- Water: tap water ad libitum
- Acclimatisation: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18±2°C
- Humidity: 55±10%
- Air changes: 16-20 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

Route of administration:
oral: gavage
Vehicle:
peanut oil
Remarks:
arachidis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Made weekly by mixing the test substance with the vehicle in a grinder using glass beads and a low speed rotor, portioned for each dosing day and refrigerated until use. Doses were adjusted daily for body weight. Dose volume was 4 mL/kg body weight. The dosing solutions contained 0, 2.5, 15 or 75 mg/mL CGA185072 tech.
VEHICLE
- arachidis oil, PHHVI (Siegfried AG, Zofingen, Switzerland)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Achieved concentration was determined and homogeneity and chemical stability were confirmed. The achieved concentrations ranged from 93.6-94.5%. Stability was confirmed for at least one week.
Details on mating procedure:
Each nulliparous female was mated with one male of proven fertility from the same strain of rabbit. Coitus was observed. The rabbits then remained together for at least one additional hour.
Duration of treatment / exposure:
Pregnancy days 7 - 19 inclusive
Frequency of treatment:
Once daily
Duration of test:
Pregnancy days 0 - 29, termination on day 29
Remarks:
Doses / Concentrations:
0, 10, 60, 300 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
20 mated females
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule: days 4, 8, 12, 16, 20, 24 and 29

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Macroscopic examination: main organs of the thoracic and abdominal cavities



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: abortion sites and dead foetuses. Uteri without visible signs of implantation were stained with ammonium sulphide to confirm pregnancy status.

Fetal examinations:
- Body weight and sex: Yes: all per litter
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter. Examination of viscera by fresh dissection. Examination of head by slicing technique of Wilson following fixation.
- Skeletal examinations: Yes: all per litter. Examination following staining of the skeleton with Alizarin red S
- Classification of foetal observations: Yes
Statistics:
Standard methods were applied for statistical analysis. Continuous data were analysed using student’s t-test, foetal observations were analysed using the Chi square test.
Indices:
Pre- and post-implantation losses

Historical control data:
Yes
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
300 mg/kg bw/day: 5 animals found dead between days 12 and 18 (treatment-related on basis of pathological findings); in addition one rabbit aborted on day 21 and was killed. No effect on maternal body weight or food consumption.
60 mg/kg/day: no deaths related to test substance (one rabbit found dead day 27 considered to be incidental).
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No effect of treatment on foetal weight. No increase in incidence of external, visceral or skeletal malformations or anomalies due to test substance. There was some indication of a delay in ossification although the incidence of foetuses affected overall was not statistically significant. There was no evidence of teratogenicity at any dose level.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1 Group Mean Maternal Body Weight Change (g) During Gestation

Days

Dose level (mg/kg bw/day)

0

10

60

300

0-7

261

280

300

235

7-10

-121

-52*

-81

-61

10-14

95

55

87

42

14-19

63

63

85

63

19-24

189

143*

142

171

24-29

124

129

133

149

0-29

613

618

667

598

7-29

352

338

367

363

7-19

38

66

92

43

P<0.05 * Statistically significant difference from control

 

Table 2 Group Mean Litter data

 

Dose level (mg/kg bw/day)

0

10

60

300

No. pregnant females

17

19

14

12

No. corpora lutea

10.1

10.9

10.9

11.0

No. implantations

8.7

8.5

8.8

8.6

% pre-implantation loss

14.7

20.9

18.5

22.1

% post-implantation loss

4.4

5.0

16.2**

10.0

No. live foetuses

8.3

8.2

7.7

7.6

% males

46.8

52.3

47.6

41.8

Foetal weight (g)

34.8

35.6

34.7

35.1

P<0.01 ** Statistically significant difference from control

 

Table 3 Group Mean Foetal Observations

 

Dose level (mg/kg bw/day)

0

10

60

300

No. litters examined

17

19

14

12

No. foetuses examined – external malformations

141

155

105

91

No. foetuses with external malformations

0

0

0

2

No. foetuses examined – visceral malformations

141

153

105

91

No. foetuses with visceral malformations

0

2

0

3

No. foetuses with visceral anomalies

0

1

0

0

No. foetuses examined – skeletal malformations

141

155

104

91

No. foetuses with skeletal malformations

0

0

0

2

No. foetuses with skeletal anomalies

3

3

2

3

No statistically significant differences from control

Conclusions:
A dose level of 300 mg CGA185072/kg bw was toxic to the pregnant female and resulted in the death of 5 animals. There was no effect on foetal weight, no increase in incidence of external, visceral or skeletal malformations or anomalies due to the test substance and no evidence of teratogenicity. A slight delay in foetal development was described for 300 mg/kg bw/day.
Based on the findings observed at 300 mg/kg bw/day the NOAEL for both dams and foetuses was 60 mg/kg bw/day.
Executive summary:

A dose level of 300 mg CGA185072/kg bw was toxic to the pregnant female resulting in the premature death of 5 rabbits (found dead between days 12 and 18). There was no effect of this dose on the body weight or food consumption of the surviving rabbits and neither was there any effect on foetal weight. There was no increase in incidence of external, visceral or skeletal malformations or anomalies although a slight delay in development was ascribed to 300 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of CGA185072.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
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

The developmental toxicity of cloquintocet-mexyl has been evaluated in the rat and rabbit, in two key guideline studies (OECD 414, 1981) conducted to GLP.

Groups of 24 time-mated female rats were administered cloquintocet-mexyl by oral gavage on days 6 -15 of pregnancy at dose levels of 0, 10, 100 or 400 mg/kg bw/day. Foetuses were obtained by caesarean section on day 21 of pregnancy and examined for external, visceral and skeletal malformations and anomalies. 

The dose level of 400 mg/kg bw/day was toxic to the pregnant female resulting in increased water consumption, increased wet bedding and odorous urine, reduced body weight and reduced food consumption. Lower mean foetal weight was seen in the presence of this maternal toxicity but there was no increase in incidence of external, visceral or skeletal malformations or anomalies. The NOAEL for maternal and developmental toxicity was 100 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of cloquintocet-mexyl.

Groups of 20 mated female rabbits were administered cloquintocet-mexyl by oral gavage on days 7 -19 of pregnancy at dose levels of 0, 10, 60 or 300 mg/kg bw/day. Foetuses were obtained by caesarean section on day 29 of pregnancy and examined for external, visceral and skeletal malformations and anomalies. 

The dose level of 300 mg/kg bw/day was toxic to the pregnant female resulting in the premature death of 5 animals (between days 12 and 18 of pregnancy) although no effect on body weight or food consumption was observed in the surviving rabbits. There was no effect of 300 mg/kg bw/day on mean foetal weight. There was no increase in incidence of external, visceral or skeletal malformations or anomalies although a slight delay in development was ascribed to 300 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of cloquintocet-mexyl.

On the basis of these studies, it is concluded that cloquintocet-mexyl is not teratogenic to either rats or rabbits at dose levels that induce maternal toxicity. Developmental toxicity, described as a reduction in mean foetal weight or a slight delay in development, was observed only in the presence of maternal toxicity i.e. at dose levels of 400 and 300 mg/kg bw/day, in rats and rabbits respectively. The NOAEL for maternal and developmental toxicity is 100 mg/kg bw/day in the rat and 60 mg/kg bw/day in the rabbit.

The studies were not conducted to current guidelines which require an extended dosing period to cover the period from implantation through to the day before termination. However, the studies are considered to be robust and no further testing is warranted.


Justification for selection of Effect on developmental toxicity: via oral route:
The developmental toxicity study in the rabbit was selected, the corresponding study in the rat showed a higher NOAEL.

Justification for classification or non-classification

There is adequate information available from which to assess the potential of cloquintocet-mexyl to induce reproductive or developmental effects and to conclude that classification under the DSD or CLP is not warranted:

- under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC, Annex VI, 4.2.3.

- under Regulation (EC) 1272/2008, Annex I, Part 3, 3.7.2.