Mecoprop

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 February 1979 to 20 April 1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The teratogenic potential of the test material by oral administration was evaluated in Sprague Dawley rats.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Mecoprop

EC Number:

230-386-8

EC Name:

Mecoprop

Cas Number:

7085-19-0

Molecular formula:

C10H11ClO3

IUPAC Name:

2-(4-chloro-2-methylphenoxy)propanoic acid

Test material form:

solid: particulate/powder

Remarks:

Buff coloured feathery powder.

Details on test material:

Storage: The sample was stored at 4 °C and protected from light.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Female rats were nulliparous and aged between 10 and 12 weeks at the start of the study. Male rats were sexually mature.
- Housing: Prior to mating, the rats were housed in groups of five of the same sex in solid floor polypropylene cages with stainless steel lids (56 cm x 38 cm x 18 cm). During mating, one male was housed with four females in similar cages. Mated female rats were housed individually in solid floor polypropylene cages with stainless steel lids (38 cm x 25 cm x 18 cm).
- Diet: Commercial pelleted diet, ad libitum.
- Water: Mains water was available from glass bottles attached to each cage. The water was changed daily and the bottles replaced at approximately weekly intervals.
- Acclimation period: The animals were acclimatised to the laboratories for a minimum period of 12 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.5 ± 5.5 °C
- Humidity (%): 69.5 ± 20.5 %
- Air changes (per hr): The room was fully air-conditioned providing 18 - 20 complete air changes per hour.
- Photoperiod (hrs dark / hrs light): The lighting of the room was entirely artificial fluorescent lighting with a controlled cycle of 12 hours light (06.00 - 18.00 hours):12 hours dark.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Methyl cellulose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- The test material was prepared as a suspension in 1 % methyl cellulose and formulated so that a constant dose volume of 10 mL/kg was used.
- Each time that suspensions were prepared, separate aliquots of test material was weighed for each dosage level.
- Batches of test material suspensions were prepared at weekly intervals. The prepared suspensions were stored in opaque plastic containers at room temperature.

VEHICLE
- 1 % methyl cellulose.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Samples of each prepared batch of test and positive control material suspensions were stored in plastic containers at 4 °C for subsequent analysis, should this be required.

Details on mating procedure:

The rats were mated on a harem basis with four females per male. Vaginal smears were checked in the morning for the presence of sperm. The day on which sperm was observed was designated day 0 of gestation. Smearing was discontinued when sperm was found. The stage of oestrus at the time of mating was also recorded.
For mating, males and females were housed together for 23 days over a 39 day period.
The day on which sperm were observed in a vaginal smear was designated day 0 of gestation.

Duration of treatment / exposure:

The test and control materials were administered once daily from day 6 to day 15 of gestation (i.e. day 6 to day 15 after mating). The appropriate individual dose volumes administered were adjusted after each weighing i.e. on days 6, 9, 12 and 15, after mating.

Frequency of treatment:

Once daily.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: mg/kg/day

Remarks:

Group 1: Control

Doses / concentrations 2

Dose / conc.:

20 other: mg/kg/day

Remarks:

Group 3

Doses / concentrations 3

Dose / conc.:

50 other: mg/kg/day

Remarks:

Group 4

Doses / concentrations 4

Dose / conc.:

125 other: mg/kg/day

Remarks:

Group 5

No. of animals per sex per dose:

Control: 30 female rats + 8 additional animals
Positive control: 12 female rats + 4 additional animals
Test material: 20 female rats + 8 additional animals

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels were selected by the client, following examination of the data from a preliminary dose ranging study in the pregnant rat (report number 679R-277/6).
- Rationale for animal assignment: Immediately after mating, the female rats were allocated to treatment groups according to body weight, so that the mean weight and weight distribution were similar in all groups. and in a manner so as to reduce temporal bias. The position of the animals in the battery was determined using computer generated random number tables. At necropsy, the animals were killed in an order dictated by random number tables.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All mated females were examined at least once daily to determine their general health and behaviour. Any changes observed were recorded. Animals dying during the study were necropsied.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each mated female rat was recorded on days 0, 3, 6, 9, 12, 15, 18 and 21, after mating.

FOOD CONSUMPTION
- Food consumption of each mated female rat was recorded on days 3, 6, 9, 12, 15, 18 and 21, after mating.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: The female rats were killed by cervical dislocation on day 21 after mating, dissected and subjected to gross necropsy.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Numbers of corpora lutea.
- Numbers and positions of foetuses and intra-uterine deaths.

Intra-uterine deaths were classified as early or late. Late intra-uterine deaths showed embryonic or foetal tissue in addition to placental tissue, whereas early intra-uterine deaths showed decidual or placental tissue only.

Fetal examinations:

External examinations: Yes
- Individual foetal weights.
- Individual foetal crown/rump lengths.
- Sex of foetuses.
- The exterior of all the foetuses was examined.

Before being weighed and measured, the foetuses were killed by an intracardiac injection of Euthatal (pentobarbitone sodium solution, 200 mg/mL).

Visceral examinations: Yes
- One half of the foetuses from each litter was dissected under x2 magnification and the viscera examined.

Skeletal examinations: Yes
- The foetuses were then eviscerated and the carcasses placed in 1 % (w/v) aqueous potassium hydroxide containing 0.005 % Alizarin Red S to stain the ossified skeleton. The specimens were processed through ascending concentrations of glycerol/ distilled water. During this process (at the 30 - 50 % mole of glycerol/ distilled water stage) they were examined. They were preserved in absolute glycerol containing thymol crystals and stored in individual 30 mL plastic universal containers.

The remaining foetuses were placed in Bouin' s fixative for at least one week to allow fixation and partial decalcification. They were then transferred to 70 % alcohol, and free-hand transverse sections were made with a razor using Wilson's technique. The sections were examined under x6 magnification. The sections from each foetus were stored individually in plastic tubing containing Bouin's fluid.
Abnormalities were recorded as major (rare and/or probably lethal) or minor (common deviations from normal). Variations in the degree of ossification of the phalanges were also recorded at skeletal examination. Incompletely or non-ossified phalanges were classed as variants.
In calculation of the number of foetuses with defects, external/visceral defects and skeletal defects were considered separately because only half of the foetuses were examined for skeletal defects. Therefore, a foetus with both external/visceral defects and skeletal defects would be included twice in the calculation of defects.

Statistics:

Data were processed where appropriate to given mean values, group mean values and standard deviation.
Certain mean values were subscripted mean 1 and mean 2. Mean 1 values included data from those animals with functional corpora lutea in the ovaries on day 21 after mating. Mean 2 values included data from those animals with live foetuses. Group mean calculations were based on mean rather than individual data.

Standard statistical tests were applied to the data where appropriate, viz:-
- Foetal weights, foetal crown/rump lengths: Wilcoxon's rank sum test.
- Pre-implantation loss, implantations, intra-uterine deaths, foetal abnormalities: Fisher's two-sum randomisation (permutation) test with a Monte Carlo simulation for computation of significance levels.

With all statistical tests, the litter was considered as the experimental unit.

Indices:

Pre-implantation losses were calculated according to the formula:

% pre-implantation loss = (number of corpora lutea - number of implantations) / number of corpora lutea x 100

Sex ratios were calculated:

1: number of females / number of males

Historical control data:

In comparing data from this study with background data, the overall cumulative total (test facility and other laboratories, vehicle tested and animals from inactive treatments) was used.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Group 3 (20 mg/kg/day test material):
- A clinical change was observed in only one animal. Number 98 (pregnant) showed red-brown discolouration of the hair on the head and neck from day 9 to day 21 after mating.

Group 4 (50 mg/kg/day test material):
- Two rats (numbers 228 and 588 - pregnant) showed red-brown discolouration of the hair on the head and neck from day 9 to day 21 after mating. No clinical changes were observed in any other animal.

Group 5 (125 mg/kg/day test material):
- A clinical change was observed in only one animal. In number 232 (pregnant), the eyes appeared pale from day 18 to day 21 after mating.
- One rat (number 203) littered on day 17 after mating. As the pups appeared normal for day 1 post-partum, it was presumed that mating actually occurred several days prior to the date recorded. The dam and progeny were killed, and the data from this animal were excluded from group totals and means.

Positive control (20 mg/kg/day aspirin)
- Two rats in this group showed clinical signs. In one (No. 31 - pregnant), hair loss was noted on the back from day 9 to day 21 after mating, and in the other (No. 72 - pregnant) difficulty in breathing prior to dosing was observed on day 11 after mating.
- One rat (No. 84 - not pregnant) was dosed in error for two days from day 3 after mating and was subsequently killed on day 15.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Group 1 (Control 1 % methyl cellulose)
- One rat died on day 14 after mating.
- No clinical changes were observed in any of the other animals.

Group 3 (20 mg/kg/day test material):
- One rat (number 136 - not pregnant) died on day 13 after mating.

Group 4 (50 mg/kg/day test material):
- No deaths occurred.

Group 5 (125 mg/kg/day test material):
- No deaths occurred.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Group mean body weights were calculated using only data from pregnant animals surviving to day 21 after mating.

Group 1 (control) animals showed a steady weight gain throughout gestation. Weight gain of group 3 animals (20 mg/kg/day test material) was similar to the group 1 controls. Group 4 animals (50 mg/kg/day test material) showed a slight retardation in weight gain between days 3 and 12 of gestation and a slightly lower overall percentage body weight gain than the group 1 controls. In group 5 (125 mg/kg/day test material) there was a retardation of weight gain in comparison with the group 1 controls from day 9 to day 21 after mating, and a lower overall body weight gain was observed. The retardation in group 5 was partly attributable to one pregnant animal (number 232) which lost weight over gestation and to another (number 42) which showed a very low weight gain. However, even if these two animals were discounted, the overall weight gain was still slightly lower than the group 1 controls.

There was a slight retardation of weight gain in group 2 (positive control) animals from day 6 to day 9 of gestation, but generally weight gain was similar to the group 1 controls.

The overall percentage weight gains (day 0 - 21 after mating) were 50.2 %, 46.2 %, 51.8 %, 43.7 % and 38.4 % in groups 1, 2, 3, 4 and 5, respectively.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Group mean food intakes were calculated using only data from pregnant animals surviving to day 21 after mating.

Mean food intake in the group 1 (control) animals increased steadily up to day 15 of gestation. Between day 15 and 18, a peak was observed. This was followed by a decrease towards the end of gestation.

Mean food intake levels in the test material treated groups were lower than in group 1 (control) before dosing commenced.

In group 3 (20 mg/kg/day test material), food intake was very slightly lower after the onset of dosing, but on days 12 to 15 it was higher than in group 1; thereafter it followed the control pattern.

In group 4 (50 mg/kg/ day test material), a reduction in mean food intake was observed at the start of the dosing period, then it increased slightly and returned to the control pattern from day 15 onward.

In group 5 (125 mg/kg/day test material), a reduction in food intake was observed between day 9 and day 15 of gestation and remained lower than in group 1 (control) throughout the post-dosing period.

In group 2 (positive control), a reduction in mean food intake was noted at the start of the dosing period (day 6 to day 9 of gestation) but then increased between days 12 and 15 and was greater than the control value. From day 15 onwards, it followed the control pattern.

The overall mean daily food intake was 25.5 g, 24.7 g, 25.3 g, 24.3 g and 22.5 g in groups 1, 2, 3, 4 and 5, respectively.

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

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Group 1 (control 1 % methyl cellulose):
- One rat died on day 14 after mating. Necropsy revealsed slight opacity of the right eye and the lungs appeared moderately congested and showed evidence of oedema.
- At necropsy on day 21 after mating, the liver of one rat (pregnant) appeared fatty and in another the uterine meseneries appeared fatty.

Group 2 (positive control, 250 mg/kg/day aspirin)
- One rat (No. 84 - not pregnant) was dosed in error for two days from day 3 after mating and was subsequently killed on day 15. No abnormalities were detected at necropsy in this or an other animal.

Group 3 (20 mg/kg/day test material):
- One rat (number 136 - not pregnant) died on day 13 after mating. At necropsy, the lungs appeared slightly congested and there was partial collapse of all lobes.
- At necropsy on day 21 after mating, three rats (number 28 - pregnant and numbers 74 and 199 - not pregnant) showed excessive fat in the abdomen. No abnormalities were detected in any other animal.

Group 4 (50 mg/kg/day test material):
- At necropsy on day 21 after mating, one rat (number 14 - not pregnant) showed adhesion of the pericardial sac and the right lung lobes to the thoracic wall. In another rat (number 135 - pregnant), all the placentae appeared enlarged. No abnormalities were observed at necropsy in any other animal.

Group 5 (125 mg/kg/day test material):
- At necropsy on day 21 after mating, one rat (number 192 - not pregnant) had excessive fat in the abdomen. In another rat (number 42 - pregnant), two placentae appeared enlarged. No abnormalities were observed at necropsy in any other animal.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Maternal developmental toxicity

Number of abortions:

not examined

Pre- and post-implantation loss:

effects observed, treatment-related

Description (incidence and severity):

Implantations
- Mean numbers of corpora lutea per dam were similar in group 1 (control) and in the test material treated groups. All values were higher than the cumulative normal mean for this strain of rat.
- Pre-implantation losses in groups 1 (control), 4 (50 mg/kg/day test material) and 5 (125 mg/kg/day test material) were similar but all values were higher than the cumulative normal mean. In group 3 (20 mg/kg/day test material), pre-implantation loss was significantly lower than in group 1 (control) (p<0.05: Fisher's test).
- The mean number of implantations per dam was similar to group 1 (control) in group 4 (50 mg/kg/day test material) and 5 (125 mg/kg/day test material) but was slightly higher in group 3 (20 mg/kg/day test material).
- In group 2 (positive control), pre-implantation loss was lower and the mean number of corpora lutea and implantations was higher than in group 1 (control).

Intra-uterine deaths
- Early intra-uterine deaths: Early intra-uterine deaths were observed in all test material treated groups and in group 1 (control). The incidence in groups 3 (20 mg/kg/day test material) and 4 (50 mg/kg/day test material) was similar to group 1 (control). The incidence in group 5 (125 mg/kg/day test material) was higher than in group 1 (control) but was not significantly different at the 95 % level of confidence (Fisher's test). The incidence in group 2 (positive control) was significantly higher than in group 1 (control) (p<0.01:Fisher's test).
- Late intra-uterine deaths: No late intra-uterine deaths were observed in groups 1 (control) or 3 (20 mg/kg/day test material) and, in group 4 (50 mg/kg/day test material), only one was noted. Five were observed in group 5 (125 mg/kg/day test material), but this number was not significantly different from the group 1 controls at the 95 % level of confidence (Fisher's test). Six late intra-uterine deaths were observed in group 2 (positive control) but the incidence was not significantly different from group 1 (control) at the 95 % level of confidence (Fisher's test).
- Total intra-uterine deaths (post-implantation loss): The incidence of total intra-uterine deaths was similar to that in group 1 (control) in groups 3 (20 mg/kg/day test material) and 4 (50 mg/kg/day test material), but significantly higher in group 5 (125 mg/kg/day test material) (p<0.05: Fisher's test). Post-implantation loss in group 2 (positive control) was significantly higher than in group 1 (control) (p<0.01:Fisher's test).

Total litter losses by resorption:

not examined

Early or late resorptions:

not examined

Dead fetuses:

not examined

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

effects observed, non-treatment-related

Description (incidence and severity):

Overall pregnancy incidences, including animals that died or were killed during the study were 65.8 %, 68.8 %, 71.4 %, 67.9 % and 75.0 % in groups 1, 2, 3, 4 and 5, respectively. The pregnancy incidences for the animals that survived to day 21 after mating were 64.9 %, 73.3 %, 74.1 %, 67.9 % and 74.1 % in groups 1, 2, 3, 4 and 5, respectively. Therefore, the number of mated females that became pregnant was unaffected by treatment.

Other effects:

not examined

Details on maternal toxic effects:

Body weight gain of animals treated at 125 mg/kg/day test material (group 5) was lower than in group 1 (control). The low group mean body weights were partly attributable to one dam which lost weight over gestation and to another which showed a very low weight gain. However, even if these two animals are discounted there was still a very slight retardation of weight gain in comparison with group 1 (control). As the weight gain in the dams given 50 mg/kg/day test material was also slightly retarded during pregnancy, these effects are considered to be a manifestation of maternal toxicity. There was no effect at the lowest dosage (20 mg/kg/day test material). These findings are consistent with the observed slight reductions in food intake among test material treated rats.

There was an indication of slight embryolethality at 125 mg/kg/day test material as post-implantation loss was statistically significantly higher than in group 1 (control). This was due to a high incidence of dams showing early intra-uterine deaths. There was no increase in post-implantation loss at the lower test material dose levels.

One rat (number 203) littered on day 17 after mating. As the pups appeared normal for day 1 post-partum, it was presumed that mating actually occurred several days prior to the date recorded. The dam and progeny were killed, and the data from this animal were excluded from group totals and means.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Remarks on result:

not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Foetal weights:
- Mean foetal weight in group 5 (125 mg/kg/day test material) was slightly lower than in group 1 (control), but the difference was not significant at the 95 % level of confidence (Wilcoxon's test). Mean foetal weight in the other test material treated groups was similar to that in group 1 (control). All values were within the cumulative normal range, but were slightly lower than the cumulative normal mean. In group 2 (positive control), mean foetal weight was significantly lower than in group 1 (control) (p<0.01: Wilcoxon's test).

Foetal crown/rump lengths:
- Mean crown/rump length in group 5 (125 mg/kg/day test material) was significantly lower than in group 1 (control) (p<0.01: Wilcoxon's test). Mean crown/rump length in the other test material treated groups was similar to group 1 (control). All values were within the cumulative normal range, but were slightly lower than the cumulative normal mean. In group 2 (positive control), mean crown/rump length was significantly lower than in group 1 (control) (p<0.01: Wilcoxon's test).

Reduction in number of live offspring:

not examined

Changes in sex ratio:

effects observed, non-treatment-related

Description (incidence and severity):

The calculated sex ratios in the test material treated groups and in group 2 (positive control) did not differ significantly from group 1 (control) values (Wilcoxon's test - 95 % level of confidence). Group mean values were 1:0.90, 1:1.02, 1:0.92, 1:0.87 and 1:1.11 in groups 1, 2, 3, 4 and 5, respectively.

Changes in litter size and weights:

effects observed, non-treatment-related

Description (incidence and severity):

Number of foetuses:
- The mean number of foetuses per dam was similar in groups 4 (50 mg/kg/day test material) and 5 (125 mg/kg/day test material) and slightly higher in group 3 (20 mg/kg/ day test material) than in group 1 (control). All values were within the cumulative normal range and were higher than the cumulative normal mean.
- The mean number of foetuses per dam in group 2 (positive control) was slightly lower than in group 1 (control) as a result of higher post-implantation loss.

Litter weights:
- Mean litter weight was higher in group 3 (20 mg/kg/day test material), slightly higher in group 4 (50 mg/kg/day test material) and slightly lower in group 5 (125 mg/kg/day test material) when compared with group 1 (control). None of the test material values was significantly different from group 1 (control) at the 95 % level of confidence (Wilcoxon's test).
- In group 2 (positive control), mean litter weight was significantly lower than in group 1 (p<0.05: Wilcoxon's test).

Anogenital distance of all rodent fetuses:

not examined

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Group 1, 3, 4 and 5 (negative control and treatment groups):
- Minor external/visceral defects: Foetuses showing minor external/visceral defects were observed in all test material treated groups and in group. 1 (control). The defects most frequently observed were dilated ureter, increased renal pelvic cavitation and subcutaneous haemorrhagic areas of the body. The incidence of foetuses showing only minor external/visceral defects was slightly, but not significantly, higher in the test material treated groups than in group 1 (control) (Fisher's test - 95 % level of confidence); the incidence was not dose related. Group percentage incidences were 8.2 %, 10.3 %, 15.4 % and 12.7 % in groups 1, 3, 4 and 5, respectively.

- Major external/visceral defects: In group 1 (control), one foetus showed a major defect. Foetus number 149/R2 showed encephalocele. No major defects were observed in group 3 (20 mg/kg/day test material). In group 4 (50 mg/kg/day test material), three foetuses from different litters showed major defects. Number 217/R6 showed encephalocele, number 228/R3 showed hydronephrosis and number 588/14 showed umbilical hernia. In group 5 (125 mg/kg/day test material), one foetus showed a major defect. Foetus number 260/R1 showed subcutaneous oedema and a short kinked tail. The percentage of foetuses showing major external/visceral defects was 0.3 %, 0.0 %, 1.4 % and 0.4 % in groups 1, 3, 4 and 5, respectively.
In group 2 (positive control) 16 of the 117 foetuses (13.7 %) showed major external and visceral defects. All the foetuses in group 2 (positive control) had variants and the number of litters affected was significantly higher than in group 1 (control) (p<0.05: Fisher's test). The nature and incidence of these defects confirms the susceptibility of this strain of rat to aspirin.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

- Minor skeletal defects: Minor skeletal defects were observed in all the test material treated groups and in group 1 (control). The defects observed were mainly incomplete sternebral ossification, bipartite thoracic vertebrae and incomplete ossification of the metatarsals. The incidence was higher in group 5 (125 mg/kg/ day test material) than in group 1 (control) but the difference was not significant at the 95 % level of confidence (Fisher's test). The increased incidence was largely due to a higher proportion of the foetuses showing retarded ossification. The percentage of foetuses showing minor skeletal defects was similar to, or lower than, group 1 ( control) in groups 3 (20 mg/kg/ day test material) and 4 (50 mg/kg/day test material). The percentage of foetuses in which the skeletons were examined, that showed minor skeletal defects was 38.8 %, 39.3 %, 29.8 % and 54.2 % in groups 1, 3, 4 and 5, respectively.

- Major skeletal defects: No major defects were observed in the test material treated groups or in group 1 (control). There were no significant differences between the control and test material treated groups in the incidences of major and minor external/visceral defects, major and minor skeletal defects and variants at the 95 % level of confidence (Fisher's test).

- Variants: The percentage of foetuses showing variants was similar to group 1 (control) in groups 3 (20 mg/kg/day test material) and 4 (50 mg/kg/day test material); the incidence was slightly but not significantly higher in group 5 (125 mg/kg/day test material) at the 95 % level of confidence (Fisher's test) .

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

See 'External malformations'.

Details on embryotoxic / teratogenic effects:

There was evidence of slight foetotoxicity at the 125 mg/kg/day test material dose level, as mean foetal weight was slightly lower and mean crown/rump length was statistically significantly shorter than in group 1 (control). These effects were reflected in the higher proportion of foetuses showing delayed ossification although the incidence of minor skeletal defects and variants in the group treated at 125 mg/kg/day test material did not differ significantly from group 1 (control) (Fisher's test - 95% level of confidence).

Major defects were observed in the control and test material treated groups. There was no consistent pattern in the type of major defect observed and no treatment related effect was seen. The nature and incidence of major defects, the marked embryolethality and the marked test material in group 2 (positive control) proved the susceptibility of this strain of rat to aspirin.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Remarks on result:

not measured/tested

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the test material showed no evidence of teratogenicity at the dose levels studied.

Executive summary:

The teratogenicity of the test material to the rat was assessed. 

Groups of sexually mature nulliparous Sprague Dawley-derived rats were dosed with the test material by oral gavage at dose levels of 20, 50 and 125 mg/kg daily (in a volume of 10 mL/kg) from day 6 to day 15 after mating. A group of animals receiving 1 % methyl cellulose (10 mL/kg) over the same period acted as the control group. In addition, a group of similar animals was dosed with aspirin (250 mg/kg/day) over the same period to serve as the positive control. (The vehicle control group and positive control group were common to a similarly designed, concurrent teratogenicity study), (report number 1996-277/7b).

There was no indication of treatment-related clinical changes in the dams.

Pregnancy incidence was unaffected by treatment with the test material. 

There was a slight retardation in the body weight gain of the group 5 dams (125 mg/kg/day test material) and a low overall body weight gain was observed. The group 4 dams (50 mg/kg/day test material) were also slightly affected, but the body weight gain of those in group 3 (20 mg/kg/day test material) was similar to that of the group 1 controls.

During the dosing period, all mecoprop treated groups showed some reduction in food intake; the effect was most pronounced in group 5 (125 mg/kg/day test material).

Pre-implantation loss and the mean number of live foetuses per litter were unaffected by treatment with the test material.

Post-implantation loss was significantly higher in group 5 (125mg/kg/day test material) (p<0.05: Fisher's test) than in group 1 (control), but was similar to the group 1 controls in the other test material treated groups.

In comparison with group 1 (control), mean foetal weight was slightly lower in group 5 (125 mg/kg/day test material).

Mean crown/rump length was similar to the group 1 controls in groups 3 (20 mg/kg/day test material) and 4 (50mg/kg/day test material) but significantly shorter in group 5 (125mg/kg/day mecoprop) (p<0.05: Wilcoxon's test).

The percentage of foetuses showing minor external and visceral defects in the test material treated groups was slightly, but not significantly, higher than in group 1 (control) (Fisher's test - 95 % level of confidence). The incidences were not dose-related.

The percentage of foetuses showing minor skeletal defects and variants was similar to, or lower than, the group 1 controls in groups 3 (20 mg/kg/day test material) and 4 (50 mg/kg/day test material). The incidence was higher in group, 5 (125 mg/kg/day test material) due largely to a higher proportion of foetuses showing retarded ossification. The incidence of major defects was unaffected by treatment with the test material.

In group 2 (positive control), findings were consistent with those expected following treatment with aspirin. These were increased post-implantation loss, reduced mean foetal weight and crown/rump length and an increased incidence of major foetal defects, in comparison with group 1 (controls).

Under the conditions of this study, the test material showed no evidence of teratogenicity at the dose levels studied.