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Diss Factsheets

Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 generation
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with no deviations
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 416: Two Generation Reproduction
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of method:
in vivo

Test material

Constituent 1
Chemical structure
Reference substance name:
2-chloropropionic acid
EC Number:
209-952-3
EC Name:
2-chloropropionic acid
Cas Number:
598-78-7
Molecular formula:
C3H5ClO2
IUPAC Name:
2-chloropropionic acid
Details on test material:
Test materials: L-CPA

Description: Colourless Liquid
Lot/Batch: Bx 19 (Assigned CTL ref YO6206/004)
Purity: 96.6% w/w by calculation of which 92.7% L- and 4% D-

Stability: chemical stability of L-CPA in diet at concentrations 150 and 1500 ppm was considered satisfactory for 7 days at room temperature or 92 days in frozen storage.

Test animals

Species:
rat
Strain:
other: Alpk:APfSD
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test animals
Species: Rat
Strain: Alpk:APfSD (Wistar-derived)
Age: 22 days old
Weight at dosing: 84.1 – 93.5g for F0 adults (includes males and females)
Source: Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire. UK
Acclimatisation period: 7 days prior to start of dosing
Diet: CT1, ad libitum
Water: Filtered mains water, ad libitum
Housing: Animals were housed, sexes separately, in multiple rat racks.
Environmental conditions
Temperature: 21 +/- 2°C
Humidity: 55 +/- 15%
Air changes: At least 15 per hour
Photoperiod: 12 hours of light/12 hours of darkness

Administration / exposure

Route of administration:
oral: feed
No. of animals per sex per dose:
Groups of 26 male and 26 female rats (F0 adults) weaning Alpk:APfSD rats were fed diets containing 0 (control), 150, 500 or 1500ppm L-chloropropionic acid (L-CPA) the racemic version of A-CPA.
Details on study design:
Groups of 26 male and 26 female rats (F0 adults) weaning Alpk:APfSD rats were fed diets containing 0 (control), 150, 500 or 1500ppm L-chloropropionic acid (L-CPA) the racemic version of A-CPA. The breeding programme was repeated in the controls, 150 and 500ppm groups with the F1 adults selected from the F1A offspring to produce the F2A litters after a 10 week pre-mating period. The 150 and 500ppm test diets were fed continuously to the males and females through the study. The 1500ppm test diet was fed continuously to the females during the first generation lactation phase when control diet was fed. At this stage the F1A litters in the 1500ppm group were between days 11 and 17 post partum. The 1500ppm diet was fed continuously to males up to termination.
Statistics:
Group mean values of the treated groups were compared with the appropriate control group using Student t-test (two sided) with the exception of pup organ weights.

Results and discussion

Effect levels

Dose descriptor:
NOEL
Remarks:
500ppm L-CPA
Remarks on result:
not measured/tested
Remarks:
Effect level not specified

Observed effects

Clinical findings which were attributed to treatment with L-CPA were confined to the 1500ppm group. During weeks 1-6 of the pre-mating period in the first generation signs of neurotoxicity were seen intermittently in several males and females and were characterised by prostration with gripping and biting the bars of the cage with some showing erection of the tail. These signs appeared to be triggered by external stimuli (cage opening), lasting for approximately 1-2 minutes and were followed by unsteady gait and muscle tremors. These signs were recorded as bizarre behaviour. Two males were killed as a result of these findings and loss of bodyweight, one in week 4 and one in week 6.

During lactation in the first generation bizarre behaviour or clonic convulsions were recorded for several females in the 1500ppm group on one or two days between days 5 and 15 post partum.

Offspring findings related to L-CPA were confined to the F1a litters of the 1500 ppm group. These findings were associated with the poor survival seen especially after day 15 in these litters. These were considered by the study director to reflect increased maternal toxicity rather than a direct response to the pups. This in turn almost certainly reflects the substantially increased feed intake during lactation, which at a constant dietary inclusion level gives a substantial increase of the received dose to the dams.

Applicant's summary and conclusion

Conclusions:
Based on this study there are no reproductive effects of L-CPA but the neurotoxic potential of the compound is confirmed in the parental animals.
Executive summary:

Clear signs of toxicity were seen in male and female rats diets containing 1500ppm L-CPA in the form of neurotoxicity with associated brain lesions and reductions in bodyweight gain and food consumption. There were no effects on fertility or offspring parameters at birth and the high incidence of F1a pup mortality in the 1500 ppm group was attributed to increased maternal toxicity most probably as a result of the increased food consumption, and therefore dose rate, during lactation. The no observed effect level was 500 ppm L-CPA in diet.