N-(carboxymethyl)-N-(phosphonomethyl)glycine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study summary presented, conduct of study meets generally accepted scientific principles, acceptable for assessment.

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Principles of method if other than guideline:

Test material is administered to mated animals from Day 6 to15 of gestation. On Gestation Day 20, all surviving females are killed, the uterine contents are examined, and the fetuses are evaluated for soft tissue and skeletal changes.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(carboxymethyl)-N-(phosphonomethyl)glycine

EC Number:

227-824-5

EC Name:

N-(carboxymethyl)-N-(phosphonomethyl)glycine

Cas Number:

5994-61-6

Molecular formula:

C5H10NO7P

IUPAC Name:

2-[(carboxymethyl)(phosphonomethyl)amino]acetic acid

Details on test material:

- Name of test material (as cited in study report): Glyphosate intermediate
- Lot/batch No.: LC-lG-01-002
- Purity: 96.86 %

Test animals

Species:

rat

Strain:

other: Charles River COBS® CD®

Details on test animals or test system and environmental conditions:

Not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

Not reported

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not applicable

Details on mating procedure:

Not reported

Duration of treatment / exposure:

Day 6 to 15 of gestation

Frequency of treatment:

Daily

Duration of test:

20 d

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 100 and 400 mg/kg/day
Basis:
actual ingested
dose volume 10 mL/kg

No. of animals per sex per dose:

Twenty five

Control animals:

yes, concurrent vehicle

Details on study design:

Not reported

Examinations

Maternal examinations:

MORTALITY: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily


BODY WEIGHT: Yes
- Time schedule for examinations: On gestation Days 0, 6, 9, 12, 16 and 20


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: On Days 6, 9, 12, 16 and 20


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- Number and location of viable and nonviable fetuses: Yes
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes

Statistics:

Not reported

Indices:

Not reported

Historical control data:

Not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality: Six of 25 dams in the high dose group died between Gestation Days 15 and 19. There was no mortality in any of the other treatment groups or control.
Clinical signs: Clinical signs of toxicity observed included yellow, brown or red matting of the fur, soft stools, hair loss and emaciation. These signs were predominantly seen in those animals which died during the study.

Body weight and food consumption: Body weight loss, decreases in body weight gain and decreases in food consumption were observed in animals of the high-dose group during the period of dosing. After the dosing period, body weight gain and food consumption were comparable to the control group.

Necropsy examination: Approximately 91 % of the surviving treatment and control animals showed no gross signs of toxicity at the terminal necropsy examination. The few observations noted included kidney hydronephrosis, pale livers and distended ureters. No treatment related toxicity was evident. The number of viable fetuses, postimplantation loss, total implantations and the number of corpora lutea per dam revealed no treatment-related effects.

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Body weight: The mean fetal body weight in the high dose group was slightly reduced (~9 %) when compared with control. This fetotoxic response was considered to be related to the maternal toxicity observed in the high-dose group.

Malformations: The total number of malformations and the total number of fetuses with malformations increased in a dose related manner. However, the total number of litters with malformations were not increased. None of the malformations were observed at abnormal litter or fetal frequencies. All malformations observed commonly occur in fetal rats and were within the historical control range. An occurrence of bent ribs were observed to be slightly increased at the high dose level. But this finding was not considered to be treatment related.

A similar pattern of increased total numbers of genetic and developmental variations was observed in the mid and high dose groups. They were considered to be related to maternal toxicity rather than a teratogenic response.

Effect levels (fetuses)

Dose descriptor:

NOEL

Effect level:

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

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:

Exposure to the test material at 25, 100 and 400 mg/kg/day resulted in significant maternal toxicity at the high dose group and signs of fetotoxicity
were observed in the high- and mid-dose groups. Although the total number of fetuses with malformations increased in a dose-related manner, none of the malformations were observed at abnormal litter or fetal frequencies. Under the conditions of the test, the teratogenic no observed effect level (NOEL) was considered to be 400 mg/kg/day.

Executive summary:

A study was conducted to evaluate the teratogenic potential of test material in Charles River COBS® CD® female albino rats.

 

Test material in 0.5 % carboxymethyl cellulose was administered via oral gavage to three groups of 25 mated animals at concentrations of 0, 25, 100 and 400 mg/kg/day from Days 6 to15 of gestation. All surviving animals were sacrificed on gestation Day 20.

 

Significant maternal toxicity was observed in the high dose (400 mg/kg/day) group. Body weight loss, decreases in body weight gain and decreases in food consumption were observed in animals of the high dose group animals during the period of dosing. Examination of the reproductive parameters, i.e. viable fetuses, postimplantation loss, total implantations and the number of corpora lutea per dam revealed no treatment-related effects. The total number of malformations and the total number of fetuses with malformations increased in a dose-related manner. However, none of the malformations were observed at abnormal litter or fetal frequencies.

Under the conditions of the test, the teratogenic no observed effect level (NOEL) was considered to be 400 mg/kg/day.