D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Toxicity to reproduction

Administrative data

Endpoint:

one-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:

1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented guideline study according to GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Glucamide 24

IUPAC Name:

Glucamide 24

Constituent 2

Reference substance name:

287735-50-6

Cas Number:

287735-50-6

IUPAC Name:

287735-50-6

Test material form:

other: solid

Details on test material:

- Name of test material: C12/14-GS-base
- TSIN: 10000506.01
- Substance type: Pure active substance
- Stability under test conditions: Stable
- Storage condition of test material: Room temperature, in dark
- Solubility: 60 mg/L (C12); 0.025 mg/L (C14)

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)IGS BR VAF/Plus

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Crl:CD(SD)IGS BR VAF/Plus was obtained from Charles River Laboratories, Inc., Kingston, New York, USA
- Age at study initiation: Approximately 37 days
- Average weight range at study initiation: (P) Males: 132 - 160 g; (P) Females: 98 - 116 g
- Fasting period before study: Not reported
- Housing: P1 generation rats were individually housed in stainless steel, wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair of rats was housed in the male rat's cage.
- Diet: Certified Rodent Diet#5002; ad libitum.
- Water: Reverse Osmosis Water; ad libitum. Chlorine was added to the processed water as a bacteriostat.
- Acclimation period: The animals were acclimated. However the period of acclimation is not provided in the study report. No contaminants at levels exceeding the maximum concentration limits for certified feed or deviations from expected nutritional requirements were detected during feed analysis. The processed water was analyzed twice annually for possible chemical contamination.

ENVIRONMENTAL CONDITIONS
- Mean temperature range: 67.3 to 69.2°F (target: 64 to 79 °F)
- Mean relative humidity range: 52.5 to 63% (target: 30 to 70%)
- Air changes: A minimum of 10 changes/hour of 100% fresh air
- Photoperiod: 12-hours light:12-hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionized

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared weekly in Reverse Osmosis Membrane Processed Deionized Water on the basis of most recently recorded body weights. Prepared formulations were stirred continuously. Prepared formulations were stored refrigerated, protected from light in amber bottles. Dose calculations were adjusted for the 97.62% purity of the test material.

VEHICLE
- Concentration in vehicle: 1.5, 15 and 35 mg/mL for 15, 150 and 350 mg/kg be respectively
- Amount of vehicle: 10 mL/kg bw
- Purity: Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Maximum of 21 days
- Proof of pregnancy: Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ were considered to be Day 0 of gestation and assigned to individual housing.
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: Not reported
- After successful mating each pregnant female was caged: Each pregnant female was housed individually in nesting boxes. Bed-o'cobs bedding was used as the nesting material. Each dam and delivered litter was housed in a common nesting box during the postpartum period.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Testing of stability of test solution and analytical verification of test concentration: Triplicate samples were taken from the top, middle and bottom of each concentration prior to the start of study and monthly thereafter. Two samples of each triplicate set were shipped for analysis; the remaining samples were retained at the Testing Facility as backup samples.

Duration of treatment / exposure:

Approximately 5 months

Frequency of treatment:

Once daily (beginning from 70 days prior to mating until the day before sacrifice)

Details on study schedule:

- Age at mating of the mated animals in the study: Approximately 107 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 15, 150 and 350 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

25 animals/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dosages were selected by the Sponsor based on the available data prior to the initiation of dosage.
- Rationale for route of administration: (i) in comparison with the dietary route, the exact dosage can be accurately administered, (ii) it is one possible route of human exposure and (iii) the test substance is unpalatable in the diet.
- Rationale for animal assignment: The rats were assigned to four dosage groups, 25 rats per sex per group, based on computer-generated (weight-ordered) randomization procedures.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for viability; Animals were observed for test substance related clinical observations daily before and approximately one hour after administration.
- Cage side observations included were: Viability, mortality and clinical observations

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Daily during the dosage period and at sacrifice

FEED CONSUMTION: Yes
- Time schedule for examinations:
Males: Weekly during the cohabitation and post cohabitation period
Females: Weekly until cohabitation, on Day 0, 6, 10, 15, 20 and 25 (if necessary) of gestation and on Day 1, 4, 7, 10 and 14 of lactation.

Oestrous cyclicity (parental animals):

Estrous cycling was evaluated by examination of vaginal cytology for 21 days prior to cohabitation.

Sperm parameters (parental animals):

Parameters examined in male parental generations:
- Right testis, left testis, left epididymis (whole and cauda), right epididymis, prostate and seminal vesicles with coagulating gland (with or without fluid) were weighed in male parental generations.
- A portion of the left cauda epididymis was used for evaluation of cauda epididymal sperm concentration and motility using computer-assisted sperm analysis. Motility was evaluated by the Hamilton Thorne IVOS with collection of a sample from the left cauda epididymis through a swim-out method. Sperm concentration (sperm per gram of tissue weight) was evaluated by the Hamilton Thorne IVOS.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on Day 4 postpartum: Yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Number and sex of pups, number of implantation sites, stillborn pups, and general condition of the litter during the postpartum period. Each litter was evaluated for viability at least twice each day. The pups present in each litter were counted once each day. Pup body weights were recorded on Days 1, 4, 7, 14 and 21. Clinical observations were recorded once daily during the postpartum period (Day 1 to Day 21 of lactation).

GROSS EXAMINATION OF DEAD PUPS: Yes, pups found dead were examined for gross lesions and for the cause of death. All pups found dead on Day 2 to 4 of lactation were preserved in Bouin's solution for possible future evaluation. All pups found dead on Day 5 to 21 of lactation were preserved in neutral buffered 10% formalin.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were sacrificed by CO2 asphyxiation, after completion of the cohabitation period.
- Maternal animals: All surviving female rats were sacrificed after completion of the Day 21 postpartum period. Rats that did not deliver a litter were sacrificed on Day 25 of gestation and were examined for pregnancy status. Rats that died were examined for the cause of death on the day that the observation was made. Female rats without a confirmed mating date that did not deliver a litter were also sacrificed on an estimated Day 25 of gestation and necropsied.

GROSS NECROPSY
Gross necropsy included an initial physical examination of external surfaces and all orifices, as well as an internal examination of tissues and organs in situ. The following were examined: external and internal portions of all hollow organs; the external surfaces of the brain and spinal column, the nasal cavity and neck with associated organs and tissues; the thoracic, abdominal and pelvic cavities with associated organs and tissues; and the musculo/skeletal carcass.
Gross lesions were retained in neutral buffered 10% formalin and examined histologically.

ORGAN WEIGHTS: The following organs were individually weighed:
Brain, pituitary gland, ovaries, uterus with cervix, right testis, left testis, left epididymis (whole and cauda), right epididymis, prostate and seminal vesicles with coagulating gland (with or without fluid).

HISTOPATHOLOGY:
Histopathological examinations were performed on following tissues of control and high dose group rats:
Brain, pituitary gland, ovaries, vagina, uterus with cervix, testes, epididymides, seminal vesicles with coagulating gland and prostate
The testes were fixed in Bouin’s solution for 48 to 96 hours and then retained in neutral buffered 10% formalin for histopathological evaluation. Histopathology was also performed on the testes of all male rats that failed to induce pregnancy and on ovaries of all female rats that were not pregnant.

Postmortem examinations (offspring):

ACRIFICE AND GROSS NECROPSY
- All pups removed from study due to standardization on Day 4 of lactation were sacrificed and examined for gross lesions. Necropsy included a single cross section of the head at the level of the frontal-parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly.
- All pups were preserved in Bouin's solution.
- All other pups were sacrificed and discarded at weaning on Day 21 of lactation.

Statistics:

- All adult and pup incidence data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution.
- Body weights, body weight changes, feed consumption data, durations of gestation and delivery, litter averages for pup body weights and percent male or pups and mortality, cumulative survival and parameters involving continuous data were analyzed using Bartlett's Test of Homogeneity of Variances and the Analysis of Variance (when appropriate).
- If the Analysis of Variance was significant (p≤0.05), Dunnett's Test was used. If the Analysis of Variance was not appropriate, the Kruskal-Wallis Test was used. In cases where the Kruskal-Wallis Test was statistically significant, Dunn's Method of Multiple Comparisons was used to identify the statistical significance of the individual groups.
- All other natural delivery data involving discrete data were evaluated using the Kruskal-Wallis Test.
- Sperm motility data were expressed as percentages and analyzed, as indicated above, by parametric methods.

Reproductive indices:

The females were evaluated for following indices:
1) Duration of gestation: Day 0 of gestation to the day the first pup was observed.
2) Precoital index: Length of time for mating to occur
3) Mating index: Percentage of mating
4) Fertility index: Percentage of matings that result in pregnancies
5) Gestation index: Percentage of pregnancies that result in birth of live litters
Maternal behavior was evaluated on Day 1, 4, 7, 14 and 21 of lactation.

Offspring viability indices:

1) Viability indices: Percentages of pups born that survive to Day 1 and 4 of lactation.
2) Lactation indices: Percentage of pups alive after culling on Day 4 of lactation that survives to Day 21 of lactation.
3) Percent survival and sex ratio (tabulated at Day 1, 4, 7, 14 and 21 of lactation)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

at 350 mg/kg body weight (slight clinical effects at 150 mg/kg body weight are not considered substance but treatment related)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

at 350 mg/kg reduced body weight and reduced feed consumption

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

at 350 mg/kg reduced body weight and reduced feed consumption

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY: No treatment related mortality was observed in the male and female animals.
- Males:
Test substance-related clinical observations observed in male rats at 150 and 350 mg/kg/day dosage groups included excess salivation, rales, chromorhinorrhea, a red or dried red perioral substance and chromodacryorrhea (350 mg/kg/day dosage group only).
- Females:
Clinical observations observed during the precohabitation, gestation and lactation periods included excess salivation and rales in 150 and 350 mg/kg/day dosage groups. These observations were considered test substance-related because they were increased in a dosage dependent manner.
All other clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test substance.

BODY WEIGHT:
- Males:
Decreased body weight gains in the 350 mg/kg/day dosage group were considered related to the test substance as they were dosage-dependent. Average body weight gains were reduced to 92% of the control group value in the 350 mg/kg/day dosage group on Day 1 to 70 of study. Body weight gains were also reduced to 75% and 89% of the control group values on Day 91 to 119 of study and Day 1 to termination, respectively, in the 350 mg/kg/day dosage group. Terminal body weights and absolute body weights on Day 112 to 119 of study were significantly reduced in the 350 mg/kg/day dosage group.
- Females:
Average body weights and body weight gains during the precohabitation period were comparable among the four dosage groups. Maternal body weight gains were significantly reduced in the 350 mg/kg/day dosage group for the entire gestation period [Days 0 to 20 of gestation] and on Day 0 to 6 of gestation. Absolute maternal body weights were significantly reduced on Day 12 and 20 of gestation, slightly reduced on all other days of the gestation period and significantly reduced on each day of the lactation period in the 350 mg/kg/day dosage group when compared to the vehicle control group values.
Average maternal body weights and body weight gains during the lactation and gestation period were unaffected by dosages of test substance as high as 150 mg/kg/day.

FOOD CONSUMPTION:
- Males: Absolute and relative feed consumption values were unaffected by dosages of test substance as high as 350 mg/kg/day.
- Females: Absolute feed consumption values were significantly reduced in the 350 mg/kg/day dosage group for the entire gestation period. Absolute and relative feed consumption values during the precohabitation period and lactation period were comparable among the four dosage groups.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE
Dosages of the test substance as high as 350 mg/kg/day did not affect estrous cycling (number of estrus stages per 14 days).

REPRODUCTIVE FUNCTION: SPERM MEASURES
No statistically significant or biologically important differences occurred in the number or the percentage of motile sperm, the number of non-motile sperm, and the sum of the motile and nonmotile sperm. Cauda epididymal sperm counts were 86%, 90% and 80% and density values were 93%, 88% and 85% of the vehicle control group values in the four respective dosage groups. These non-statistically significant reductions were not considered biologically important because mating and fertility parameters were comparable among the dosage groups.

REPRODUCTIVE PERFORMANCE
- The precoital index, the fertility and mating indices and the number of rats with confirmed mating dates during the first and second week of cohabitation were comparable in the four dosage groups.
- All female rats were mated. Pregnancy occurred in 23 (92.0%), 23 (92.0%), 21 (100%) and 22 (88.0%) female rats in the four respective dosage groups (0, 15, 150 and 350 mg/kg bw).
- Natural delivery observations were unaffected by dosages of the test substance as high as 350 mg/kg/day. The gestation index, the number of dams delivering litters, the duration of gestation, averages for implantations and dams with stillborn pups were comparable among the four dosage groups and did not differ significantly.

ORGAN WEIGHTS:
The absolute organ weights and the ratios of these organ weights to the terminal body weight or absolute brain weight of the P1 generation male and female rats were comparable in all four dosage groups.

GROSS PATHOLOGY
- Males: All necropsy observations were considered unrelated to the test substance due to following reasons:
(i) The incidences were not dosage-dependent.
(ii) The observation commonly occurs in this strain of rat and/or;
(iii) The observation occurred in the rats that were found dead.
- Females: Necropsy observations in rats that survived until scheduled sacrifice were limited to two clear fluid-filled cysts on the left kidney of one rat in the vehicle control group. This observation was not considered test substance-related because the observation occurred in a vehicle control group rat.

HISTOPATHOLOGY: There were no test substance-related microscopic changes observed in the brain, pituitary or reproductive tissues of male and female rats in the 350 mg/kg/day dosage group. Microscopic examination of the testes of male rats and ovaries of female rats that failed to reproduce that revealed no findings that could be correlated with infertility.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Reduced body weight gains and slight reductions in feed consumption values at 350 mg/kg bw. Slight clinical findings at 150 mg/kg body weight not considered substance but treatment related

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

CLINICAL SIGNS: All clinical observations in the F1 generation pups were considered unrelated to the test substance.

BODY WEIGHT AND ALL OTHER PARAMETERS: All litter parameters were unaffected by dosages of the test substance as high as 350 mg/kg/day. These included the number of pups found dead or presumed cannibalized from Day 1 to 21 of lactation, viability index, lactation index, pup body weights, surviving pups, percent male pups and live litter sizes at weighings. The number of pups found dead or presumed cannibalized was significantly increased (p≤0.01) in the 350 mg/kg/day dosage group on Day 1 of lactation. This increase was not considered test substance-related because the viability and lactation indices were comparable among the dosage groups.

NECROPSY: All necropsy observations in the F1 generation pups were considered unrelated to the test substance. Necropsy of pups that were found dead revealed no milk in stomach in 3, 2, 1 and 1 pup from the four respective dosage groups (0, 15, 150 and 350 mg/kg bw). All pups appeared normal at necropsy on Day 4 and 21 of lactation.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 350 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Overall effects on litter parameters

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The reproductive toxicity NOAEL for Glucamide 24 when administered orally at 0, 15, 150 and 350 mg/kg/day in rats was ≥ 350 mg/kg bw.

The NOAEL for parental toxicity was established at 150 mg/kg bw (based on reduced body weight gains and slight reductions in feed consumption).

Executive summary:

The one generation reproduction toxicity study of Glucamide 24was determined following methods comparable to theOECD Guideline 415 (One-Generation Reproduction Toxicity Study).

One hundred male and one hundred female Crl:CD®(SD)IGS BR VAF/Plus rats received from Charles River Laboratories, Inc., Kingston, New York, USA were used in this study. The animals were housed individually in stainless steel, wire-bottomed cages except during the cohabitation and postpartum periods. During the mating period, each pair of rats was housed in the male rat's cage. During the treatment period, the animals were fed a certified rodent diet, ad libitum. The animals were randomly assigned to the following four dosage groups with 25 rats per sex per dosage group:

Group 1 (Vehicle control): 0 mg/kg bw

Group 2 (Low dose group): 15 mg/kg bw

Group 3 (Mid dose group): 150 mg/kg bw

Group 4 (High dose group): 350 mg/kg bw

Reverse osmosis membrane processed deionized water (R.O. deionized water) served as a vehicle control. The test substance was administered orally (via gavage) to male and female rats once daily (beginning 70 days prior to mating until the day before sacrifice) at a constant volume of 10 mL/kg bw.

The P1 generation animals were mated in a 1:1 ratio for a maximum period of 21 days or until the presence of a copulatory plug was confirmed. Following breeding, each pregnant female was housed individually in a nesting box.

All P1 generation rats were observed for viability at least twice daily. Animals were observed for test substance related clinical observations daily before and approximately one hour after administration. Additionally, female rats were observed daily for abortions and premature deliveries. Body weights were recorded daily during the dosage period and at sacrifice. Feed consumption values for male rats were recorded weekly during the study. Feed consumption values for female rats were recorded weekly until cohabitation, on Day 0, 6, 10, 15, 18, 20 and 25 (if necessary) of gestation and on Day 1, 4, 7, 10 and 14 of lactation.

The female rats were evaluated for duration of gestation, precoital index, mating index, viability index, fertility index, gestation index, number and sex of offspring per litter, number of implantation sites, general condition of the dam and litter during the postpartum period. Variations from expected maternal behavior were recorded during the postpartum period.

Each litter/pup was evaluated for viability, viability indices, lactation index and percent survival and sex ratio. Pup body weights were recorded on Days 1, 4, 7, 14 and 21 of lactation. The pups present in each litter were counted once each day. Clinical observations were recorded once daily during the postpartum period.

After completion of the mating period, P1 generation males were subjected to gross necropsy. Sperm evaluations were also conducted in parental male animals. P1 generation female rats were sacrificed after completion of the 21-day postpartum period. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed in both male and female rats and the gross lesions were retained and examined histologically. The following organs were weighed: brain, pituitary gland, ovaries, vagina, uterus with cervix, testes, epididymides, seminal vesicles with coagulating gland and prostate. Histopathological examinations were performed on the above referenced tissues of all control and high dosage group rats.

Further, histopathology was also performed on the testes of all male rats that failed to induce pregnancy and on ovaries of all female rats that were not pregnant.

All F1 generation pups removed from study due to standardization on Day 4 of lactation were sacrificed and examined for gross lesions. Pups found dead were examined for gross lesions and for the cause of death. Further, all surviving F1 generation pups were sacrificed after the postpartum period and discarded.

No P1 generation male or female rats died as a result of treatment with test substance during this study.

Test substance-related clinical observations observed in male rats in the 150 and 350 mg/kg/day dosage groups included excess salivation, rales, chromorhinorrhea, a red or dried red perioral substance and chromodacryorrhea (350 mg/kg/day dosage group only). Clinical observations observed during the precohabitation, gestation and lactation periods of female rats included excess salivation and rales in the 150 and 350 mg/kg/day dosage groups. These observations were considered test substance-related because they increased in a dosage dependent manner.

Reduced body weight gains in males and females at 350 mg/kg/day were considered related to the test substance. Absolute and relative feed consumption values in males were unaffected by the highest test substance dose (350 mg/kg/day). However in females, the absolute feed consumption values were significantly reduced at 350 mg/kg/day for the entire gestation period. Absolute and relative feed consumption values during the precohabitation period and lactation period of females were comparable among the four dosage groups.

The absolute organ weights and the ratios of these organ weights to the terminal body weight or absolute brain weight of the P1 generation male and female rats were comparable in all four dosage groups. No test substance related necropsy observations were noted in P1 generation male and female rats. There were no test substance-related microscopic changes observed in the brain, pituitary or reproductive tissues of male and female rats in the 350 mg/kg/day dosage group. Microscopic examination of the testes of male rats and ovaries of female rats that failed to reproduce revealed no findings that could be correlated with infertility.

Dosages of the test substance as high as 350 mg/kg/day did not affect estrous cycling (number of estrus stages per 14 days). No statistically significant or biologically important differences occurred in the number or the percentage of motile sperm, the number of non-motile sperm, and
the sum of the motile and non-motile sperm. The precoital index, the fertility and mating indices and the number of rats with confirmed mating dates during the first and second week of cohabitation were comparable in the four dose groups. All female rats were mated and pregnancy occurred in 23 (92.0%), 23 (92.0%), 21 (100%) and 22 (88.0%) female rats in the four respective dosage groups (0 (vehicle), 15, 150 and 350 mg/kg bw).

Natural delivery and litter observations were unaffected after administration of the test substance as high as 350mg/kg/day.All clinical and necropsy observations in the F1 generation pups were considered unrelated to the test substance. All litter parameters were unaffected by dosages of the test substance as high as 350 mg/kg/day.

Based on above, the reproductive toxicity NOAEL for Glucamide 24in a one generation study was ≥ 350 mg/kg bw.

The parental toxicity NOAEL for Glucamide 24was established at 15 mg/kg bw (based on adverse clinical observations, reduced body weight gains and slight reductions in feed consumption).

This one-generation reproduction toxicity study is classified as acceptable, and satisfies the guideline requirements of the OECD 415 method.