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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Study Type

Species

Findings

 Guideline

Reliability 

2-Generation Feeding Study   

Rat 

Parental NOEL=0.1mg/kg/day (RBC AChE activity);

 

Neonatal NOEL=1 mg/kg/day (based on bodyweight and reduced survival index)

OECD 416, EPA OPP 83-4 

1
Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EEC Directive 87/302/EEC: Two-generation Reproduction Toxicity Test
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Toxicity Testing Guidelines for Reproduction Studies
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
AGR 273801
Purity: 98.5 or 97.8%
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
This strain of rat was selected because of its general acceptance and suitability for toxicity testing, and the availability of a reliable commercial source.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Portage, Michigan
- Age at study initiation: Approximately 6 weeks of age
- Fasting period before study: No
- Housing: Rats were housed singly in wire-mesh, stainless steel cages in racks provided with deotized cage board to minimize odor and aid in maintaining a clean environment. During the gestation/lactation phases of the study, females were housed in plastic cages provided with ground corn cob nesting material.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Atleast one week

ENVIRONMENTAL CONDITIONS
- The animal rooms of the facility were designed to maintain adequate environmental conditions concerning temperature, relative humidity, airflow and lighting, and were regulated for the species on test.
Route of administration:
oral: feed
Vehicle:
other: feed
Details on exposure:
DIET PREPARATION: Diets were prepared by serially diluting a test material/feed concentrate (premix). The mixing procedures used to prepare the diets produced a homogeneous distribution of the test substance in the rodent chow.
Details on mating procedure:
Breeding of the F0 and F1 adults commenced after approximately 10 and 12 weeks of treatment, respectively. Each breeding program consisted of three 7-day cohabitation periods with one female and one male of the respective treatment group. For the F1 mating, cohabitation of male and female litter mates was avoided. During each breeding period, daily vaginal lavage samples were evaluated for the presence of sperm as an indication of mating.
The day on which sperm were detected was considered Day 0 of gestation. Sperm positive females were separated and placed in nesting cages. Females which failed to mate during the first 7-day mating period were placed with an alternate male from the same treatment group for the second 7-day period; the same procedure was followed for the third 7-day mating period. The adult females continued to receive the respective test diet throughout gestation, lactation and until all litters on study were weaned as previously outlined. After the mating periods, males continued to receive the test diet until necropsied.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses of the test diets to determine the concentration of the test material were performed at least three times per generation. The average concentration of the test substance in the diets during the course of the study ranged from 93 to 100% of the targeted concentrations.
Duration of treatment / exposure:
Treatment started for F0 animals approximately 6 weeks of age for 2 generations until the F2 litters are weaned on day 21 postpartum.
Frequency of treatment:
7 days per week
Details on study schedule:
The treatment of the F0 rats began at approximately 6 weeks of age. After approximately 10 weeks on test diets, F0 rats were mated (one male to one female of the respective treatment group) to produce the F1 litters. Following weaning (3 weeks of age) of the F1 litters, 30 males and 30 females from each treatment group were randomly selected and assigned to the respective treatment group to become the parents for the next generation. After approximately 12 weeks of treatment following weaning of the last F1 litter, the F1 adults were bred to produce the F2 litters.
Dose / conc.:
0.1 mg/kg bw/day
Dose / conc.:
1 mg/kg bw/day
Dose / conc.:
5 mg/kg bw/day
No. of animals per sex per dose:
30 (F0 adults)
30 (F1 adults)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The dose levels were selected based on the results of the previous dietary toxicity studies in rats. The high dose level in both the males and females was expected to produce depressions in brain, plasma and RBC cholinesterase.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT AND FOOD CONSUMPTION: All F0 animals had body weights and feed consumption recorded weekly, during the 10-week pre-breeding treatment period, beginning on or before the first week of the study. Body weights for males were recorded weekly throughout the course of the study. Sperm positive females were weighed on Days 0, 7, 14 and 21 of gestation. Females that delivered litters were weighed on Days 1, 4, 7, 14, and 21 of lactation. During breeding, feed consumption was not measured in males or females due to cohousing. Following completion of the breeding periods, weekly feed consumption was again measured in males, and dietary concentrations adjusted accordingly. During gestation, feed consumption was measured at weekly intervals in sperm positive females. After parturition, feed consumption was measured once during the first week of lactation, twice during the second week of lactation and at 2 - 3 day intervals during the last week of lactation. A similar schedule was followed for the F1 generation.
Litter observations:
All litters were examined as soon as possible after delivery. The following parameters were recorded on each litter: the date of parturition, litter size on the day of parturition (Day 0), the number of live and dead pups on Days 0, 1, 4, 7, 14, and 21 postpartum, and the sex and weight of each pup on Days 1, 4 (before and after culling), 7, 14, and 21 of lactation. Visible physical abnormalities or demeanor changes in the neonates were recorded during the lactation period.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after the last litters in each generation were weaned
- Maternal animals: All surviving animals after the last litter of each generation was weaned

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Tissues routinely collected (Table 1) were preserved in neutral, phosphate-buffered 10% formalin. The testes of 10 F1 control and high dose males were also preserved in Bouin's Fixative. The lungs were infused with formalin to their approximate normal inspiratory volume. The nasal cavity was flushed with formalin via the pharyngeal duct to ensure rapid fixation of the tissue. Histologic examination of potential target organs and reproductive tissues (Table 1) was performed on the control and high-dose groups. In addition, the livers of 10 control and high-dose F1 adult males were examined microscopically. Examination of tissues from the low and middle groups was limited to the adrenals which demonstrated treatment-related histologic changes in the high-dose group, or gross lesions.
Postmortem examinations (offspring):
SACRIFICE
- At the time of weaning, 10 pups/sex/dose level from the F1 and F2 litters were randomly selected for a complete necropsy.

GROSS NECROPSY
- Grosspathologic examination was performed as described above for adults, except that terminal body weights were not recorded.

HISTOPATHOLOGY / ORGAN WEIGTHS
- Histologic examination of tissues was not performed.
Statistics:
Body weights, body weight gains and plasma, RBC and brain cholinesterase levels were evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, either a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, a Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed.
Descriptive statistics (means and standard deviations) were reported for feed consumption. Statistical outliers were identified by the method of Grubbs and excluded from these calculations. Gestation length, average time to mating and litter size were analyzed using a non parametric ANOVA. If the ANOVA was significant, the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. The fertility indices were analyzed by the Fisher exact probability test. Evaluation of the neonatal sex ratio was performed by the binomial distribution test. Survival indices and other incidence data among neonates were analyzed using the litter as the experimental unit by the Wilcoxon test as modified by Haseman and Hoel.

The nominal alpha levels to be used are as follows:
Bartlett's Test (Winer, 1971): α=0.01
Parametric ANOVA (Steel and Torrie, 1960): α=0.10
Nonparametric ANOVA (Hollander and Wolfe, 1973): α=0.10
Dunnett's Test (Winer, 1971): α=0.05 two-sided
Wilcoxon Rank-Sum Test (Hollander and Wolfe, 1973): α=0.05, two-sided with Bonferroni correction (Miller, 1966)
Fisher's Test (Siegel, 1956): α=0.05 one-sided
Censored Wilcoxon Test (Haseman and Hoel, 1974): α=0.05 one-sided
Outlier Test (Grubbs, 1969): α=0.02 two-sided
Binomial Distribution Test (Steel and Torrie, 1960): α=0.05 two-sided
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects on behavior or demeanor were observed in males or females at any dose level during the exposure period.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control male was found dead on test Day 125, seven days prior to the scheduled necropsy. No remarkable clinical observations were recorded for this rat prior to its death. Upon gross pathologic examination this animal was found to have perineal soiling, blood around the muzzle and general visceral congestion; however, the cause of death could not be determined.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No significant treatment-related effects on body weights were observed at any dose level in males throughout the entire study or in females during the premating, gestation or lactation periods. Similarly, the body weight gains of females during gestation were unaffected by treatment. However, the total body weight gain of females from the 5.0 mg/kg/ day dose group was slightly but statistically decreased during the lactation day interval 1 through 21. This decrease in body weight gain was attributed to the combined stress of the test substance exposure and lactation, and was consistent with the slight decreases in feed consumption observed in high-dose dams during the last two weeks of lactation. The body weight gains of females in the 0.1 or 1.0 mg/kg/day dose groups were not affected by treatment during lactation.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No significant treatment-related effects on feed consumption were observed at any dose level in males throughout the entire study or in females during the premating, gestation or lactation periods. However, the feed consumption of dams given 5.0 mg/kg/day was slightly decreased during the last two weeks of lactation.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
An increased incidence of histopathologic alterations in the adrenal gland was observed in males and females in the 5.0 mg/kg/ day dose group. The histologic alterations were limited to cells of the zona fasciculata and were characterized as very slight to slight vacuolation (consistent with fatty change) in males, and very slight vacuolation and altered tinctorial properties in females.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Dose-related statistically significant decreases in plasma and RBC cholinesterase were observed in males and females in the 1.0 and 5.0 mg/kg/ day dose groups. Statistically significant decreases in brain cholinesterase were also observed in males and females in the 5.0 mg/kg/day dose group. Brain cholinesterase values in males and females from the 5.0 mg/kg/ day dose groups were decreased to 52 and 51%, respectively, of the control values. No significant effect on brain cholinesterase was observed in males or females in the 0.1 or 1.0 mg/kg/day dose groups.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed on the male or female fertility indices, length of gestation, time to mating, pup sex ratio or litter size in any dose group. The statistically identified decreases in the female conception and fertility index observed in the 0.1 mg/kg/day dose group were considered spurious, in view of the lack of effects on these parameters at 1.0 or 5.0 mg/kg/day.
Key result
Dose descriptor:
NOEL
Effect level:
0.1 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of serum cholinesterase depression
Remarks on result:
other: No effects on fertility were observed at any dose level tested.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects on behavior or demeanor were observed in males or females at any dose level during the exposure period.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male from the 0.1 mg/kg/day dose group was found dead on test Day 66. No remarkable clinical observations were recorded for this rat prior to its death. Upon gross pathologic examination this animal was found to have bilateral renal and urinary calculi. The kidneys were enlarged with a thin cortex and contained foul-smelling urine. The cause of death of this animal was attributed to the renal and bladder calculi.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weights of adult males in the 5.0 mg/kg/ day dose group were slightly decreased throughout the test period when compared with the control group; however, the decreases were not statistically significant. The lower body weights of males in the high dose group were consistent with the lower weights of these animals during lactation. Conversely, no effects on body weights were observed at any dose level in females during the premating, gestation or lactation periods. Similarly, the body weight gains of females during gestation and lactation were not affected by treatment. Since the body weight of females in the 5.0 mg/kg/day group recovered from the decreases observed as pups during lactation, the neonatal weight affects in females F0 pups were considered to be of no toxicologic significance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant treatment-related effects on feed consumption were observed at any dose level in males throughout the entire study or in females during the premating, gestation or lactation periods.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related gross pathologic alterations were observed in male or female F1 adults at any dose level.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
An increased incidence of histopathologic alterations in the adrenal gland was observed in males and females in the 5.0 mg/kg/ day dose group. The histologic alterations were limited to cells of the zona fasciculata and were characterized as very slight to slight vacuolation, consistent with fatty change in males and very slight altered tinctorial properties in females.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Dose-related statistically significant decreases in plasma and RBC cholinesterase were observed in males and females in the 1.0 and 5.0 mg/kg/ day dose groups. The statistically significant decrease in RBC cholinesterase observed in males at 0.1 mg/kg/day was not considered biologically significant due to the lack of effect on this parameter in either males or females given 0.1 mg/kg/day in the Fl generation or in females given 0.1 mg/kg/day in the F2 generation. Statistically significant decreases in brain cholinesterase were also observed in males and females in the 5.0 mg/kg/day dose group. Brain cholinesterase values in males and females from the 5.0 mg/kg/ day dose groups were decreased to 47 and 42%, respectively, of the control values. No significant effects on brain cholinesterase were observed at 0.1 or 1.0 mg/kg/day.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed on the male or female fertility indices, length of gestation, time to mating, pup sex ratio, pup survival or litter size in any dose group.
Key result
Dose descriptor:
NOEL
Effect level:
0.1 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of serum cholinesterase depression
Remarks on result:
other: No effects on fertility were observed at any dose level tested.
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related, clinical observations or physical alterations were observed in pups from any dose group
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Pup survival, however, was statistically decreased on days 14 and 21 of lactation in the 5.0 mg/kg/ day dose group. No significant effects on pup survival were observed at earlier time points in the 5.0 mg/kg/day dose group or in the 0.1 or 1.0 mg/kg/day dose groups at any time during lactation. Importantly, the decrease in pup survival observed at 5.0 mg/kg/ day occurred only at a dose level that produced parental toxicity (significant decreases in brain cholinesterase and histopathologic alterations of the adrenal zona fasciculata).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weights of male and female pups from the 5.0 mg/kg/day dose group were slightly decreased on day 1 of lactation and statistically decreased on days 4, 7, 14 and 21 of lactation. The decreased pup weights at the high dose were consistent throughout the lactation period, were accompanied by decreased survival and lower body weight gain of dams in this dose group during lactation, and therefore, appeared to be treatment-related. The decreased pup weights occurred only at a dose level that produced parental toxicity (significantly decreased brain cholinesterase and histopathologic alterations of the adrenal zona fasciculata). No treatment related effects were observed at dose levels of 0.1 or 1.0 mg/kg/day.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related gross pathologic alterations were observed in weanlings at any dose level
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
Description (incidence and severity):
No significant treatment-related effects on clinical observations were observed in any dose group. However, the incidence of weak, thin, or cold pups and pups with no milk in their stomach was increased in both the control and the 5.0 mg/kg/ day dose groups. Most of these observations occurred early in the lactation period, preceded pup death and were associated with the death of entire litter; and therefore, were considered secondary to maternal neglect. The apparent increased incidence of these observations in the 5.0 mg/kg/day dose group, relative to the control, were not considered treatment-related, as most of the observations were considered secondary to maternal neglect and occurred in an equal number (five) of litters in both the control and 5.0 mg/kg/day dose groups.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Pup survival, was lower than expected during lactation in both the control and the 5.0 mg/kg/ day dose group. The decreased pup survival in these groups was due to the death of three entire litters (25 pups) in the control group and five entire litters (48 pups) in the 5.0 mg/kg/ day dose group, was associated with an increased incidence of weak, thin, or cold pups or pups with no milk in their stomach, and was considered secondary to maternal neglect. Although the survival of pups in the 5.0 mg/kg/ day dose group was also lower than the control group, the decrease was due to a greater number (five) of dams that neglected their litters relative to the number of control dams that neglected their litters (three). Since the decreased pup survival in the 5.0 mg/kg/ day dose group was due to a limited number of litters and was not a general finding across most litters, the lower pup survival observed at 5.0 mg/kg/ day was not statistically significant and was not considered to be treatment-related. Analyses of pup survival, excluding entire litters that were lost due to dam neglect (three in the control, one at 1.0 mg/kg/ day and five at 5.0 mg/kg/ day), clearly show that no treatment-related effects on pup survival were observed at any dose level.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No differences in male or female pup weights were observed between the treated groups and the control group.
Key result
Dose descriptor:
NOEL
Generation:
F2
Effect level:
1 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
Key result
Reproductive effects observed:
no

Table 1: Tissues collected and preserved at necropsy 

Adrenals*

Kidneys*

Prostate*

Aorta

Lacrimal/harderian glands

Rectum

Auditory sebaceous glands

Larynx

Salivary glands

Bone

Liver

Seminal vesicles*

Bone marrow

Lungs

Skeletal muscle

Brain (cerebrum, brainstem, cerebellum)*

Mammary gland - females only

Skin

Cecum

Mediastinal lymph node

Spinal cord (cervical, thoracic, lumbar)

Cervix*

Mediastinal tissues

Spleen

Coagulating glands*

Mesenteric lymph node

Stomach

Colon

Mesenteric tissues

Testes*

Duodenum

Nasal tissues

Thymus

Epididymides*

Oral tissues

Thyroid gland

Esophagus

Ovaries*

Tongue

Eyes

Oviducts*

Trachea

Gross lesions*

Pancreas

Urinary bladder

Heart

Parathyroid glands

Uterus*

Ileum

Peripheral nerve

Vagina*

Jejunum

Pituitary*

 

*Indicates tissues from control and high dose adults that were routinely processed for histological examination

 

Conclusions:
No effects on fertility were observed at any dose level tested.
Prental NOEL: 0.1 mg/kg/day (based upon the absence of serum cholinesterase depression)
Neonatal NOEL: 1.0 mg/kg/day
Executive summary:

The 2-generation study was conducted according to the guidelines OECD 416 and FIFRA 83-4. The objective of this 2-generation dietary reproduction study was to evaluate the effects of the test substance on the reproductive capability and neonatal growth and survival in rats. Groups of 30 male and 30 female Sprague-Dawley rats, approximately 6 weeks of age, were administered diets that provided 0, 0.1, 1.0 or 5.0 mg/kg/ day of test substance, 7 days per week for two generations. Following 10 weeks of dietary exposure, the F0 adults were mated to produce the F1 litters. After weaning, 30 pups/sex/dose were randomly selected to become F1 adults. Following 12 weeks of exposure, the F1 adults were mated to produce the F2 litters.

Dietary exposure of adult male and female rats to 1.0 and 5.0 mg/kg/day resulted in dose-related parental effects. F0 and F1 adult males and females had statistically significant decreases in plasma and RBC cholinesterase levels. In addition, both the F0 and F1 males and females in the 5.0 mg/kg/day dose group had statistically significant decreases in brain cholinesterase (52 to 42% of the control values) and histopathologic alterations in the zona fasciculata of the adrenal gland. The histopathologic alterations in the adrenal gland were characterized as very slight to slight vacuolation (consistent with fatty change) in males, and very slight vacuolation and/or altered tinctorial properties in females. The significant decreases in brain cholinesterase and histopathologic alterations of the adrenal zona fasciculata observed in males and females given 5.0 mg/kg/day were considered to represent significant parental toxicity. Although parental effects were observed at 1.0 and 5.0 mg/kg/ day, no effects on fertility were observed at any dose level and no neonatal effects were observed at 0.1 or 1.0 mg/kg/day in the F1 or F2 litters. However, the parental toxicity at the high dose was accompanied by neonatal effects at 5.0 mg/kg/ day in the F1 litters. F1 pups from dams given 5.0 mg/kg/day had decreased body weight and slight, but statistically increased mortality.

In conclusion, no effects on fertility were observed at any dose level tested. The parental no-observed-effect level (NOEL) was 0.1 mg/kg/day based upon the absence of serum cholinesterase depression. The neonatal NOEL was 1.0 mg/kg/day. Although neonatal effects were observed in the F1 pups at the high dose of 5.0 mg/kg/day, the significance of the neonatal effects were questionable in view of the presence of significant maternal toxicity at this dose level and the lack of reproducible neonatal effects in the F2 litters. The neonatal NOEL in this study was consistent with the results of previously conducted reproduction and fertility studies with the test substance.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.1 mg/kg bw/day
Study duration:
subchronic
Experimental exposure time per week (hours/week):
168
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

In a 2-generation dietary reproduction study rats were administered diets that provided 0, 0.1,1.0 or 5.0 mg/kg/day of chlorpyrifos, 7 days per week for two generations. The parental no-observed-effect level (NOEL) was 0.1 mg/kg/ day based upon the absence of serum cholinesterase depression. The neonatal NOEL was 1.0 mg/kg/day. Although neonatal effects were observed in the F1 pups at the high dose of 5.0 mg/kg/day, the significance of the neonatal effects were questionable in view of the presence of significant maternal toxicity at this dose level and the lack of reproducible neonatal effects in the F2litters. 

Effects on developmental toxicity

Description of key information

Study Type

Species

Findings

 Guideline

Reliability 

Developmental Gavage Study 

Rat

Maternal NOAEL = 3 mg/kg/day (based on excessive salivation, urination, defecation and lacrimation)

 

Not embryotoxic or teratogenic  

no guideline followed  

2

Developmental Gavage Study 

Rat 

Maternal NOEL=1 mg/kg/d (based on muscle fasciculations, hyperpnea, hyperreactivity). 

 

Fetal NOEL = 1 mg/kg/d

(based on body weight, food consumption and effects on brain)

US EPA Subdivision F, Human and domestic animals, Addendum 10, Neurotoxicity 82-7

1

Developmental Gavage Study 

Mouse

Maternal NOEL = 0.1 mg/kg/d (based on plasma and erythrocyte cholinesterase levels)

 

Fetal NOEL = 10 mg/kg/d (based on skeletal variants and decreased fetal body measurements)

no guideline followed  

2 
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
other: US EPA Subdivision F, Human and domestic animals, Addendum 10, Neurotoxicity 82-7
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Substance ID: TSN100227
MM930503-17
Purity: 99.8%
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
GD6 to GD24 (rats that do not deliver a litter) or lactation day 11 (dams that deliver a litter)
Frequency of treatment:
Daily
Duration of test:
Approximately 5 months
Dose / conc.:
0.3 mg/kg bw/day
Dose / conc.:
1 mg/kg bw/day
Dose / conc.:
5 mg/kg bw/day
No. of animals per sex per dose:
25 presumed pregnant rats per dose
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Toxicity was limited to the highest dosage level and consisted muscle fasciculations, hyperpnea, hyperreactivity mostly during the lactation period, but fasciculations also occurred late in the gestation period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Small decreases in body weight gain in high dose level
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduction (4.2 to 14.5%) in feed consumption during the lactation dosing in high dose level
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
brain cholinesterase inhibited by ~90% in high dosage group
Key result
Dose descriptor:
NOEL
Effect level:
1 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
other: cholinergic toxicity
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
In the high dosage group more litters with pups died between days 1 and 5 (decreased viability index).
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
In the high dosage group, lower body weight (~5 to 20%) over all time intervals (between DPs 1 and 66) and decreased postweaning food consumption.
External malformations:
effects observed, treatment-related
Description (incidence and severity):
In the high dosage group, delayed pinna detachment, vaginal patency, preputial separation were observed.
Details on embryotoxic / teratogenic effects:
No effects were seen in the pups in the absence of maternal toxicity. In the high dosage group, the lower birth weights and delayed developmental landmarks were indicative af a maturational delay.
Key result
Dose descriptor:
NOEL
Effect level:
1 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
external malformations
Key result
Developmental effects observed:
yes
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Conclusions:
NOEL (maternal and pup toxicity): 1 mg/kg/day
Executive summary:

The purpose of this study was to evaluate the potential of the test substance to cause developmental neurotoxicity in offspring when administered by gavage from gestation day 6 through lactation day 11 (birth being lactation day 1) to rat dams at dosages of 0, 0.3, 1 and 5 mg/kg/day. The test substance did not cause any effects in the offspring when administered to dams during gestation and lactation at dosage levels of 0.3 or 1 mg/kg/day. No effects were detected in pups at dosages that were not maternally toxic. A developmental delay and pup decreased viability were observed at a maternally toxic dosage (i.e., 5 mg/kg/day) and were consistent with undernutrition and potentially altered maternal care of the pups. Lower body weight gains were accompanied by decreased food consumption and by a transient decrease in brain weight and layer thickness of some brain areas in either male or female pups (in the absence of neuropathology). The no-observed- effect-level (NOEL) for maternal and pup toxicity in this study was 1 mg/kg/day.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
The purpose of the present study was to assess the potential of chlorpyrifos to adversely affect embryonal and fetal development. Pregnant CF-l mice were given 0, 1, 10, or 25 mg/kg/day of chlorpyrifos by gavage on days 6 through 15 of gestation. Evidence of severe maternal toxicity, including clinical signs of cholinesterase inhibition, decreased body weight, decreased food and water consumption, and death of some animals, was observed among pregnant mice given 25 mg/kg of the test compound. Clinical determinations revealed that plasma and erythrocyte cholinesterase levels were significantly reduced among maternal mice at all dose levels.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
DURSBAN F (MM-03257-1)
Lot No. AGR 155052
Purity: 96.8%
Species:
mouse
Strain:
CF-1
Route of administration:
oral: gavage
Vehicle:
cotton seed oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
days 6 through 15 of gestation
Frequency of treatment:
daily
Duration of test:
gestation day 18
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
0.1 mg/kg bw/day (nominal)
Dose / conc.:
1 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
25 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Control = 51
1 mg/kg: 40
10 mg/kg: 44
25 mg/kg: 47
Control animals:
yes, concurrent vehicle
Maternal examinations:
Daily observations and clinical signs of cholinesterase depressionwere recorded. In addition, maternal body weight, the weight of the maternal livers, and the weight of the gravid uterus including ovaries were recorded at the time of cesarean section, day 18 of gestation. The food and water consumption of mice was measured at 3-day intervals starting on day 6 of gestation.

Erythrocyte and plasma cholinesterase depression was also measured.
Fetal examinations:
On day 18 of gestation, the bred mice were sacrificed by carbon dioxide inhalation; the uterine horns· were exteriorized through a mid-line incision in the abdominal wall, and the number and position of live, dead, and resorbed fetuses were recorded. The uteri of animals which did not appear to be pregnant were stained with a 10% solution of sodium sulfide and were examined for evidence of implantation sites. This procedure was conducted to determine the incidence of pregnancy only; the incidence of fetal resorptions was not determined on the basis of this procedure.

After being weighed, measured (crown-rump length), and sexed, all fetuses were examined for external alterations and cleft palate. One-third of the fetuses in each litter, selected at random, were examined immediately for evidence of soft-tissue alterations by dissection under a stereo microscope. The head of each fetus which was examined for soft tissue alterations was placed in Bouin's solution and subsequently examined by the razor section technique of Wilson. All fetuses were cleared with potassium hydroxide and stained with alizarin red-S to permit examination for skeletal alterations.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of cholinesterase inhibition were observed at 25 mg/kg/day.
Mortality:
mortality observed, treatment-related
Description (incidence):
Death of some animals was observed among pregnant mice given 25 mg/kg of the test compound.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreased body weight was observed among pregnant mice given 25 mg/kg of the test compound.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased food and water consumption was observed among pregnant mice given 25 mg/kg of the test compound.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical determinations revealed that plasma and erythrocyte cholinesterase levels were significantly reduced among maternal mice at all dose levels. Because of the absence of a dose response for the occurrence of exencephaly, additional groups of mice were given 0, 0.1, 1, or 10 mg chlorpyrifos/kg on days 6 through 15 of gestation. Plasma and erythrocyte cholinesterase levels were significantly decreased at 1 and 10 mg/kg but not at the lowest dose level, 0.1 mg/kg.
Key result
Dose descriptor:
NOEL
Effect level:
0.1 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical biochemistry
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The increased incidence of exencephaly observed in the initial study was not repeated in the second phase of the study
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Fetotoxicity was noted among litters of mice given 25 mg/kg of chlorpyrifos as evidenced by decreased fetal body measurements and an increased incidence of minor skeletal variants. These effects are associated in part with the severe maternal toxicity observed in the mice at this dose level and are not evidence of a teratogenic effect.
Details on embryotoxic / teratogenic effects:
No evidence of a teratogenic response was observed in mice given 0.1, 1, or 10 mg/kg of chlorpyrifos.
Key result
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
skeletal malformations
Conclusions:
No evidence of a teratogenic response was observed in mice given 0.1, 1, or 10 mg/kg of chlorpyrifos. NOEL for teratogenic effect = 10 mg/kg
NOEL for maternal toxicity = 0.1 mg/kg.
Executive summary:

The purpose of the present study was to assess the potential of chlorpyrifos to adversely affect embryonal and fetal development. Pregnant CF-l mice were given 0, 1, 10, or 25 mg/kg/day of chlorpyrifos by gavage on days 6 through 15 of gestation. Evidence of severe maternal toxicity, including clinical signs of cholinesterase inhibition, decreased body weight, decreased food and water consumption, and death of some animals, was observed among pregnant mice given 25 mg/kg of the test compound. Clinical determinations revealed that plasma and erythrocyte cholinesterase levels were significantly reduced among maternal mice at all dose levels.

 

Fetotoxicity was noted among litters of mice given 25 mg/kg of chlorpyrifos as evidenced by decreased fetal body measurements and an increased incidence of minor skeletal variants. These effects are associated in part with the severe maternal toxicity observed in the mice at this dose level and are not evidence of a teratogenic effect. Exencephaly was seen among control litters as well as chlorpyrifos litters. The incidence was statistically. significantly different from control only at the lowest dose level, 1 mg chlorpyrifos/kg/day. Because of the absence of a dose response for the occurrence of exencephaly, additional groups of mice were given 0, 0.1, 1, or 10 mg chlorpyrifos/kg on days 6 through 15 of gestation. Plasma and erythrocyte cholinesterase levels were significantly decreased at 1 and 10 mg/kg but not at the lowest dose level, 0.1 mg/kg. No evidence of a teratogenic response was observed in mice given 0.1, 1, or 10 mg/kg of chlorpyrifos. The incidence of malformations at these dose levels was comparable to that seen historically among control fetuses in this laboratory. The increased incidence of exencephaly observed in the initial study was not repeated in the second phase of the study. Thus, since the observation was not repeatable and was not found at 10- and 25- fold higher dose levels in the original study, chlorpyrifos was not considered to be teratogenic in mice at dose levels up to 25 mg/kg/day. No adverse effects in any parameter were observed at a dose level of 0.1 mg/kg/day.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted to evaluate the teratogenic potential of the test substance when administered orally to bred rats during the period of major organogenesis (days 6 through 15 of gestation). Dams were sacrificed on day 21 of gestation and their concepti were examined for evidence of a teratogenic effect. A subgroup of 10 animals per dose level was sacrificed on day 15 of gestation to obtain plasma and erythrocyte levels of cholinesterase.
GLP compliance:
yes
Specific details on test material used for the study:
AGR 190183
Purity: 96.6%
Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, New York
- Weight: Approximately 175 to 220 g at breeding
- Housing: Housed in wire-bottomed cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Atleast 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 22°C
- Humidity: Approximately 50%
- Photoperiod: 12 hrs dark /12 hrs light
Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test solutions were prepared by dissolving the test material in corn oil such that a dose volume of 4 mL/kg of body weight/day yielded the appropriate dose level.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: Cohoused
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of gestation
Duration of treatment / exposure:
G6 to G15
Frequency of treatment:
Daily
Dose / conc.:
0.1 mg/kg bw/day
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
15 mg/kg bw/day
No. of animals per sex per dose:
31, 31, 32 and 33 bred rats at dose levels of 0, 0.1, 3.0 and 15 mg/kg respectively
Control animals:
yes, concurrent vehicle
Maternal examinations:
OBSERVATIONS: Animals were observed daily throughout the experi~ental period for indications of toxicity

BODY WEIGHT: Body weights for rats were recorded on gestation days 6 through 16 and on day 21 of gestation

FOOD CONSUMPTION AND WATER CONSUMPTION: Food and water consumption were recorded for each rat at 3-day intervals starting on day 6 of gestation.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- number and position of fetuses in utero
- number of live and dead fetuses
- number and position of resorption sites
- the number of corpora lutea
- the sex, body weight and crown-rump length of each fetus
- any gross external alteration
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
Body weights, food and water consumption, hematological parameters, and absolute and relative organ weights were evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, a parametric or nonparametric analysis of variance (ANOVA) was performed followed by Dunnett's test or followed by the Wilcoxon Rank-Sum test With Bonferroni's correction (Steel and Torrie, 1960) if the ANOVA was significant. Statistical evaluation of the frequency of pre-implantation loss and of resorptions among litters and the fetal population was made by a censored Wilcoxon test (Haseman and Hoel, 1974) with Bonferroni's correction. Other incidence data were analyzed by the Fisher exact probability test (Siegel, 1956).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of maternal toxicity including excessive salivation, urine staining in the perineal region, porphyrin deposits about the eyes, vaginal bleeding and tremors were noted throughout the dosing period among animals in the 15 mg/kg/day dose group. However, all animals survived until their scheduled necropsy. No effects on the general appearance or demeanor of animals in the control, 0.1 or 3.0 mg/kg/day dose groups were noted.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Overall, the high dose rats gained less weight than did the control rats. Statistical decreases were noted in body weight gain on days 9 through 11 and body weights on days 12 and 16. Body weights at 0.1 and 3.0 mg/kg/day levels were comparable to controls throughout the study.
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant effect on the weight of the liver was observed at any dose level
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Data collected from groups of 10 bred rats/dose level that were necropsied on day 15 of gestation indicated that cholinesterase levels in the plasma and erythrocytes were significantly decreased among rats given 3 or 15 mg/kg/day. Cholinesterase levels in the plasma of rats from the 3 and 15 mg/kg/day dose groups were found to be only 10 and 3 percent (respectively) of the plasma cholinesterase levels in the control animals. Mean erythrocyte cholinesterase levels of animals in the 3 and 15 mg/kg/day dose groups were found to be 25 and 20 percent (respectively) of the control group mean. No effect on cholinesterase levels was observed among rats receiving 0.1 mg/kg/day.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
Upon staining with sodium sulfide stain, implantation sites which had undergone resorption daily in gestation were detected in the uterus of one rat from the 15 mg/kg/day dose group.
Total litter losses by resorption:
no effects observed
Details on maternal toxic effects:
No adverse effects on litter size, resorption rate, fetal body weight or fetal crown-rump length were observed among any of the treatment groups.
Key result
Remarks on result:
other: Severe maternal toxicity was observed among rats given 15 mg/kg/day
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Several malformations were observed scattered throughout the dose levels at incidences consistent with the historical background observed in this laboratory. Microphthalmia (small eyes) was observed in one fetus in the control group, in one fetus in the 3.0 mg/kg group and in 2 fetuses in the 15 mg/kg dose group. Anopthalmia (eye absent) was observed in one fetus from the control group and in one fetus from the 3.0 mg/kg dose group. One fetus from the 0.1 mg/kg dose group exhibited fused ribs. A single case of cleft palate (soft-palate) was observed in a fetus from in the 15 mg/kg dose group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No significant effect was observed on the skeletal development of fetuses. Variations observed also appeared to be randomly distributed throughout the dose groups and included extra site of ossification near the sternebrae (one control fetus) and lumbar spurs (2 control fetuses, 4 fetuses in 0.1 mg/kg, 2 fetuses in 15 mg/kg).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Three fetuses from a different litter in the 15 mg/kg/day dose group exhibited severely dilated renal pelvis. Variations observed also appeared to be randomly distributed throughout the dose groups and included patent ductus arteriosous (one control fetus), hemorrhage of the liver (one fetus in 0.1 mg/kg), convoluted ureter (one fetus in 0.1 mg/kg and 2 in 15 mg/kg group)
Key result
Remarks on result:
other: No evidence of embryo or fetotoxicity was observed at any of the dose levels
Key result
Developmental effects observed:
no
Conclusions:
Test substance was not considered teratogenic in rats at levels up to 15 mg/kg/day, a maternally toxic level.
Executive summary:

The objective of this study was to evaluate the teratogenic potential of the test substance when administered orally to bred rats during the period of major organogenesis. Bred rats received 0, 0.1, 3.0 or 15 mg/kg body weight/day on days 6 through 15 of gestation. Dams were sacrificed on day 21 of gestation and their concepti were examined for evidence of a teratogenic effect. A subgroup of 10 animals per dose level was sacrificed on day 15 of gestation to obtain plasma and erythrocyte levels of cholinesterase.

Oral administration of the test substance at a dose level of 0.1 mg/kg/day to bred rats did not produce any evidence of maternal toxicity. Cholinesterase levels were significantly depressed among rats in the 3.0 mg/kg/day dose group but no other signs of toxicity were observed in this group. Severe maternal toxicity was observed among rats given 15 mg/kg/day. Cholinesterase levels were drastically reduced compared to controls and clinical signs of organophosphate poisoning (excessive salivation, urination, defecation, and lacrimation) were observed. No evidence of embryo- or fetotoxicity or increase incidence of malformations was observed at any dose level. Based on these data, the test substance was not considered teratogenic in rats at levels up to 15 mg/kg/day, a maternally toxic level.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
3 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
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

In a rat teratology study, chlorpyrifos was administered orally to bred rats during the period of major organogenesis. Bred rats received 0, 0.1, 3.0 or 15 mg chlorpyrifos/kg body weight/day on days 6 through 15 of gestation. Dams were sacrificed on day 21 of gestation and their conception were examined for evidence of a teratogenic effect. A subgroup of 10 animals per dose level was sacrificed on day 15 of gestation to obtain plasma and erythrocyte levels of cholinesterase. Oral administration of chlorpyrifos at a dose level of 0.1 mg/kg/day to bred rats did not produce any evidence of maternal toxicity. Cholinesterase levels were significantly depressed among rats in the 3.0 mg/kg/day dose group but no other signs of toxicity were observed in this group. Severe maternal toxicity was observed among rats given 15 mg/kg/day. Cholinesterase levels were drastically reduced compared to controls and clinical signs of organophosphate poisoning (excessive salivation, urination, defecation, and lacrimation) were observed. No evidence of embryo- or fetotoxicity or increased incidence of malformations was observed at any dose level. Based on these data, chlorpyrifos was not considered teratogenic in rats at levels up to 15 mg/kg/day, a maternally toxic level.

In a developmental neurotoxicity study,Chlorpyrifos was administered by gavage from gestation day 6 through lactation day II (birth being lactation day I) to rat dams at dosages of 0, 0.3, 1 and 5 mg/kg/day. Chlorpyrifos did not cause any effects in the offspring when administered to dams during gestation and lactation at dosage levels of 0.3 or 1 mg/kg/day. No effects were detected in pups at dosages that were not maternally toxic. A developmental delay and pup decreased viability were observed at a maternally toxic dosage (i.e., 5 mg/kg/day) and were consistent with undernutrition and potentially altered maternal care of the pups. Lower body weight gains were accompanied by decreased food consumption and by a transient decrease in brain weight and layer thickness of some brain areas in either male or female pups (in the absence of neuropathology). Increased auditory startle latency and, possibly decreased peak response were documented in the pups, consistent with previously reported motor slowing. Cognitive functions (learning, memory, habituation) were not impaired in the pups at any time at any dosage. These data demonstrate that chlorpyrifos is not a selective developmental neurotoxicant in the rat. The no observed- effect-Ievel (NOEL) for maternal and pup toxicity in this study was 1 mg/kg/day.

In another developmental study in mice, 0, 1, 10, or 25 mg/kg/day of chlorpyrifos by gavage on days 6 through 15 of gestation were given. Fetotoxicity was noted among litters of mice given 25 mg/kg of chlorpyrifos as evidenced by decreased fetal body measurements and an increased incidence of minor skeletal variants. These effects are associated in part with the severe maternal toxicity observed in the mice at this dose level and are not evidence of a teratogenic effect. Exencephaly was seen among control litters as well as chlorpyrifos litters. The incidence was statistically significantly different from control only at the lowest dose level, 1 mg chlorpyrifos/kg/day. Because of the absence of a dose response for the occurrence of exencephaly, additional groups of mice were given 0, 0.1, 1, or 10 mg chlorpyrifos/kg on days 6 through 15 of gestation. Plasma and erythrocyte cholinesterase levels were significantly decreased at 1 and 10 mg/kg but not at the lowest dose level, 0.1 mg/kg. No evidence of a teratogenic response was observed in mice given 0.1, 1, or 10 mg/kg of chlorpyrifos. The incidence of malformations at these dose levels was comparable to that seen historically among control fetuses in this laboratory. The increased incidence of exencephaly observed in the initial study was not repeated in the second phase of the study. Thus, since the observation was not repeatable and was not found at 10- and 25- fold higher dose levels in the original study, chlorpyrifos was not considered to be teratogenic in mice at dose levels up to 25 mg/kg/day. No adverse effects in any parameter were observed at a dose level of 0.1 mg/kg/day.

Justification for classification or non-classification

There is no evidence to suggest that the test substance causes adverse effects on reproduction or development of the offspring. Therefore, the test substance is not classified for reproductive or developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information