Carbamic acid, [(1S,2S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]-, methyl ester

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

November 10, 1997 to August 13, 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to GLP and per OECD Guideline 407.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chlorohydrine Intermediate

IUPAC Name:

Chlorohydrine Intermediate

Details on test material:

The test material Chlorohydrine Intermediate was received from the Sponsor on October 2 1, 1997, and stored at room temperature. It was described as a white powder.

Test animals

Species:

rat

Strain:

other: Crl:CD (SD)BR

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: methylcellulose

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:

other: A no-observable-effect level (NOEL) was not observed.

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Eight 1000 mg/kg/day (five males; three females) rats died between study Days 3 and 5. Among the signs preceeding death were ataxia, hypoactivity, and convulsion (females only). Histologically, centrolobular coagulative necrosis and congestion were observed in the livers of almost all of these animals and were likely related to the cause of death.

 

 

Biologically important clinical signs in animals that survived until the scheduled sacrifice were restricted to the 1000 mg/kg/day group. These consisted of ataxia (not observed after Day 13), hypoactivity (not observed after Day 1 l), convulsions (females only; not observed after Day 4), and rough haircoat. No clinically significant ophthalmic changes were found.

 

 

The mean body weight of 1000 mg/kg/day males was significantly lower than that of control males from the beginning of Week 2 onward. This difference reflected an extremely low mean food consumption for this group during Week 1 that was accompanied by an actual loss in the group mean body weight. During Week 2. This group’s mean food consumption, as a percentage of the mean body weight at the beginning of the week, was markedly higher than that of the control group and the mean body weight change was significantly higher than the control value. In subsequent weeks, the mean food consumption and body weight, as a percentage of the mean body weight at the beginning of the week, of 1000 mg/kg/day males were similar to that of the control group. Significantly lower mean food consumption values were also observed in 200 and 500 mg/kg/day males during Week 1) with a significantly lower mean body weight change occurring for 500 mg/kg/day males. No corresponding clinical signs were observed in these groups. The absence of these clinical signs or meaningful mean body weight and food consumption differences during Weeks 3 and 4 in the 1000 mg/kg/day group and the less severe pattern in the 200 and 500 mg/kg/day groups suggest a transient dose-related toxic or pharmacological effect followed by adaption.

 

 

In females, a similar, but less severe, pattern was observed. Mean food consumption values for the 500 and 1000 mg/kg/day groups were significantly lower than that of the control group during Week 1. The mean food consumption value of the 200 mg/kg/day group was also low during Week 1. The mean body weight change of the 1000 mg/kg/day group was significantly lower than that of the control group during Week 1. During Week 2, the mean body weight change for the 500 and 1000 mg/kg/day groups, as a percentage of the mean body weight at the beginning of the week, was higher than that of the control group. Clinical signs observed in 1000 mg/kg/day females during this period included convulsions, hypoactivity, and ataxia. As with the males, this pattern suggests a transient dose-related toxic or pharmacological effect followed by adaption.

 

 

Treatment-related, often significant, alterations in the mean clinical pathology data included increases in segmented neutrophil counts in 1000 mg/kg/day animals and monocytes in 1000 mg/kg/day males, alanine aminotransferase: aspartate aminotransferase, gamma glutamyltransferase, and triglycerides in 1000 mg/kg/day animals, and total cholesterol in 200, 500, and 1000 mg/kg/day animals. Possible treatment-related lower mean platelet counts were observed in 500 mg/kg/day males and 1000 mg/kg/day animals. Possibly indirectly related to the test material were significantly higher mean values for total protein and albumin in 500 and 1000 mg/kg/day females and globulin in 1000 mg/kg/day females. These changes suggest

hemoconcentration due to dehydration.

 

 

Generally, liver weights in all groups that received the test material were higher than the sex-matched control value. This elevation was dose related, biologically significant, and clearly related to the histomorphological changes observed. Adrenal weights in 500 and 1000 mg/kg/day females were elevated in a stepwise fashion. No histomorphological correlate was observed in 1000 mg/kg/day female adrenals.

 

 

Biologically significant macroscopic organ changes were restricted to the liver and consisted of enlargement, particularly in 1000 mg/kg/day animals, and dark appearance. Histomorphologically, a dose-related centrolobular hepatocellular hypertrophy was present in all groups that received the chlorohydrine intermediate. In addition, in the 1000 mg/kg/day group, a centrolobular coagulative necrosis with an accompanying chronic active inflammation was observed.

Applicant's summary and conclusion

Conclusions:

In summary, oral gavage with the chlorohydrine intermediate for at least 28 days in rats resulted in mortality (1000 mg/kg/day); differences in clinical signs (1000 mg/kg/day), body weight (1000 mg/kg/day), body weight change (500 mg/kg/day males; 1000 mg/kg/day animals), and food consumption (200, 500, 1000 mg/kg/day); hematology (1000 mg/kg/day); hepatocellular and hepatocellular-related serum chemistries (200,500, 1000 mg/kg/day); liver weights (200, 500, 1000 mg/kg/day); female adrenal weights (500, 1000 mg/kg/day); hepatocellular size (200, 500. and 1000 mg/kg/day); and hepatocellular integrity (1000 mg/kg/day). Taken together, these changes are consistent with an acute hepatocellular toxicity and, at 1000 mg/kg/day, a possible secondary hepatic encephalopathy, which can lead to either death or adaptation.

A no-observable-effect level (NOEL) was not observed.

Executive summary:

This study was designed to evaluate the toxicity of a chlorohydrine intermediate, when administered daily by oral gavage to rats for at least 28 days.

 

 

Male and female Crl:CD (SD)BR rats were assigned to 4 groups (1 O/sex in Groups 1 and 4; S/sex in Groups 2 and 3). Groups 2, 3, and 4 received, respectively, 200, 500, or 1000 mg/kg/day of the test material in a methylcellulose-water vehicle. Group 1 served as a concurrent control and received the vehicle alone.

 

 

Diet and water were provided ad libitum. The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity. During Days 1-14, each animal was observed for signs of toxicity at approximately 1 hour postdose. In addition, at least once each week, each animal was removed from its cage and examined for abnormalities and signs of toxicity. Body weights and food consumption data were collected weekly. Ophthalmic examinations were done before initiation of treatment and at termination. Blood samples were collected for hematology and clinical chemistry tests at the termination of treatment. After at least 28 days of treatment, the animals were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, selected organs were weighed, and selected tissues were collected and preserved. Animals that died on test or were sacrificed at an unscheduled interval were also necropsied. Tissues from each animal in Groups 1 and 4 and from each animal that died or was sacrificed at an unscheduled interval were examined histologically. Macroscopic lesions, liver, and kidneys were also examined microscopically from each animal in Groups 2 and 3.

 

 

Eight 1000 mg/kg/day (five males; three females) rats died between study Days 3 and 5. Among the signs preceeding death were ataxia, hypoactivity, and convulsion (females only). Histologically, centrolobular coagulative necrosis and congestion were observed in the livers of almost all of these animals and were likely related to the cause of death.

 

 

Biologically important clinical signs in animals that survived until the scheduled sacrifice were restricted to the 1000 mg/kg/day group. These consisted of ataxia (not observed after Day 13), hypoactivity (not observed after Day 1 l), convulsions (females only; not observed after Day 4), and rough haircoat. No clinically significant ophthalmic changes were found.

 

 

The mean body weight of 1000 mg/kg/day males was significantly lower than that of control males from the beginning of Week 2 onward. This difference reflected an extremely low mean food consumption for this group during Week 1 that was accompanied by an actual loss in the group mean body weight. During Week 2. This group’s mean food consumption, as a percentage of the mean body weight at the beginning of the week, was markedly higher than that of the control group and the mean body weight change was significantly higher than the control value. In subsequent weeks, the mean food consumption and body weight, as a percentage of the mean body weight at the beginning of the week, of 1000 mg/kg/day males were similar to that of the control group. Significantly lower mean food consumption values were also observed in 200 and 500 mg/kg/day males during Week 1) with a significantly lower mean body weight change occurring for 500 mg/kg/day males. No corresponding clinical signs were observed in these groups. The absence of these clinical signs or meaningful mean body weight and food consumption differences during Weeks 3 and 4 in the 1000 mg/kg/day group and the less severe pattern in the 200 and 500 mg/kg/day groups suggest a transient dose-related toxic or pharmacological effect followed by adaption.

 

 

In females, a similar, but less severe, pattern was observed. Mean food consumption values for the 500 and 1000 mg/kg/day groups were significantly lower than that of the control group during Week 1. The mean food consumption value of the 200 mg/kg/day group was also low during Week 1. The mean body weight change of the 1000 mg/kg/day group was significantly lower than that of the control group during Week 1. During Week 2, the mean body weight change for the 500 and 1000 mg/kg/day groups, as a percentage of the mean body weight at the beginning of the week, was higher than that of the control group. Clinical signs observed in 1000 mg/kg/day females during this period included convulsions, hypoactivity, and ataxia. As with the males, this pattern suggests a transient dose-related toxic or pharmacological effect followed by adaption.

 

 

Treatment-related, often significant, alterations in the mean clinical pathology data included increases in segmented neutrophil counts in 1000 mg/kg/day animals and monocytes in 1000 mg/kg/day males, alanine aminotransferase: aspartate aminotransferase, gamma glutamyltransferase, and triglycerides in 1000 mg/kg/day animals, and total cholesterol in 200, 500, and 1000 mg/kg/day animals. Possible treatment-related lower mean platelet counts were observed in 500 mg/kg/day males and 1000 mg/kg/day animals. Possibly indirectly related to the test material were significantly higher mean values for total protein and albumin in 500 and 1000 mg/kg/day females and globulin in 1000 mg/kg/day females. These changes suggest

hemoconcentration due to dehydration.

 

 

Generally, liver weights in all groups that received the test material were higher than the sex-matched control value. This elevation was dose related, biologically significant, and clearly related to the histomorphological changes observed. Adrenal weights in 500 and 1000 mg/kg/day females were elevated in a stepwise fashion. No histomorphological correlate was observed in 1000 mg/kg/day female adrenals.

 

 

Biologically significant macroscopic organ changes were restricted to the liver and consisted of enlargement, particularly in 1000 mg/kg/day animals, and dark appearance. Histomorphologically, a dose-related centrolobular hepatocellular hypertrophy was present in all groups that received the chlorohydrine intermediate. In addition, in the 1000 mg/kg/day group, a centrolobular coagulative necrosis with an accompanying chronic active inflammation was observed.

 

 

In summary, oral gavage with the chlorohydrine intermediate for at least 28 days in rats resulted in mortality (1000 mg/kg/day); differences in clinical signs (1000 mg/kg/day), body weight (1000 mg/kg/day), body weight change (500 mg/kg/day males; 1000 mg/kg/day animals), and food consumption (200, 500, 1000 mg/kg/day); hematology (1000 mg/kg/day); hepatocellular and hepatocellular-related serum chemistries (200,500, 1000 mg/kg/day); liver weights (200, 500, 1000 mg/kg/day); female adrenal weights (500, 1000 mg/kg/day); hepatocellular size (200, 500. and 1000 mg/kg/day); and hepatocellular integrity (1000 mg/kg/day). Taken together, these changes are consistent with an acute hepatocellular toxicity and, at 1000 mg/kg/day, a possible secondary hepatic encephalopathy, which can lead to either death or adaptation.

A no-observable-effect level (NOEL) was not observed.