(pentabromophenyl)methyl acrylate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23/10/1991-13/12/1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP comparable to OECD guideline

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Qualifier:

according to guideline

Guideline:

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

Principles of method if other than guideline:

/

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles Rive (UK) Ltd., Margate, Kent, England
- Age at study initiation: 28 +/- 1 days
- Weight at study initiation: 68-81
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):in groups of five rats according to sex in metal cages with wire mesh floors
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.5-22.5°C
- Humidity (%): 41-62%
- Air changes (per hr):20
- Photoperiod (hrs dark / hrs light): 12hrs light/12hrs dark

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily


VEHICLE
- Concentration in vehicle: 0.3; 3 and 20%
- Amount of vehicle (if gavage): 5ml/kg/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no details presented. Analysis were conducted by HRC Department of analytical chemistry.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
15 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
150 mg/kg/bw
Basis:
actual ingested

Remarks:

Doses / Concentrations:
1000 mg/kg/bw
Basis:
actual ingested

No. of animals per sex per dose:

For 15 and 150 mg/kg/bw: 5 per sex
For 1000mg/kg/bw: 10 per sex

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on available toxicity data (rat acute oral LD50 > 5 g/kg) and a 7 day preliminary oral toxicity study in rats (Seven-day preliminary oral toxicity study in rats with 95%PBB-MA/5% PBB-OH, Report No. 9171D/DSB/ 40/ST, Huntingdon Research Centre Ltd. 13/01/1992). (See attachment). The results of the preliminary study indicated that 1000mg/kg/bw was a suitable choice for the high dosage level.

Positive control:

/

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations:prior to dosing and at weekly inervals throughout the study

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: daily
- Anaesthetic used for blood collection: Yes (identity): ether
- Animals fasted: Yes overnight prior to collection of samples
- How many animals: of the five male and 5 female rats from group1 and 4 and all rats of group 2 and 3.
- Parameters checked in table [No.?] were examined: packed cell volume, haemoglobine, red blood cell count, platelet count, Mean corpuscular haemoglobin concentration, mean corpuscular volume, total white blood cell count, differential white blood cell count, thrombotest

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: daily
- Animals fasted: Yes overnight prior to collection of samples
- How many animals: of the five male and 5 female rats from group1 and 4 and all rats of group 2 and 3.
- Parameters checked in table [No.?] were examined: triglycerides, glucose, glutamic-pyruvic transaminase - glutamic-oxaloacetic transaminase, Gamma-glutamyltransferase, alkaline phosphatase

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine: daily
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes overnight prior to collection of samples
- Parameters checked in table [No.?] were examined. : volume, pH, specific gravity, protein, qualitative test (total reducing substances, glucose, ketones, bile pigments, urobilinogen, heam pigments

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
MICRO PATHOLOGY: Reference Extension of histology in subacute toxicity study: FR-1025M (Report No. DSB 77/932216, Huntingdon Research Ltd., 22/12/1993) (see attachment)

Other examinations:

organ weight

Statistics:

The following sequence of statistical tests was used for bodyweight, food consumption organ weight and clinical pathology data:
1) If the data consisted predominantly of one particular value (relative frequency of the mode exceeded 75%), the proportion of values different from the mode was analysed by Fisher's exact test followed by Mantel's test for a trent in proportions. Otherwise:

(ii) Bartlett's test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
(iii) If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one way analysis of variance was carried out. If signigicant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
(iv) Analyses of variance were followed by Student's 't' test and William's test for dose-related repsonse, altough only the one thought more appropriate for the response pattern observed was reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the 't' test and Williams' test (Shirley's test).

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: No mortalities. At 1000mg/kg/day the following observations were made: slight ot moderate increase in salivation, hunched posture, waddling and lethargy. Periods of slight alopecia. Slight or moderate ptosis for four males and seven females, flushed extremities for five males and seven females, thin appearance for two males and six females. Transient slight or moderate noisy respiration for one male and one female along with digitigrade locomotion or abnormal distension for one male and one female. Slight red/brown staining around the nose and mouth for one male rat and slight brown staining of the anogenital region in four females.
At 150mg/kg/day, increased salivation in slight or moderate degree.
At 15mg/kg/day: slight or moderate increase in salivation for males one. No clinical observations for females.

BODY WEIGHT AND WEIGHT GAIN: For 1000mg/kg/day bodyweight gains for male and female were lower than controls and consistently lower actual bodyweights were also recorded for these animals. However, a notable bodyweight gain was recorded at week 4 for females resulting in this group commencing the recovery period at the same mean weights as the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Lower food consumption reflected the lower bodyweights for male rats receiving 1000mg/kg/day throughout the treatment period. For females at this dosage, food consumption was depressed during the first half of the study and similar to, or slightly exceeding, the control consumption during the second half; this latter observation reflected the Week 4 bodyweight gain for these animals.
During the recovery period male consumption was slightly increased and female consumption was similar to controls, reflecting the bodyweight changes noted for these animals.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Visual and gravimetric observation revealed a notable increase in water consumption in rats of both sexes receiving 1000 mg/kg/day. A slightly higher consumption was recorded for female rats at 150mg/kg/day altough no essential difference from controls was seen for the male rats at this dosage.
For recovery animals of the high dosage, visual observation revealed an initial continuation of this increased consumption; however, no obvious difference was recorded in comparison with controls at the end of the recovery period.

HAEMATOLOGY: Small disturbances in red blood cell parameters were recorded following the treatment period for male and female rats treated at 1000mg/kg/day and included lower packed cell volume, decreased haemoglobin content and lower red blood cell counts; shorter thrombotest times were recorded for males only. White blood cells were also affected with lower total white blood cell count seen in both sexes, arising mainly from lower lymphocyte levels.
For rats receiving 150mg/kg/day, slightly lower haemoglobin content, lower total red blood cell counts and slightly shorter thrombotest times were seen for males only.
Following the recovery period these parameters remained slightly depressed in comparison with controls.

CLINICAL CHEMISTRY: Small electrolyte disturbances were seen following the treatment period for rats receiving 1000mg/kg/day involving increased sodium and chloride ion levels for both sexes and higher phosphorus and lower potassium levels for females. Triglyceride levels were notably increased and lower urea nitrogen levels were also recorded at this dosage for female rats.
At 150mg/kg/day, most of these disturbances were also noted but to a lesser degree than at the high dosage.
Following the recovery period, changes were limited to minor increases in sodium and chloride ion levels for male rats only.

URINALYSIS: Following the treatment period, urinary volume was increased and the specific gravity was lower for rats of both sexes treated at 1000mg/kg/day.
At 150mg/kg/day, increased urinary volume and decreased specific gravity were also recorded for rats of both sexes.
Among rats receiving 15mg/kg/day, a small increase in urinary volume was noted for males and females and a slight decrease in specific gravity was noted for females only.
No differences from controls were noted in urinary parameters following the recovery period.

ORGAN WEIGHTS: Following the 4-week treatment period a marked increase in unadjusted kidney weights was noted for female rats treated at 1000 and 150mg/kg/day. Among male rats a small increase in adjusted kidney weight, taking final bodyweight into consideration, was noted at the high dosage.
Following the recovery period, unadjusted kidney weights remained higher than controls for the females.

GROSS PATHOLOGY: Macroscopic changes noted at the terminal sacrifice for animals receiving 1000mg/kg/day involved enlarged kidneys for five females, irregular cortical scarring of the kidneys for one male and two females and alopecia for three females; two females treated at 150mg/kg/day had enlarged kidneys.
Following the recovery period, kidneys were enlarged in four females and uniform cortical scarring of the kidney was noted for two males and three females.

MICROSCOPIC PATHOLOGY: Oral exposure at 1000mg/kg/day produced renal tubular lesions consisting of cortical wedge and ray-shaped tubular basophilia, in four male and five female rats following four weeks of treatment. Following the recovery period similer, less severe, changes were seen in two male and four female animals indicating no further progression of the lesion.
Sections of brain, spinal cord and sciatic nerve from animals 1-5 (male) and 31+35 (female, control) as well as animals 21-25 (male) and 51-55 (female) (1000mg/kg/day) have been examined. No histological abnormalities were seen in any of the sections from either control or treated animals that were available for examination.

Dose descriptor:

other: NOTEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Conclusions:

Based on the results of this study, 150mg/kg/day was considered to be a no observable toxic effect level (NOTEL) for administration of 95% PBB-MA/5% PBB-OH to the rat.

Executive summary:

FR-1025M was administered to groups of rats at dosages of 15, 150 and 1000mg/kg/day for a minimum of 28 consecutive days. Control animals received the vehicle alone.

All rats of Groups 2 and 3 (15 and 150mg/kg/day) and five males and five females from each of groups 1 and 4 (controls and 1000mg/kg/day) were killed following the four-week treatment period (Day 32). The remaining animals (five males and five females from groups 1 and 4) were retained for a minimum two-week recovery period, following which they were also killed (Day 46).

The following comments relating to real or possible treatment related findings are made in summary:

Clinical signs:

For rats receiving 1000mg/kg/day increased salivation was seen following dosing in all rats throughout most of the dosing period, accompanied by periods of hunched posture, waddling and lethargy. Greasy fur was apparent during the latter part of the treatment period and alopecia was commonly seen from day 4 to the end of dosing. These signs were generally slight or moderate in degree. Ptosis and flushed extremities were observed less frequently in the majority of rats and a thin appearance was noted for eight rats. Sporadically or infrequently observed signs included noisy respiration, digitrade locomotion, abdominal distension, red-brown staining around the nose and mouth and brown anogenital staining. These signs were generally slight in nature. Jaw muscle contraction on the dosing gag before proper insertion and resulting in difficulty to administer the dose was infrequently recorded for ten rats.

Greasy fur persisted throughout most of the recovery period for males and for the first eight days for females; alopecia persisted until the second recovery week for three females. However, recovery period hunched posture and waddling noted for two males and flushed extremities and lethargy seen in one of these animals had all resolved by Day 32.

For rats treated at 150mg/kg/day, increased salivation, seen following dosing, was present for males and females throughout most of the treatment period and during the latter half of the study this was accomponied by greasy fur. Both signs were slight or moderate in degree.

For rats treated at 15mg/kg/day, slightly increased salivation was noted following dosing among males on up to three occasions and slightly greasy fur was apparent from week 3 to termination.

Slightly greasy fur persisted for controles males from day 21 to day 32 with no other clinical signs observed for rats during the treatment and recovery periods.

Bodyweight:

During the treatment period, bodyweight gains for male and female rats receiving 1000mg/kg/day were generally lower than controls and consistently lower actual bodyweights were also recorded for these animals. However, a notable bodyweight gain was recorded at week 4 for females resulting in this group commencing the recovery period at the same mean weight as the controls.

During the recovery period a marked increase in bodyweight gain was recorded for males only at this dosage.

Food consumption:

Lower food consumption reflected the lower bodyweights for male rats receiving 1000mg/kg/day througout the treatment period. For females at this dosage, food consumption was depressed during the first half of the study and similar to, or slightly exceeding, the control consumption during the second half, this latter observation reflected the week 4 bodyweight gain for these animals.

During the recovery period male consumption was slightly increased and female consumption was similar to controls, reflecting the bodyweight changes noted for these animams.

Water consumption:

Visual and gravimetrical observation revealed a notable increase in water consumption in rats of both sexes receiving 1000mg/kg/day. A slightly higher consumption was recorded for female rats at 150mg/kg/day although no essential difference from controls was seen for the male rats at this dosage.

For recovery animals of the high dosage, visual observation revealed an initial continuation of this increased consumption; however, no obvious difference was recorded in comparison with controls at the end of the recovery period.

Haematology:

Small disturbances in red blood cell parameteres were recorded following the treatment period for male and female rats treated at 1000mg/kg/day and included lower packed cell volume, decreased haemoglobin content and lower red blood cell counts; shorter thrombotest times were recorded for males only. White blood cells were also affected with lower total white blood cell count seen in both sexes, arising mainly from lower lymphocyte levels.

For rats receiving 150mg/kg/day, slightly lower haemoglobin content, lower total red blood cell counts and slightly shorter thrombotest times were seen for males only.

Following the recovery period these parameters remained slightly depressed in comparison with controls.

Biochemistry:

Small electrolyte disturbances were seen following the treatment period for rats receiving 1000mg/kg/day involving increased sodium and chloride ion levels for both sexes and higher phosphorus and lower potassium levels for females. Triglyvceride levels were notably increased and lower urea nitrogen levels were also recorded at this dosage for the female rats.

At 150mg/kg/day, most of these disturbances were also noted but to a lesser degree.

Following the recovery period, changes were limited to minor increases in sodium and chloride ion levels for male rats only.

Urinalysis

Following the treatment period, urinary volume was increased and the specific gravity was lower for rats of both sexes treated at 1000mg/kg/day.

At 150mg/kg/day, increased urinary volume and decreased specific gravity were also recorded for rats of both sexes.

Among rats receiving 15mg/kg/day, a small increase in urinary volume was noted for males and females and a slight decrease in specific gravity was noted for females only.

No differences from controls were noted in urinary parameters following the recovery period.

Organ weights:

Following the four-week treatment period a marked increase in unadjusted kidney weights was noted for female rats treated at 1000 and 150mg/kg/day. Among male rats a small increase in adjusted kidney weight, taking final bodyweight into consideration, was noted at the high dosage.

Following the recovery period, unadjusted kidney weights remained higher than controls for the females.

Macroscopic pathology:

Macroscopic changes noted at the terminal sacrifice for animals receiving 1000mg/kg/day involved enlarged kidneys for five females, irregular cortical scarring of the kidneys for one male and two females and alopecia for three females; two females treated at 150mg/kg/day had enlarged kidneys.

Following the recovery period, kidneys were enlarged in four females and uniform cortical scarring of the kidney was noted for two males and three females.

Microscopic pathology

Oral exposure at 1000mg/kg/day produced renal tubular lesions consisting of cortical wedge and ray-shaped tubular epithelial basophilia, in four male and five female rats following four weeks of treatment. Following the recovery period similar, less severe, changes were seen in two male and four female animals indicating no further progression of the lesion.

Conclusion:

Based on the results of this study, 150mg/kg/day was considered to be a no observable toxic effect level (NOTEL) for administration of 95% PBB-MA/5% PBB-OH to the rat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A dermal repeated dose toxicity test was waived based on the fact that FR-1025M is a skin sensitiser.

An inhalation repeated dose toxicity test was waived as exposure of humans via inhalation is unlikely taking into account the vapour pressure of the substance. FR-1025M is a monomer in a polymer, which is not likely to evaporate.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
One study available

Justification for classification or non-classification

Justification for non-classification is included in the attachment in the IUCLID end point summary section 7.5 and was provided by Dr. Helmut Fleig. (HFC ChemSafe - Dr. Helmut Fleig, Consulting Chemikaliensicherheit, Viktoriastraße 5, 68165 Mannheim)