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Diss Factsheets

Administrative data

Description of key information

Oral NOAEL (Rat): ≥ 1056 mg/Kg (1.28 mL/Kg) (similar to OECD TG 408)

Inhalation NOAEC (Rat): 690 ppm (3950 mg/m3) (similar to OECD TG 413)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given:comparable to guidelines/standards.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
- Concentration in vehicle: constant volume dosage of 5 ml/kg bw
Duration of treatment / exposure:
30 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0.14 ml/kg/day (~116 mg/kg bw)
Basis:
other: nominal
Remarks:
Doses / Concentrations:
0.42 ml/kg/day (~347 mg/kg bw)
Basis:
other: nominal
Remarks:
Doses / Concentrations:
1.28 ml/kg/day (~1056 mg/kg bw)
Basis:
other: nominal
No. of animals per sex per dose:
5 female/5 male
Control animals:
yes, concurrent vehicle
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, organs examined include kidneys and livers.
HISTOPATHOLOGY: Yes, organs examined include kidneys.
Other examinations:
Clinical chemistry- including plasma glucose
hematology - including lymphocyte and platelet counts, cell volume, hemoglobin concentration, and erythrocyte counts;
Urinanalysis - including protein concentrations
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
The majority of animals in the 0.42 and 1.48 ml/kg/day groups showed salivation and/or brown facial staining from day 4 onwards, as did three animals in the 0.14 ml/kg/day group. Salivation was normally for a short period, and the staining resolved within 24 hrs.

HAEMATOLOGY
Males rats in the 1.28 ml/kg/day group showed higher lymphocyte and platelet numbers, and slightly lower packed cell volume, hemoglobin concentration and erythrocyte counts.

CLINICAL CHEMISTRY
Plasma glucose levels of rats in the 1.28 ml/kg/day group were lower than controls.

URINALYSIS
Urinary protein concentrations were higher in all male rats in the two higher dose groups, and in 2 males in the lowest dose group.

ORGAN WEIGHTS
Male rats showed a dosage related increase in liver and kidney weights. Female rats only showed higher liver weight at the highest dose level.

GROSS PATHOLOGY
One male rat in the 1.28 ml/kg/day dose group had occasional cystic spaces in the parenchyma of the left kidney.

HISTOPATHOLOGY: NON-NEOPLASTIC
The changes in the kidneys were a slight degeneration of the cells lining the proximal tubules in all treatment groups. There was tubular cell degeneration, tubular dilation with intratubular protein and regeneration. These changes were only found in three males in the low dose groups, and four males each in the medium and high dose groups.

Key result
Dose descriptor:
NOAEL
Effect level:
1.28 other: ml/kg/day
Sex:
female
Basis for effect level:
other: 1056 mg/kg bw
Key result
Dose descriptor:
LOAEL
Effect level:
0.14 other: ml/kg/day
Sex:
male
Basis for effect level:
other: This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans.
Critical effects observed:
not specified
Conclusions:
The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day.
Executive summary:

The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day. 

 

This study examined the oral 30 -day subchronic toxicity of BP 8313 to rats. Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 30 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to a alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage.

The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

Endpoint:
sub-chronic toxicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
Species:
rat
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 056 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
1 key read across study available from structural analogues.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.

TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Total hydrocarbon analyser fitted with a flame-ionization detector.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Remarks:
Doses / Concentrations:
1293 ppm (7400 mg/m3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
690 ppm (3950 mg/m3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
345 ppm (1975 mg/m3)
Basis:
analytical conc.
No. of animals per sex per dose:
18 per sex
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.

HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined.
Statistics:
Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.

BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly than controls. High exposure females also had body weights slower than controls.

FOOD CONSUMPTION
No significant differences in food consumption were observed.

WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.

HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.

CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.

ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.

GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.

HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.

Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.

Lungs - No treatment related effects were noted.
Key result
Dose descriptor:
NOAEC
Effect level:
690 ppm
Sex:
female
Basis for effect level:
other: 3950 mg/m3
Key result
Dose descriptor:
LOAEC
Effect level:
345 ppm
Sex:
male
Basis for effect level:
other: 1975 mg/m3; Increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
Key result
Dose descriptor:
LOAEC
Effect level:
1 293 ppm
Sex:
female
Basis for effect level:
other: 7400 mg/m3
Critical effects observed:
not specified

Mean Body Weights of Male Rats (g)

Week

Control

345 ppm

690 ppm

1293 ppm

Standard Deviation of a Single Observation

0

397

396

396

398

24.9

1

422

422

396

396

20.9 (cage effect)

2

435

434

400

402

21.7

3

444

441

407

407

26.0

4

450

444

423

413

25.5

5

455

452

432

423

25.4

6

464

461

443

431

25.0

7

471

473

449

437

34.2 (cage effect)

8

480

479

460

445

28.2

9

486

486

466

448

30.9

10

494

490

469

453

35.6

11

495

491

478

458

34.9

12

502

495

481

466

36.7

13

512

503

491

473

38.4

Mean Body Weights of Female Rats (g)

Week

Control

345 ppm

690 ppm

1293 ppm

Standard Deviation of a Single Observation

0

244

245

244

245

14.2

1

249

253

252

245

6.2

2

256

261

257

248

9.0

3

264

264

263

252

10.1

4

264

269

266

254

13.5 (cage effect)

5

266

271

267

261

12.9 (cage effect)

6

269

274

269

261

11.4

7

274

278

273

264

11.5

8

275

277

274

263

12.5

9

275

277

272

266

13.8 (cage effect)

10

274

278

273

264

11.3

11

275

279

276

267

12.0

12

280

284

280

271

12.1

13

286

291

289

273

13.3

Conclusions:
The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The LOAEC was established at 1293 ppm (7400 mg/m3) due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm (3950 mg/m3).
Executive summary:

This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The LOAEC was established at 1293 ppm (7400 mg/m3) due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm (3950 mg/m3).  

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 4 weeks males, 5 weeks females
- Weight at study initiation: males 142-214 g, females 140-189 g
- Housing: elevated stainless steel wire mesh cages, individually outside of chamber, pairs within exposure chamber
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period:

IN-LIFE DATES: From: April 17, 1978 To: July 12, 1978
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chamber, 760 l
- Method of conditioning air: Test substance was metered using a syringe pump driven 50 cc Tomac glass syringe from a 500 ml Erlenmeyer flask into a heated flask and flash evaporated. Clean air was passed through this flask to pick up vapor. The test atmosphere was then fed into the chamber air inlet line where it was diluted to the desired concentration.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 134 lpm
- Air change rate: 7.46 min, with a 99% equilibration time of 34.3 min.



TEST ATMOSPHERE
- Brief description of analytical method used: Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
Duration of treatment / exposure:
6 hrs/day
Frequency of treatment:
5 days/week for 12 weeks
Remarks:
Doses / Concentrations:
100 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
103 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
294 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
35 per sex/per dose
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly starting five days prior to exposure

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: hemoglobin, hematocrit, erythrocyte count, clotting time, total and differential leucocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
10 animals per sex per group were sacrificed at 4, 8, and 12 weeks (all survivors) by exsanguination with anesthesia. The adrenals, brain, gonads, kidneys, liver, and lungs were weighed.

HISTOPATHOLOGY: Yes
The organs of the sacrificed animals from groups I and III were examined histopathologically. The following organs were examined: adrenals, bone marrow, brain, eye, gonad, heart, colon, duodenum, ileum, kidneys, liver, lung, lymph node, mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin, spinal cord, spleen, stomach, thyroid, trachea, urinary bladder, uterus or prostate, gross lesions, tissue masses.

Statistics:
hematology, and clinical chemistry: Snedecor, GS, and Cochran, WG, Statistical Methods. 6th ed., Iowa State University Press, Ames, 1967, 104-106, 114-119.

body weight, organ weight, and organ/body weight ratios: Dunnett, CW, J. Am. Stat. Assn. 50: 1096-1121, 1955, and Biometrics 20: 482, September, 1964.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There was no mortality during the study. Females in both exposure groups had yellow staining of the ano-genital fur, which was possibly treatment related. Several animals in all groups exhibited dry rales, mucoid nasal discharge, and red nasal discharge. There was not a clear treatment related pattern. A few animals in all groups exhibited moist rales, chromodacryorrhea, excessive lacrimation, excessive salivation, alopecia, and brown staining of the ano-genital area. There was singular observations of a film covered eye and labored breathing in the high exposure group, and also one observation of loose stool in this group.

BODY WEIGHT AND WEIGHT GAIN
Male body weights were significantly increased at week 2 in both exposure groups. Females in the 300 ppm exposure group had significantly decreased body weights at day 0, week 1, and week 3. These weight differences were not considered to be treatment related.

HAEMATOLOGY
A significant decrease in hematocrit levels was seen in males exposed to 300 ppm at week 8 and week 12. Females in the 100 ppm group had decreased hematocrit values at week 4, and week 8, and females in the 300 ppm group had decreased values at week 4 only. Hemoglobin values were decreased in 100 ppm and 300 ppm exposed females at week 4, and 300 ppm exposed females had significantly decreased mean red blood cell counts at week 4. None of these findings appeared to be biologically significant. Males in the 300 ppm exposure group had elevated mean total leucocyte values at week 12. This was possibly treatment related.

CLINICAL CHEMISTRY
A significant increase in blood urea was seen in both groups of exposed males, indicating a possible treatment related effect. The males in the 100 ppm group had decreased mean glucose level at week 12. Females in the 300 ppm exposure group had decreased mean serum glutamic pyruvic transaminase level in week 4. These effects did not show a treatment related pattern, or indicate an abnormal condition, so they were not considered significant.

ORGAN WEIGHTS
Male kidney weight and kidney/body weight ratios were significantly elevated in the 100 ppm group at the week 4 sacrifice. At the week 12 sacrifice, males in both exposure groups had significantly elevated kidney/body weight ratios, and males in the 300 ppm group also had significanlty elevated kidney weights. At the week 8 sacrifice, females in the 300 ppm exposure group also had elevated kidney weights, and kidney/body weight ratios. These effects did not follow a clear dose related pattern.

HISTOPATHOLOGY
No treatment related effects were observed.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 300 ppm
Sex:
female
Basis for effect level:
other: Lack of adverse treatment-related effects observed at the highest concentration tested
Key result
Dose descriptor:
LOAEC
Effect level:
100 ppm
Sex:
male
Basis for effect level:
other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
Critical effects observed:
not specified

Mean Body Weight of Male Rats

Week

Control

100 ppm

300 ppm

0

Mean (g)

187

185

185

Standard deviation (g)

11

14

12

Number of Animals

35

35

35

1

Mean (g)

240

241

238

Standard deviation (g)

12

17

15

Number of Animals

35

35

35

2

Mean (g)

268

285

283

Standard deviation (g)

17

20

19

Number of Animals

35

35

35

3

Mean (g)

324

323

326

Standard deviation (g)

17

24

25

Number of Animals

35

35

35

4

Mean (g)

336

338

347

Standard deviation (g)

22

28

27

Number of Animals

35

35

35

5

Mean (g)

379

368

387

Standard deviation (g)

26

36

36

Number of Animals

25

24

25

6

Mean (g)

408

400

413

Standard deviation (g)

29

35

39

Number of Animals

25

25

25

7

Mean (g)

430

420

435

Standard deviation (g)

32

36

43

Number of Animals

25

25

25

8

Mean (g)

447

434

451

Standard deviation (g)

24

40

49

Number of Animals

25

25

25

9

Mean (g)

468

460

487

Standard deviation (g)

40

40

56

Number of Animals

15

15

15

10

Mean (g)

481

470

499

Standard deviation (g)

42

41

58

Number of Animals

15

15

15

11

Mean (g)

494

484

516

Standard deviation (g)

45

42

61

Number of Animals

15

15

15

12

Mean (g)

495

491

520

Standard deviation (g)

43

43

62

Number of Animals

15

15

15

Mean Body Weight of Female Rats

Week

Control

100 ppm

300 ppm

0

Mean (g)

163

162

158

Standard deviation (g)

10

10

9

Number of Animals

35

35

35

1

Mean (g)

188

186

181

Standard deviation (g)

11

12

10

Number of Animals

35

35

35

2

Mean (g)

202

203

199

Standard deviation (g)

12

14

13

Number of Animals

35

35

35

3

Mean (g)

226

223

219

Standard deviation (g)

14

16

13

Number of Animals

35

33

35

4

Mean (g)

230

229

224

Standard deviation (g)

15

20

15

Number of Animals

35

35

35

5

Mean (g)

253

251

248

Standard deviation (g)

17

21

17

Number of Animals

25

25

25

6

Mean (g)

265

263

258

Standard deviation (g)

19

22

17

Number of Animals

25

25

25

7

Mean (g)

272

270

270

Standard deviation (g)

19

23

19

Number of Animals

25

25

25

8

Mean (g)

279

277

275

Standard deviation (g)

20

24

18

Number of Animals

25

25

25

9

Mean (g)

289

285

284

Standard deviation (g)

23

28

22

Number of Animals

15

15

15

10

Mean (g)

292

289

285

Standard deviation (g)

26

30

20

Number of Animals

15

15

15

11

Mean (g)

297

291

289

Standard deviation (g)

26

31

23

Number of Animals

15

15

15

12

Mean (g)

298

291

289

Standard deviation (g)

24

31

24

Number of Animals

15

15

15

Conclusions:
For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
Executive summary:

This study examined the subchronic toxicity of MRD-78-25 to rats via inhalation. Groups of 35 rats per sex were exposed to 0, 100, or 300 ppm of test substance vapors. Exposure was 6 hrs/day, 5 days/week, for 12 weeks. 10 rats/sex from each group were sacrificed at week 4 and week 8. Animals were observed for clinical signs daily, and weighed weekly. At the end of the study, all surviving animals were sacrificed. After sacrifice, hematological, clinical chemistry, and histopathological parameters were examined. There was no treatment related mortality during the study, and no treatment related body weight effects. For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
3 950 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two key read across studies availablle from structural analogues. NOAEC based on effects on body weight at highest concentration tested.

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

There is data available for Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%). Additionally, data is also available for structural analogue, Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%). This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Oral

Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

A key repeat dose sub-chronic oral toxicity study (DHC, 1984a), examined the oral 30 -day subchronic toxicity of Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) in rats. Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 30 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to a alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage.

 

The LOAEL for male rats was 0.14 mL/Kg/day based on renal damage (specific to male rats, and is not relevant to humans). The female NOAEL was 1.28 (1056 mg/Kg) mL/Kg.

Additionally, in order to comply with standard information requirements for Annex X substances, OECD Guideline 90-day sub-chronic (OECD 408) toxicity tests are proposed for structural analogues Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) (EC# 919-164-8) and Hydrocarbons, C11-C15, aromatics, <1% naphthalene (EC# 922-153-0). The testing proposals for the same have been presented in the lead registrant dossiers for these substances already submitted to ECHA. These studies will be conducted subsequent to ECHA's approval and this endpoint will be updated upon completion of the above studies.

Inhalation

Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

A key sub-chronic repeated dose study (Shell, 1980a) evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The LOAEC was established at 1293 ppm (7400 mg/m3) due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm (3950 mg/m3).  

 

A second key sub-chronic repeated dose study (ExxonMobil, 1979a) examined the subchronic toxicity of the test material to rats via inhalation. Groups of 35 rats per sex were exposed to 0, 100, or 300 ppm of test substance vapors. Exposure was 6 hrs/day, 5 days/week, for 12 weeks. 10 rats/sex from each group were sacrificed at week 4 and week 8. Animals were observed for clinical signs daily, and weighed weekly. At the end of the study, all surviving animals were sacrificed. After sacrifice, hematological, clinical chemistry, and histopathological parameters were examined. There was no treatment related mortality during the study, and no treatment related body weight effects. For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. 

These results do not warrant classification under the new Reguation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Justification for classification or non-classification

Based on available read-across from structurally related substances, Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, 2-25% aromatics does not meet the criteria for classification for repeated dose toxicity (STOT-RE) under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).