Stoddard solvent

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

It is concluded that the substance Stoddard solvent does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Type of information:

other: published data

Adequacy of study:

weight of evidence

Study period:

21 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

JP-8(CAS RN: 8008-20-6; an aliphatic carbon range of C8-C16, aromatics <25%)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source:
Charles River Breeding Labs, Kingston, New York
- Weight at study initiation: 180 to 220 grams
- Housing: Individually, except during cohabitation (1 male with 1 female)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25 °C
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

- M/F ratio per cage: 1 to 1
- Length of cohabitation: Not reported
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Not reported

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

Males were treated for 70 to 90 days. Females were treated for 21 weeks.

Frequency of treatment:

Daily

Dose / conc.:

750 mg/kg bw/day (actual dose received)

Remarks:

Males

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

Remarks:

Males

Dose / conc.:

3 000 mg/kg bw/day (actual dose received)

Remarks:

Males

Dose / conc.:

325 mg/kg bw/day (actual dose received)

Remarks:

Females

Dose / conc.:

750 mg/kg bw/day (actual dose received)

Remarks:

Females

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

Remarks:

Females

No. of animals per sex per dose:

A minimum of 20 male rats per dose were used to test male fertility and a minimum of 35 female rats were used to test effects on female fertility.

Control animals:

yes, sham-exposed

Details on study design:

Dose selection rationale: Doses were based on a previous 90-day study.

Positive control:

None reported

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Not reported
- Cage side observations examined were not reported.
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes- Time schedule for examinations:Daily
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 data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OTHER: Hematology , clinical chemistry (, and urinalysis was performed on a maximum of 10 females per treatment. In the same rats used for haematology and clinical chemistry, the brain, kidneys, liver, spleen, and ovaries were weighed.

Oestrous cyclicity (parental animals):

Not performed

Sperm parameters (parental animals):

Parameters examined in P male parental generations:sperm count in epididymides, sperm motility, velocity, linearity, maximum and mean amplitude of lateral head displacement, beat/cross frequency, mean radius, number of circular cells, % circular cells/motile cells, % circular cells/all cells

Litter observations:

STANDARDISATION OF LITTERS- Performed on day 5 postpartum: Four male and four female pups
PARAMETERS EXAMINEDThe following parameters were examined in F1 offspring:number and sex of pups, stillbirths, live births, weight gain
GROSS EXAMINATION OF DEAD PUPS:no

Postmortem examinations (parental animals):

SACRIFICE- Male animals: All surviving animals were sacrificed on day 90 of treatment (mating occurred during days 70 to 90 of treatment
.- Maternal animals: All surviving animals were sacrificed 1 day after weaning.
GROSS NECROPSY- Gross necropsy details were not reported.
HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues iwere prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

No postmortem examinations were conducted on the offspring.

Statistics:

General toxicity data: an ANOVA with or without multiple comparisonsReproductive measures: a one- or two-factor ANOVA and a post-hoc comparison of dose using two-tailed t-test with pooled error was used for continuous data; a Chi-square test of proportions followed by a Fischer's Exact test was used for categorical data

Reproductive indices:

Pregnancy rate, gestation duration, litter size

Offspring viability indices:

Live and dead offspring, pup weight on postnatal days 1, 4, 7, 14, 21, and 90

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):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): There were no changes in clinical signs or mortality.BODY WEIGHT AND WEIGHT GAIN (PARENTAL ANIMALS): Body weights in male rats were decreased in a dose-dependent manner. Terminal body weights were approximately 545 grams, 520 grams, 475 grams, and 315 grams in the control, 750, 1500, and 3000 mg/kg/day, respectively (results were approximated from a figure). In females, body weight was only significantly reduced in the high-dose group, but the differences were not significant at terminal sacrifice. The body weight in females at 20 weeks (1 week before sacrifice) was approximately 400 grams, 385 grams, 382 grams, and 335 grams in the control, 375, 750, and 1500 mg/kg/day, respectively.HAEMATOLOGY (PARENTAL ANIMALS): Haematology was not measured in the males and no effects were noted in the females.CLINICAL CHEMISTRY (PARENTAL ANIMALS): Clinical chemistry was not measured in the males and no effects were noted in the females.URINALYSIS (PARENTAL ANIMALS): Urinalysis was not measured in the males and no effects were noted in the females.ORGAN WEIGHTS (PARENTAL ANIMALS): Absolute and relative liver weights were increased in mid- and high-dose females (Table 5), but were not accompanied by any histological findings.HISTOPATHOLOGY (PARENTAL ANIMALS): The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats (Table 6).OTHER FINDINGS (PARENTAL ANIMALS): There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females.

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Effect level:

>= 3 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

reproductive performance

Remarks on result:

other: duration of pregnancy; pregnancy rate; sperm characterization

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

reproductive performance

Remarks on result:

other: duration of pregnancy; live birth index; pregnancy rate; litter size; litter weight

Critical effects observed:

not specified

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

VIABILITY (OFFSPRING): There were no effects on offspring viability.
BODY WEIGHT (OFFSPRING): There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other: pup weight

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Conclusions:

The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.

Executive summary:

This was a reproductive study performed in two parts.

In the firstpart, male rats were given 0, 750, 1500 or 3000 mg/kg neat JP-8(CAS RN: 8008-20-6; an aliphatic carbon range of C8-C16, aromatics <25%) daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters (similar to OECD TG 416). Males were allowed to mate while continuing to receive treatment. Aside from a biologically significant decrement in male body weight in the 3000 mg/kg bw/day dose group, no clinical signs were observed. There were no statistical differences noted in any reproductive parameter measured. The reproductive NOAEL = 3000 mg/kg bw/day for male rats.

In the second part, female rats were dosed (0, 325, 750, 1500 mg/kg) with neat JP-8 (CAS RN: 8008-20-6; an aliphatic carbon range of C8-C16, aromatics <25%) daily by gavage for a total of 21 weeks (90-day plus mating with naive males, gestation and lactation) in an effort to assess general toxicity, fertility and reproductive endpoints (similar to OECD TG 416). Female rats in the 1500 mg/kg/day dose experienced a biologically significant weight decrease (~22% of control). Likewise, the pups in the 1500 mg/kg bw/day group also experienced a decreased birth weight of ~12% of control. Given the decrease observed in the maternal rats, the reduced body weight in the pup is not considered to be a specific effect on reproduction or development. The NOAEL was 1500 mg/kg bw/day for female fertility, the highest dose tested. The NOAEL for the pup was 750 mg/kg bw/day based on a decrease in body weight which correlated with a decrease in maternal body weight at 1500 mg/kg bw/day. 

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

hydrodesulfurized kerosine (C9-16 mixed aliphatics/aromatics with 18% aromatic content),

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, Kingston, New York
- Age at study initiation: Males and females were approximately 8 weeks old
- Weight at study initiation: (P) Males: 275 to 285 grams; Females: 183 to 187 grams
- Use of restrainers for preventing ingestion (if dermal): yes- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22- Humidity (%): 40 to 60%
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

dermal

Vehicle:

other: Squibb mineral oil (340 SUS)

Details on exposure:

TEST SITE- Area of exposure: Entire dorsal back
- Type of wrap if used: None
- Time intervals for shavings or clippings: Once a week
REMOVAL OF TEST SUBSTANCE- Washing (if done): Washing was only stated to have been done during mating and consisted of wiping the area clean with a piece of gauze
.- Time after start of exposure: A minimum of 6 hours
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 1 ml/kg body weight/day
- Concentration (if solution): 0, 20%, 40%, or 60%
- Constant volume or concentration used: yes
VEHICLE- Justification for use and choice of vehicle (if other than water): Vehicle was used to reduce skin irritation without compromising dermal absorption. - Amount(s) applied (volume or weight with unit): 1 ml/kg body weight/day
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, Elizabethan collars were used.

Details on mating procedure:

M/F ratio per cage: 1 to 1
- Length of cohabitation: Overnight
- Proof of pregnancy: Vaginal plug or sperm in vaginal lavage sample referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Details only specify that all test solutions were within +/- 5.42% of the original calculated concentration or of the nominal concentration.

Duration of treatment / exposure:

Exposure period: 14 days premating to day 20 of gestation with males treated for an additional weekPremating exposure period (males): 14 daysPremating exposure period (females): 14 days

Frequency of treatment:

Daily, 7 days/week

Dose / conc.:

165 mg/kg bw/day

Dose / conc.:

330 mg/kg bw/day

Dose / conc.:

494 mg/kg bw/day

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Dose selection rationale: Doses were selected based on a two-week range finding study.

Positive control:

None reported

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice a day, but once a day on weekends and holidays
BODY WEIGHT: Yes
- Time schedule for examinations: Males were weighed on the first day of dosing, weekly thereafter, and at study termination. Females were weighed on the first day of dosing, weekly thereafter until mating was confirmed, then on gestational days 0, 3, 6, 10, 13, 16, and 20, on postpartum day 0 and 4, and at terminal sacrifice.
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 data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

Sperm parameters (parental animals):

Parameters examined in P male parental generations: testis weight

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: No
PARAMETERS EXAMINEDThe following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain
GROSS EXAMINATION OF DEAD PUPS: Yes, for external abnormalities; possible cause of death was not determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were sacrificed after all the females had been sacrificed
. - Maternal animals: Surviving animals that did not deliver were sacrificed on gestation day 25. Dams that delivered were sacrificed on postpartum day 4 to postpartum day 6.
GROSS NECROPSY- Gross necropsy consisted of external and internal examinations with emphasis on the reproductive organs.
HISTOPATHOLOGY / ORGAN WEIGHTSThe liver, kidneys, adrenals, thymus, spleen, brain and heart of all parental animals were weighed. In addition the testes and epididymides of parental males were weighed. Skin from treated sites, ovaries and testes and epididymides were prepared for histological examination. Pathological evaluation was performed on reproductive organs from all males and pregnant females in both control groups and the high dose group and on treated skin from all groups.

Postmortem examinations (offspring):

No tissues from offspring were retained.

Statistics:

Quantitative data (body weight and food consumption) were analyzed by parametric methods: analysis of variance (ANOVA) and associated F-test, followed by Dunnet's test for multiple comparisons, provided there was statistical significance in the ANOVA. Maternal reproductive data were evaluated by ANOVA followed by group comparisons using Fisher's exact test. Differences between control and treatment groups were considered statistically significant only if the probability of the differences being due to chance was less than 5% (P< 0.05).

Reproductive indices:

Fertility index, corpora lutea, implantation sites, litters with live born pups

Offspring viability indices:

Number of pups delivered, live birth index, pup mortality, pups surviving to postnatal day 4 (viability index), pup weight

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): There were no treatment-related effects on clinical signs or mortality.BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): There were no significant effects on body weight, but high-dose males had slightly (<10%) lower body weight gain compared to the controls.REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no treatment-related effects on reproductive performance.ORGAN WEIGHTS (PARENTAL ANIMALS): There was a significant increase in the relative kidney weight in high-dose males compared to the sham control that was likely related to the slightly lower terminal body weight in this group. There were no treatment-related changes in reproductive organ weights.GROSS PATHOLOGY (PARENTAL ANIMALS): Skin irritation was the only effect observed.HISTOPATHOLOGY (PARENTAL ANIMALS): There were no treatment-related changes in histopathology.OTHER FINDINGS (PARENTAL ANIMALS): Mild to moderate skin irritation was observed in both males and females. There was a dose-dependent increase in skin irritation in the males, but skin irritation was only observed in high-dose females. The vehicle (mineral oil) caused a slight increase in irritation in both males and females. Histopathology confirmed the dermal irritation.

Dose descriptor:

NOAEL

Effect level:

>= 494 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

not specified

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

The test compound did not cause any reproductive or developmental toxicity.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 494 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental (offspring) toxicity

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Conclusions:

NOAEL for reproductive and developmental toxicity in this study was 494 mg/kg.

Executive summary:

A reproductive/developmental toxicity screening study was conducted in rats with an analogue substance, hydrodesulfurized kerosine (C₉-₁₆mixed aliphatics/aromatics with 18% aromatic content), by the dermal route of exposure In this study, 0, 165, 330, and 494 mg/kg test material was administered daily for approximately seven weeks (pre-mating, mating and through Day 19 of gestation) to groups of 10 female rats via dermal application, at a dose volume of 1 ml/kg. Male rats also received daily administration of the same concentrations and dose volume. In addition, one "sham" treated control group (10 males and 10 females) received no test material. Exposure began two weeks prior to mating for 7 days/week. F0 males continued to be exposed daily throughout mating, female gestation and postpartum period and throughout the female necropsy period. F0 females continued to be exposed throughout the mating period and gestation days 0-19. Dams and their litters were sacrificed on one of postpartum days 4 through 6. Male rats were sacrificed after the female necropsies were complete.   

In this study, slight to moderate skin irritation was produced at 494 mg/kg dose group in both sexes, but no apparent maternal, reproductive or developmental toxicity was observed. No clinical signs of toxicity and no effects on body weights, food consumption, fertility or absolute organ weights were observed. Relative kidney weights were higher in male rats at the high dose. No microscopic changes in testes, epididymides or ovaries of parental animals were observed. However, skin changes were observed in male rats in all groups and in female rats in the high dose group. There were no differences in mean number of corpora lutea, implantation sites and live pups per litter.

Pups born from treated dams showed comparable body weights and weight gain. Viability index on postpartum day 4 was >97%. No gross anomalies were observed in the pups.

In summary, the NOAEL for reproductive and developmental toxicity in this study was 494 mg/kg.

Reference 3

Endpoint:

two-generation reproductive toxicity

Remarks:

QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: .Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

GLP compliance:

no

Remarks:

not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Limit test:

no

Species:

other: fish (trout) and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

1.1. CAS number:
8052-41-3
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
stoddard solvent
1.4. Structure codes:
a. SMILES:
CCCCCCCCCC
1.5. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, non cyclic structure
OECD HPV Chemical Categories
C9-13 Aliphatics hydrocarbon solvents (less than 2 percent aromatics)
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
Low (Class I)
US-EPA New Chemical Categories
Not categorized

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

clinical signs

body weight and weight gain

water consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive performance

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Stoddard solvent have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Stoddard solvent does not cause reproductive toxicity.
1.1. CAS number:
8052-41-3
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
stoddard solvent
1.4. Structure codes:
a. SMILES:
CCCCCCCCCC
1.5. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, non cyclic structure
OECD HPV Chemical Categories
C9-13 Aliphatics hydrocarbon solvents (less than 2 percent aromatics)
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
Low (Class I)
US-EPA New Chemical Categories
Not categorized

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Generation:

F1

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

sexual maturation

clinical signs

mortality

body weight and weight gain

clinical biochemistry

organ weights and organ / body weight ratios

gross pathology

histopathology: neoplastic

other:

Remarks on result:

other: Non-ER binder due to non-cyclic molecular structure.

Reproductive effects observed:

not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Non-ER binder due to non-cyclic molecular structure.Stoddard solvent have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Stoddard solvent does not cause reproductive toxicity.

Conclusions:

Non-ER binder due to non-cyclic molecular structure.Stoddard solvent have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Stoddard solvent does not cause reproductive toxicity.

Executive summary:

Non-ER binder due to non-cyclic molecular structure. Stoddard solvent have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Stoddard solvent does not cause reproductive toxicity.

1.1. CAS number:

8052-41-3

1.2. Other regulatory numbers:

Not reported

1.3. Chemical name(s):

stoddard solvent

1.4. Structure codes:

a. SMILES:

CCCCCCCCCC

1.5. Profiling results:

DNA binding by OECD

No alert found

Est rogen Receptor Binding

Non binder, non cyclic structure

OECD HPV Chemical Categories

C9-13 Aliphatics hydrocarbon solvents (less than 2 percent aromatics)

Protein binding by OECD

No alert found

Protein binding potency

Not possible to classify according to these rules (GSH)

Superfragments

No superfragment

Toxic hazard classification by Cramer (original)

Low (Class I)

US-EPA New Chemical Categories

Not categorized

 

Reference 4

Endpoint:

reproductive toxicity, other

Remarks:

other: QSAR model

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: Estrogen Receptor Binding method

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: fish and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent (CAS# 8052-41-3 ) and therefore Stoddard solvent does not cause reproductive toxicity.

Dose descriptor:

other: QSAR model

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent (CAS# 8052-41-3 ) and therefore Stoddard solvent does not cause reproductive toxicity.

Remarks on result:

other: Generation: QSAR model

Critical effects observed:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent (CAS# 8052-41-3 ) and therefore Stoddard solvent does not cause reproductive toxicity.

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Generation:

F1

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

clinical signs

mortality

body weight and weight gain

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent (CAS# 8052-41-3 ) and therefore Stoddard solvent does not cause reproductive toxicity.

Remarks on result:

other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent

Critical effects observed:

not specified

Reproductive effects observed:

not specified

No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent  (CAS# 8052-41-3 ) and therefore Stoddard solvent  does not cause reproductive toxicity.

Conclusions:

No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Stoddard solvent (CAS# 8052-41-3 ) and therefore Stoddard solvent does not cause reproductive toxicity.

Reference 5

Endpoint:

reproductive toxicity, other

Remarks:

Protein expression was analyzed in preparations from whole testis of the rats.

Type of information:

other: published data

Adequacy of study:

weight of evidence

Study period:

13 weeks

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:

Adult male rats were exposed 6 hours/day for 91 days to vapor of the test material at doses of 0, 250, 500, or 1000 mg/m3 ± 10% . Protein expression was analyzed in preparations from whole testis of the rats.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

JP-8(CAS RN: 8008-20-6; an aliphatic carbon range of C8-C16, aromatics <25%)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source:
Charles River Breeding Labs, Kingston, New York
- Weight at study initiation: 180 to 220 grams
- Housing: Individually,
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25 °C
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

6 hours/day, 91 days

Frequency of treatment:

Daily

Dose / conc.:

0 mg/m³ air

Dose / conc.:

258 mg/m³ air

Dose / conc.:

500 mg/m³ air

Dose / conc.:

1 000 mg/m³ air

No. of animals per sex per dose:

A minimum of 20 male rats per dose were used to test male fertility and a minimum of 35 female rats were used to test effects on female fertility.

Control animals:

yes

Details on study design:

Doses / Concentrations:0, 250, 500, 1000 mg/m3 ± 10%Basis:nominal conc.

Positive control:

None reported

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

During exposure the rats did not exert any overt signs of clinical toxicity. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. The expression levels of the following proteins showed a dose-related increase: HsP86, nicotinic acetylcholine receptor alpha subunit, serum albumin and T-complex protein 1. However, the increased expression of these proteins cannot directly be related to reproductive malfunctioning.

Dose descriptor:

NOAEC

Effect level:

>= 1 000 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

Remarks on result:

other: lack of clinical toxicity, lack of direct reproductive malfunctioning

Critical effects observed:

not specified

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

not examined

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Conclusions:

During exposure the rats did not exert any overt signs of clinical toxicity. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. However, the expression of these proteins cannot directly be related to reproductive malfunctioning, so the NOAEC is determined to be greater than or equal to the highest dose tested, 1000 mg/m3 vapour.

Executive summary:

Male Sprague-Dawley rats were exposed for 6 hours/day for 91 consecutive days to JP-8 Jet Fuel vapour at concentrations of 0, 250, 500 and 1000 mg/m3. After exposure the rats were sacrificed and testes were dissected, solubilised, separated and analyzed for expression of testis proteins. During exposure the rats did not exert any overt signs of clinical toxicity. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. The expression levels of the following proteins showed a dose-related increase: HsP86, nicotinic acetylcholine receptor alpha subunit, serum albumin and T-complex protein 1. However, the increased expression of these proteins cannot directly be related to reproductive malfunctioning. Based on this, the NOAEC is determined to be greater than or equal to the highest dose tested, 1000 mg/m3 vapour.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Oral exposure
There was a reproductive study performed in two parts.
In the firstpart, male rats were given 0, 750, 1500 or 3000 mg/kg an aliphatic carbon range of C8-C16, aromatics <25%) daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters (similar to OECD TG 416). Males were allowed to mate while continuing to receive treatment. Aside from a biologically significant decrement in male body weight in the 3000 mg/kg bw/day dose group, no clinical signs were observed. There were no statistical differences noted in any reproductive parameter measured. The reproductive NOAEL = 3000 mg/kg bw/day for male rats.

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 000 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Inhalation exposure:
Male Sprague-Dawley rats were exposed for 6 hours/day for 91 consecutive days to JP-8 Jet Fuel vapour at concentrations of 0, 250, 500 and 1000 mg/m3 . After exposure the rats were sacrificed and testes were dissected, solubilised, separated and analyzed for expression of testis proteins. During exposure the rats did not exert any overt signs of clinical toxicity. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. The expression levels of the following proteins showed a dose-related increase: HsP86, nicotinic acetylcholine receptor alpha subunit, serum albumin and T-complex protein 1. However, the increased expression of these proteins cannot directly be related to reproductive malfunctioning. Based on this, the NOAEC is determined to be greater than or equal to the highest dose tested, 1000 mg/m3 vapour.

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

494 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Dermal exposure:
A reproductive/developmental toxicity screening study was conducted in rats with an analogue substance, hydrodesulfurized kerosine (C9-16mixed aliphatics/aromatics with 18% aromatic content), by the dermal route of exposure In this study, 0, 165, 330, and 494 mg/kg test material was administered daily for approximately seven weeks (pre-mating, mating and through Day 19 of gestation) to groups of 10 female rats via dermal application, at a dose volume of 1 ml/kg.
NOAEL for reproductive and developmental toxicity in this study was 494 mg/kg.

Additional information

Non-ER binder due to non-cyclic molecular structure. Stoddard solvent have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Stoddard solvent does not cause reproductive toxicity.

 

Oral exposure

There was a reproductive study performed in two parts.

In the first part, male rats were given 0, 750, 1500 or 3000 mg/kg an aliphatic carbon range of C8-C16, aromatics <25%) daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters (similar to OECD TG 416). Males were allowed to mate while continuing to receive treatment. Aside from a biologically significant decrement in male body weight in the 3000 mg/kg bw/day dose group, no clinical signs were observed. There were no statistical differences noted in any reproductive parameter measured.

The reproductive NOAEL = 3000 mg/kg bw/day for male rats.

      

 

Dermal exposure:

 

A reproductive/developmental toxicity screening study was conducted in rats with an analogue substance, hydrodesulfurized kerosine (C9-16mixed aliphatics/aromatics with 18% aromatic content), by the dermal route of exposure In this study, 0, 165, 330, and 494 mg/kg test material was administered daily for approximately seven weeks (pre-mating, mating and through Day 19 of gestation) to groups of 10 female rats via dermal application, at a dose volume of 1 ml/kg.

NOAEL for reproductive and developmental toxicity in this study was 494 mg/kg.

 

 

Inhalation exposure:

Male Sprague-Dawley rats were exposed for 6 hours/day for 91 consecutive days to JP-8 Jet Fuel vapour at concentrations of 0, 250, 500 and 1000 mg/m3 . After exposure the rats were sacrificed and testes were dissected, solubilised, separated and analyzed for expression of testis proteins. During exposure the rats did not exert any overt signs of clinical toxicity. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. The expression levels of the following proteins showed a dose-related increase: HsP86, nicotinic acetylcholine receptor alpha subunit, serum albumin and T-complex protein 1. However, the increased expression of these proteins cannot directly be related to reproductive malfunctioning.

Based on this, the NOAEC is determined to be greater than or equal to the highest dose tested, 1000 mg/m3 vapour.

 

Effects on developmental toxicity

Description of key information

There are conclusive but not suffcient data for the classification of substance Stoddard solvent with regard to Developmental toxicity / teratogenicity

Link to relevant study records

Reference

Reference 1

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m3 (0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics)

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 71 days
- Weight at study initiation: 261-264 g
- Housing: Individually housed in suspended stainless-steel cages with wire mesh floors and fronts- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 38-74
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on mating procedure:

Impregnation procedure:
cohoused- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: nightly
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

days 6 to 15 of gestation

Frequency of treatment:

once daily

Duration of test:

up to day 3 post partum

Dose / conc.:

0 mg/m³ air

Dose / conc.:

600 mg/m³ air

Remarks:

100 ppm

Dose / conc.:

2 400 mg/m³ air

Remarks:

400 ppm

No. of animals per sex per dose:

26 and 27 animals per group

Control animals:

yes, concurrent vehicle

Details on study design:

A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m3 (0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation.

Statistics:

2x2 Coningency tables; Chi Square testcorrected for discontinuity using Yates correction; 2x2 tables,
Fisher 's exact Probability test, ANOVA, Kruskal-Wallis H test, Student's t-test

Indices:

Reproductive Index; Gestation Index; Viability Index

Clinical signs:

effects observed, non-treatment-related

Mortality:

no mortality observed

Details on results:

No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:
Control mean body weight: 3.6 g;
100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;
400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.
The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Dose descriptor:

NOAEC

Effect level:

2 400 mg/m³ air

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other:

Remarks:

based on expressions of retarded growth and not malformations

Abnormalities:

not specified

Fetal body weight changes:

effects observed, treatment-related

Details on embryotoxic / teratogenic effects:

No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:
Control mean body weight: 3.6 g;
100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;
400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.
The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Dose descriptor:

NOAEC

Effect level:

2 400 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Remarks on result:

other:

Remarks:

based on significant reduced mean body weight when compared to control and to the mean of the treatment group

Abnormalities:

not specified

Developmental effects observed:

not specified

A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m³(0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation. No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:

Control mean body weight: 3.6 g;

100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;

400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.

The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Conclusions:

The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Executive summary:

A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m³(0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation. No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:

Control mean body weight: 3.6 g;

100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;

400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.

The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Reference 2

Endpoint:

developmental toxicity

Type of information:

other: published data

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:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

hydrodesulfurized kerosine (C9-16 mixed aliphatics/aromatics with 18% aromatics)

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts
- Age at study initiation: 12 weeks old
- Weight at study initiation: Not reported
- Housing: Individually in wire cages
- Diet (e.g. ad libitum): ad libitum except during exposure period-
Water (e.g. ad libitum): Not reported
- Acclimation period:13 days

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dynamic 0.25 cubic metre stainless steel and plexiglass chamber operated under negative pressure
- Method of holding animals in test chamber: Stainless steel and plexiglass chamber
- System of generating vapour: Metering it into a warmed flask and passing compressed air through the flask , then diluted with room air as it entered the chamber
- Temperature, humidity, pressure in air chamber: 21.1 to 23.7 degrees Celsius, humidity not reported, chamber air flow rate was 28.3 litres/minute
- Air flow rate: Not reported
- Air change rate: Not reported
TEST ATMOSPHERE
- Brief description of analytical method used: Hourly samples were analyzed using a Scott Model 216 Hydrocarbon Analyzer previously calibrated with known concentrations of kerosine with methane used as an internal standard- Samples taken from breathing zone: no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Intended exposure concentrations were 0, 100, and 400 ppm, 66 to 73 hourly samples were obtained over the course of the exposure period, the average concentrations were 0, 106.4 +/- 10.23, and 364.0 +/- 37.53 ppm, respectively.

Details on mating procedure:

- Impregnation procedure: cohoused
- If co-housed:
- M/F ratio per cage: 1 male to 1 female
- Length of cohabitation: Not reported
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

Six hours each day

Frequency of treatment:

Daily

Duration of test:

10 days from gestational day 6 through gestational day 15

Dose / conc.:

0 mg/m³ air

Dose / conc.:

606.9 mg/m³ air

Remarks:

106 ppm

Dose / conc.:

2 084 mg/m³ air

Remarks:

363 ppm

No. of animals per sex per dose:

20 pregnant females

Control animals:

yes

Details on study design:

- Dose selection rationale: Only stated that doses were selected by the American Petroleum Institute

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Gestational days 0, 6, 15, and 20
.FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Visceral and thoracic organs

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes Examinations included:- Gravid uterus weight: No - Number of corpora lutea: No - Number of implantations: Yes- Number of early resorptions: Yes - Number of late resorptions: Yes - Other: It was only stated that the number of resportion sites were reported. The placement of the implantation sites in the uterine horns were replicated. The number of live and dead fetuses were recorded.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one
-third of the fetuses- Skeletal examinations: Yes:
two thirds of the fetuses- Head examinations: Yes: one
-third of the fetuses (the same ones that had soft tissue examinations)

Statistics:

The litter was used as a basic sampling unit for statistical analysis. Dunnett's t-test was used to determine statistical significance (P<0.05) with regard to differences between means with near-normal distribution (body weights and food consumption of dams, mean pup weight based on litter averages). Ratios (nidation index and implantation/corpora lutea ratio) were analyzed with a 2 x 2 contingency table with Yates' correction. Wilcoxon Rank Sum was used for discontinuous parameters as measured by the number of abnormal foetuses within a litter.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Details on results:

Maternal toxic effects:no effects

Dose descriptor:

NOAEC

Effect level:

2 084 mg/m³ air

Based on:

test mat.

Basis for effect level:

clinical signs

other: maternal toxicity

Remarks on result:

other:

Remarks:

based on expressions of not malformations

Abnormalities:

not specified

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOAEC

Effect level:

2 084 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Based on this information, the developmental NOAEC = 2084 mg/m3 or 364 ppm, the highest concentration tested.

Executive summary:

A developmental inhalation toxicity study was conducted in Sprague-Dawley rats with an analogue substance, hydrodesulfurized kerosine (C9-16 mixed aliphatics/aromatics with 18% aromatics). In this study, pregnant female rats (20/dose group) were exposed to 0, 100 and 400 ppm kerosine for 6 hours per day on days 6 through 15 of gestation.

Actual doses received were 106.4 ppm and 364 ppm . There were no treatment-related deaths in the study. Lung mottling was observed at necropsy in two females exposed to 100 ppm, but this was not considered to be treatment-related. No other maternal abnormalities were noted. There were no statistically significant differences between the control and treated animals with respect to clinical observations, body weights, food consumption or uterine measurements. No visible differences were observed in the pups treated with 106.4 ppm and 364 ppm compared to controls.

No statistically significant differences were observed in sex ratios, number of litters, litter size, live fetuses, or fetal weights between treated and control groups. Some skeletal changes, mainly related to retarded bone ossification, were noted in both the control and treated fetuses. However, these changes have routinely been observed by this laboratory in this particular strain of rat. Neither the frequency nor character of these changes indicated an adverse effect on fetal growth and development. In summary, under the conditions of this study, kerosene did not produce any evidence of an adverse treatment-related effect on dams, terata, variation in sex ratio, embryo toxicity or inhibition of fetal growth and development.

The NOAEC for both maternal and developmental effects was 364 ppm.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Oral exposure
The NOAEL was considered to be 750 mg/kg bw/day for developmental toxicity study.
NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2 400 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Inhalation exposure:
A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m3(0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation. No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:
Control mean body weight: 3.6 g;
100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;
400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.
The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

494 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Dermal exposure:
NOAEL for reproductive and developmental toxicity was 494 mg/kg.

Additional information

There are conclusive but not suffcient data for the classification of substance Stoddard solvent with regard to Developmental toxicity / teratogenicity

 

Oral exposure

 

The NOAEL was considered to be 750 mg/kg bw/day for developmental toxicity study.

NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups.

 

The NOAEL was 750 mg/kg bw/day.

 

Inhalation exposure:

A Prenatal Development Toxicity Study equivalent or similar to OECD TG 414 was conducted using groups of 26 or 27 Sprague-Dawley female rats. Female rats were exposed by inhalation to white spirit (Stoddard solvent; boiling range, 157° to 204° C; 43% normal/branched aliphatics, 33% cyclic aliphatics, 24% aromatics) at concentrations of 0, 600, or 2400 mg/m3(0, 100, and 400 ppm, respectively) for 6 hours per day on days 6 to 15 of gestation. No maternal toxicity or differences in litter size or average fetal weight were seen between the groups. There were no statistical differences for skeletal variations between the control group and the 100 ppm or the 400 ppm exposed group. The study director noted that pups in one litter in the 100 ppm group one litter in 400 ppm exposed groups had at least one unusual skeletal finding. The unusual variations were reduced ossification in various bones of the pups. The pups from these two litters had a significant reduced mean body weight when compared to control and to the mean of the treatment group:

Control mean body weight: 3.6 g;

100 ppm mean body weight: 3.7g, 100 ppm litter with unusual findings: 1.4g;

400 ppm mean body weight: 3.7g, 400 ppm litter with unusual findings: 2.0g.

The study concluded that the effects were considered expressions of retarded growth rather than malformations. Based on this information, the developmental NOAEC = 2400 mg/m3 or 400 ppm, the highest concentration tested.

 

 

Dermal exposure:

NOAEL for reproductive and developmental toxicity was 494 mg/kg.

                  

 

Justification for classification or non-classification

Justification for classification or non classification:

Based on the hazard assessment of Stoddard solventin section 2.1 and 2.2. in IUCLID6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

 

 

Directive 67/548

Toxicity to reproduction/development Repr. Cat. 1; R61 May cause harm to the unborn child. Repr. Cat. 2; R61 May cause harm to the unborn child. Repr. Cat. 3; R63 Possible risk of harm to the unborn child. Toxicity to reproduction/fertility  Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Repr. Cat. 3; R62 Possible risk of impaired fertility

CLP

Reproductive toxicity Repr. 1A Repr. 1B Repr. 2 H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

 

It is concluded that the substance Stoddard solvent does not meet the criteria to be classified for human health hazards for Reproductive toxicity